Structure and function of retroviral integrase

In the paper

“The structures revealed unexpected architectural diversity among intasomes from different retroviral genera.”

What the sources say

• Disputed

  The Abstract reports a crystal structure of the prototype foamy virus intasome, not structures from different retroviral genera. In “Overall architecture of the PFV intasome” (page unavailable), the authors instead suggest that the HIV-1 intasome could have a similar overall architecture and topology. The paper does not report the claimed cross-genera architectural diversity. (LLM, conf=0.78)

  Checked by a reasoning model — may be wrong.

  cites [25] Hare, S., Gupta, S. S., Valkov, E., Engelman, A. & Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464, 232–236 (2010). The first high-resolution structure of a retroviral intasome reveals the IN–viral DNA architecture underlying DNA recombination as well as the mechanism of clinical INSTI action. sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Abstract (page not available) reports structures of prototype foamy virus intasomes and says they may help model HIV integration intermediates. A search for architectural diversity and comparisons across retroviral genera found no passage reporting such a comparison or its result. (LLM, conf=0.77)

  cites [29] Maertens, G. N., Hare, S. & Cherepanov, P. The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature 468, 326–329 (2010). The first high-resolution structures of retroviral target capture and strand transfer intasome complexes reveal the requirement for target DNA distortion during integration. sourceExperimental — accuracy not yet measured
• Supported

  The Abstract describes the RSV intasome as an octamer with a novel architecture, contrasting it with the tetrameric PFV intasome. It explicitly says this comparison highlights previously unappreciated diversity in retroviral intasome assemblies, supporting the citing sentence. (LLM, conf=0.94)

  cites [30] Yin, Z. et al. Crystal structure of the Rous sarcoma virus intasome. Nature 530, 362–366 (2016). Together with Ballandras-Colas et al. (2016), these intasome structures first reveal the requirement for more than four IN protomers for functional integration. source
• Supported

  The Abstract contrasts the previously characterized tetrameric PFV intasome with the paper’s unexpected octameric MMTV intasome. These structures come from different retroviral genera and support the claim of architectural diversity. (LLM, conf=0.94)

  cites [31] Ballandras-Colas, A. et al. Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function. Nature 530, 358–361 (2016). source
• Supported

  The supplied passages compare intasomes from several retroviral genera: the paper describes a 16-integrase lentiviral assembly alongside simpler previously characterized structures (Abstract, passages 2 and 4). It also explicitly refers to the “remarkable differences between intasome structures” (passage 1). No page numbers are provided in our copy. (LLM, conf=0.94)

  cites [32] Ballandras-Colas, A. et al. A supramolecular assembly mediates lentiviral DNA integration. Science 355, 93–95 (2017). Cryo-EM structures of intasomes derived from the sheep lentivirus MVV reveal a higher-order macromolecular machine composed of 16 IN protomers and define the conserved intasome core shared by all retroviral intasome structures. source
• ?Not checked — no full text of the sourcecites [33] Passos, D. O. et al. Cryo-EM structures and atomic model of the HIV-1 strand transfer complex intasome. Science 355, 89–92 (2017). Initial cryo-EM structures of HIV-1 strand transfer complex intasomes reveal a higher-order IN dodecamer architecture. source
• Supported

  In “Structure of the HIV-1 CSC intasome assembled with P5-IN” (page not available), the paper describes HIV-1 intasomes with different integrase assemblies and contrasts their heterogeneity with the greater homogeneity of intasomes from other retroviral species. This supports the claim’s broad point that intasome structures vary across retroviruses, although the paper also emphasizes a conserved core. (LLM, conf=0.84)

  cites [34] Li, M. et al. A peptide derived from lens epithelium-derived growth factor stimulates HIV-1 DNA integration and facilitates intasome structural studies. J. Mol. Biol. 432, 2055–2066 (2020). source
• Partly supported

  The passage comparing SIVrcm and maedi-visna virus intasomes (labeled Abstract; page unavailable) describes different assembly patterns, supporting architectural diversity. But those examples are both lentiviruses. The paper’s comparison with a different retroviral genus, prototype foamy virus, identifies differences in the environment of bound drugs rather than establishing the claimed architectural diversity across genera. (LLM, conf=0.79)

  cites [35] Cook, N. J. et al. Structural basis of second-generation HIV integrase inhibitor action and viral resistance. Science 367, 806 (2020). High-resolution cryo-EM structures of simian immunodeficiency virus intasomes reveal the mechanism of INSTI resistance. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [36] Passos, D. O. et al. Structural basis for strand-transfer inhibitor binding to HIV intasomes. Science 367, 810 (2020). This study provides high-resolution cryo-EM structures of HIV-1 intasomes with several advanced INSTIs. source
• Supported

  The Introduction describes a remarkable diversity of integrase–DNA complex assemblies across retroviral genera, from tetrameric to hexadecameric forms. This supports the claim of architectural diversity among intasomes. (LLM, conf=0.93)

  cites [37] Bhatt, V. et al. Structural basis of host protein hijacking in human T-cell leukemia virus integration. Nat. Commun. 11, 3121 (2020). Together with Barski et al. (2020), cryo-EM studies reveal that deltaretrovirus intasomes are composed of IN tetramers and visualize details of the IN–PP2A interface. source

In the paper

“Counterintuitively, the underlying mode of ALLINI action is not via inhibition of integration140,142,174–177,179–181.”

What the sources say

• ?Not checked — no full text of the sourcecites [140] Jurado, K. A. et al. Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation. Proc. Natl Acad. Sci. USA 110, 8690–8695 (2013). This is the first study to reveal that ALLINIs potently inhibit HIV-1 maturation. source
• Partly supported

  The Introduction and Discussion say that NCINIs’ primary antiviral effect occurs during virus production, through disrupted core maturation, rather than through inhibition of integration. But the Results also show that GS-B blocks integration when applied to target cells at high concentrations. The categorical claim that ALLINIs do not act by inhibiting integration therefore overstates the paper’s finding. (LLM, conf=0.91)

  cites [142] Balakrishnan, M. et al. Non-catalytic site HIV-1 integrase inhibitors disrupt core maturation and induce a reverse transcription block in target cells. PLoS ONE 8, e74163 (2013). sourceExperimental — accuracy not yet measured
• Disputed

  The paper describes a dual mode of action at integration and post-integration, rather than saying ALLINIs do not act by inhibiting integration. In the “A B” section (page not supplied), it explicitly attributes the integration block to inhibition of integrase strand transfer and the integrase–LEDGF interaction; it reports that the post-integration effect is stronger. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  cites [174] Le Rouzic, E. et al. Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage. Retrovirology 10, 144 (2013). sourceExperimental — accuracy not yet measured
• Supported

  The Discussion reports that ALLINIs are linked mainly to post-integration effects associated with integrase self-association. It also notes weaker inhibition of early replication, so the claim is supported as a statement about the principal mode of action, not an absence of any early effect (Discussion; page unavailable). (LLM, conf=0.88)

  cites [175] Gupta, K. et al. Allosteric inhibition of human immunodeficiency virus integrase: late block during viral replication and abnormal multimerization involving specific protein domains. J. Biol. Chem. 289, 20477–20488 (2014). source
• Disputed

  The Discussion says LEDGINs block HIV-1 integration and that this study confirms inhibition at the integration step while identifying an additional late-stage effect. The source therefore contradicts the claim that their action is not via inhibition of integration. (LLM, conf=0.90)

  Checked by a reasoning model — may be wrong.

  cites [176] Desimmie, B. A. et al. LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions. Retrovirology 10, 57 (2013). sourceExperimental — accuracy not yet measured
• Disputed

  The Introduction says ALLINIs inhibit both early and late stages of HIV-1 replication and that, in target cells, they impair integration. The comparative-analysis section likewise reports that the ALLINI GS-B blocks integration in target cells. The paper distinguishes this from KF116, a MINI that does not detectably affect integration at therapeutically relevant concentrations. (LLM, conf=0.89)

  Checked by a reasoning model — may be wrong.

  cites [177] Sharma, A. et al. A new class of multimerization selective inhibitors of HIV-1 integrase. PLoS Pathog. 10, e1004171 (2014). sourceExperimental — accuracy not yet measured
• Supported

  The Abstract explicitly says ALLINIs interfere with viral particle assembly rather than DNA integration. The Introduction adds that their effects on early replication steps are modest, while their disruption of late steps is potent. (LLM, conf=0.94)

  cites [179] Gupta, K. et al. Structural basis for inhibitor-induced aggregation of HIV Integrase. PLoS Biol. 14, e1002584 (2016). source
• Supported

  The Introduction (page unavailable) distinguishes ALLINIs from integrase strand-transfer inhibitors and says their potent activity occurs during virion maturation: they induce integrase multimerization and disrupt integrase–viral RNA interactions. It also describes a weaker secondary activity during early infection, so the claim is supported as a statement about their underlying antiviral mode, not as a denial of all early-stage effects. (LLM, conf=0.90)

  cites [180] Koneru, P. C. et al. HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors. eLife 8, e46344 (2019). source
• ?Not checked — no full text of the sourcecites [181] Gupta, K. et al. Allosteric HIV integrase inhibitors promote formation of inactive branched polymers via homomeric carboxy-terminal domain interactions. Structure 29, 213–225.e5 (2021). source

In the paper

“The intasomes from several retroviral species were assembled from purified components and visualised by X-ray crystallography or single-particle cryogenic electron microscopy (cryo-EM)25,29–39 (Figs. 2A, 3).”

What the sources say

• Supported

  The “Crystallization of the PFV intasome” section reports assembling PFV intasomes from recombinant integrase and synthetic DNA. The Methods Summary reports crystallizing the complex and determining its structure from X-ray diffraction data. This paper supports the claim as one example within the cited group; it does not need to cover every retroviral species or cryo-EM method. (LLM, conf=0.91)

  cites [25] Hare, S., Gupta, S. S., Valkov, E., Engelman, A. & Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464, 232–236 (2010). The first high-resolution structure of a retroviral intasome reveals the IN–viral DNA architecture underlying DNA recombination as well as the mechanism of clinical INSTI action. source
• Supported

  The Methods section describes assembling PFV intasomes from integrase and synthetic donor DNA, purifying them, and determining their crystal structures by X-ray diffraction. This paper supplies a PFV X-ray crystallography example for the sentence’s group of citations; the sentence does not attribute cryo-EM or work on other species to this source alone. (LLM, conf=0.91)

  cites [29] Maertens, G. N., Hare, S. & Cherepanov, P. The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature 468, 326–329 (2010). The first high-resolution structures of retroviral target capture and strand transfer intasome complexes reveal the requirement for target DNA distortion during integration. source
• Supported

  The RSV intasome preparation section describes assembling the complex from purified integrase and synthetic DNA, and Structure determination describes its X-ray crystal structure. The paper also discusses PFV intasome structures and a mouse mammary tumor virus intasome observed by cryo-EM, supporting the broader statement for which it is one of several citations. The indexed passages have no page numbers. (LLM, conf=0.91)

  cites [30] Yin, Z. et al. Crystal structure of the Rous sarcoma virus intasome. Nature 530, 362–366 (2016). Together with Ballandras-Colas et al. (2016), these intasome structures first reveal the requirement for more than four IN protomers for functional integration. source
• Supported

  The MMTV intasome assembly and cryo-EM sections describe assembling intasomes from integrase and viral DNA components, purifying the complexes, and imaging them by single-particle cryo-EM. The atomic-model section also identifies an X-ray structure of the PFV intasome, and the paper says PFV intasomes were assembled by an analogous strategy. Together these passages support the claim about intasomes from more than one retroviral species. (LLM, conf=0.87)

  cites [31] Ballandras-Colas, A. et al. Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function. Nature 530, 358–361 (2016). source
• Supported

  The paper reports assembling a functional maedi-visna virus intasome using integrase, viral-DNA-mimicking oligonucleotides, and LEDGF, then isolating the complex by chromatography (Abstract; page unavailable). It also reports visualizing that intasome by single-particle cryo-EM. As one citation in a group covering several species and imaging methods, this paper supports the maedi-visna virus example. (LLM, conf=0.92)

  cites [32] Ballandras-Colas, A. et al. A supramolecular assembly mediates lentiviral DNA integration. Science 355, 93–95 (2017). Cryo-EM structures of intasomes derived from the sheep lentivirus MVV reveal a higher-order macromolecular machine composed of 16 IN protomers and define the conserved intasome core shared by all retroviral intasome structures. source
• ?Not checked — no full text of the sourcecites [33] Passos, D. O. et al. Cryo-EM structures and atomic model of the HIV-1 strand transfer complex intasome. Science 355, 89–92 (2017). Initial cryo-EM structures of HIV-1 strand transfer complex intasomes reveal a higher-order IN dodecamer architecture. source
• Supported

  In “Structure of the HIV-1 CSC intasome assembled with P5-IN” (page not provided), the paper says structures of many retroviral intasomes have been determined and reports its own HIV-1 intasome structure by cryo-EM. “CSC intasome preparation for cryo-EM” describes assembling that intasome from integrase and a DNA substrate; the References also identify a crystal structure of a Rous sarcoma virus intasome. Together, these passages support the cited broad statement. (LLM, conf=0.88)

  cites [34] Li, M. et al. A peptide derived from lens epithelium-derived growth factor stimulates HIV-1 DNA integration and facilitates intasome structural studies. J. Mol. Biol. 432, 2055–2066 (2020). source
• Supported

  The paper reports forming SIVrcm intasome complexes in vitro and visualizing their structure by single-particle cryo-EM (Abstract; page unavailable). Its author-contributions statement says the team prepared recombinant proteins and complexes. As one of several citations, this paper supplies an example of the claimed approach; it need not itself study several species or use X-ray crystallography. (LLM, conf=0.89)

  cites [35] Cook, N. J. et al. Structural basis of second-generation HIV integrase inhibitor action and viral resistance. Science 367, 806 (2020). High-resolution cryo-EM structures of simian immunodeficiency virus intasomes reveal the mechanism of INSTI resistance. source
• ?Not checked — no full text of the sourcecites [36] Passos, D. O. et al. Structural basis for strand-transfer inhibitor binding to HIV intasomes. Science 367, 810 (2020). This study provides high-resolution cryo-EM structures of HIV-1 intasomes with several advanced INSTIs. source
• Supported

  The Introduction (page not provided) describes structural studies of intasomes from several retroviral species. The Results section reports assembly of an HTLV-1 intasome from its components and visualization by single-particle cryo-EM; the References also identify X-ray crystal structures of other retroviral intasomes. (LLM, conf=0.88)

  cites [37] Bhatt, V. et al. Structural basis of host protein hijacking in human T-cell leukemia virus integration. Nat. Commun. 11, 3121 (2020). Together with Barski et al. (2020), cryo-EM studies reveal that deltaretrovirus intasomes are composed of IN tetramers and visualize details of the IN–PP2A interface. source

In the paper

“The stoichiometric state of primate lentiviral intasomes from HIV-1 and the simian immunodeficiency virus (SIV) remain a subject of debate, with complexes containing four and eight to sixteen IN molecules observed by cryo-EM and negative stain electron microscopy33–36.”

What the sources say

• ?Not checked — no full text of the sourcecites [33] Passos, D. O. et al. Cryo-EM structures and atomic model of the HIV-1 strand transfer complex intasome. Science 355, 89–92 (2017). Initial cryo-EM structures of HIV-1 strand transfer complex intasomes reveal a higher-order IN dodecamer architecture. source
• Partly supported

  The Introduction and ‘Structure of the HIV-1 CSC intasome assembled with P5-IN’ section report heterogeneous HIV-1 intasomes, including tetramers and dodecamers, and describe a cryo-EM reconstruction. Our copy does not substantiate the claim about SIV intasomes, sixteen-integrase complexes, or observations by negative-stain electron microscopy. (LLM, conf=0.85)

  cites [34] Li, M. et al. A peptide derived from lens epithelium-derived growth factor stimulates HIV-1 DNA integration and facilitates intasome structural studies. J. Mol. Biol. 432, 2055–2066 (2020). sourceExperimental — accuracy not yet measured
• Partly supported

  The paper reports dodecamer-like particles in both HIV-1 and SIVrcm preparations and a cryo-EM model of an SIVrcm repeat unit containing two integrase tetramers. It does not report a four-integrase HIV-1 or SIV intasome; its explicit observation of predominantly sixteen-integrase complexes concerns maedi-visna virus instead. The cited passages are labeled Abstract in our copy, with no page number provided. (LLM, conf=0.85)

  cites [35] Cook, N. J. et al. Structural basis of second-generation HIV integrase inhibitor action and viral resistance. Science 367, 806 (2020). High-resolution cryo-EM structures of simian immunodeficiency virus intasomes reveal the mechanism of INSTI resistance. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [36] Passos, D. O. et al. Structural basis for strand-transfer inhibitor binding to HIV intasomes. Science 367, 810 (2020). This study provides high-resolution cryo-EM structures of HIV-1 intasomes with several advanced INSTIs. source

In the paper

“While the intasomes from the prototype foamy virus (PFV, a simiispumavirus) as well as the δ-retroviruses HTLV-1 and simian T-cell lymphotropic virus (STLV) contain four IN subunits (arranged as a dimer-of-dimers)25,29,37,38”

What the sources say

• Partly supported

  The “Crystallization of the PFV intasome” section (page unavailable) reports that two PFV integrase dimers form a tetramer, supporting the PFV portion of the claim. The paper does not establish the stated arrangement for HTLV-1 or STLV intasomes. (LLM, conf=0.88)

  cites [25] Hare, S., Gupta, S. S., Valkov, E., Engelman, A. & Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464, 232–236 (2010). The first high-resolution structure of a retroviral intasome reveals the IN–viral DNA architecture underlying DNA recombination as well as the mechanism of clinical INSTI action. sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract describes the PFV intasome as a tetramer of integrase with a cleft between IN dimers, supporting the four-subunit, dimer-of-dimers arrangement for PFV. The paper does not address HTLV-1 or STLV intasomes, so it does not support that part of the claim. (LLM, conf=0.88)

  cites [29] Maertens, G. N., Hare, S. & Cherepanov, P. The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature 468, 326–329 (2010). The first high-resolution structures of retroviral target capture and strand transfer intasome complexes reveal the requirement for target DNA distortion during integration. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction describes the PFV intasome as tetrameric, and the Results (IN tetramer in the HTLV-1 intasome; page not provided) describe HTLV-1 as four integrase subunits forming two inner–outer pairs. Our copy does not establish the claimed four-subunit arrangement for STLV. (LLM, conf=0.86)

  cites [37] Bhatt, V. et al. Structural basis of host protein hijacking in human T-cell leukemia virus integration. Nat. Commun. 11, 3121 (2020). Together with Barski et al. (2020), cryo-EM studies reveal that deltaretrovirus intasomes are composed of IN tetramers and visualize details of the IN–PP2A interface. sourceExperimental — accuracy not yet measured
• Partly supported

  The Architecture section reports four integrase subunits in the STLV-1 intasome, and the Fig. 2 caption describes them as a dimer of dimers. The Discussion says PFV also has a tetrameric intasome. The paper does not establish the corresponding intasome arrangement for HTLV-1; its structural analysis of the assembled intasome uses STLV-1. (LLM, conf=0.83)

  cites [38] Barski, M. S. et al. Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ. Nat. Commun. 11, 5043 (2020). sourceExperimental — accuracy not yet measured

In the paper

“those from ASLV and mouse mammary tumour virus (MMTV, β-retrovirus) harbour eight IN chains (a tetramer-of-dimers)30,31,39.”

What the sources say

• Supported

  The Abstract (no page supplied) describes the RSV intasome as eight integrase molecules arranged in four dimers and identifies RSV as an avian alpharetrovirus. It also reports that a similar octameric intasome assembly was observed for mouse mammary tumor virus. (LLM, conf=0.91)

  cites [30] Yin, Z. et al. Crystal structure of the Rous sarcoma virus intasome. Nature 530, 362–366 (2016). Together with Ballandras-Colas et al. (2016), these intasome structures first reveal the requirement for more than four IN protomers for functional integration. source
• Supported

  The paper’s Abstract states that the MMTV intasome has eight integrase chains arranged as two core dimers and two flanking dimers. This directly supports the MMTV portion of the multiply cited sentence. (LLM, conf=0.92)

  cites [31] Ballandras-Colas, A. et al. Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function. Nature 530, 358–361 (2016). source
• Supported

  The introductory passage (page unavailable) states that RSV and MMTV intasomes each contain eight integrase subunits, and describes the RSV complex as four integrase dimers. The Discussion (page unavailable) also describes distal dimers in the MMTV octameric complex. The paper studies RSV as the ASLV example in the claim. (LLM, conf=0.88)

  cites [39] Pandey, K. K. et al. Cryo-EM structure of the Rous sarcoma virus octameric cleaved synaptic complex intasome. Commun. Biol. 4, 330 (2021). source

In the paper

“Inserted into this assembly, the vDNA ends make extensive interactions with all three types of IN domains within the CIC.”

What the sources say

• Supported

  The ‘IN-DNA interactions within the PFV intasome’ section says that residues from each domain of the inner integrase subunits interact with the viral DNA ends. It identifies all three canonical domains—NTD, CCD, and CTD—as contributors to extensive contacts within the functional complex. (LLM, conf=0.94)

  cites [25] Hare, S., Gupta, S. S., Valkov, E., Engelman, A. & Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464, 232–236 (2010). The first high-resolution structure of a retroviral intasome reveals the IN–viral DNA architecture underlying DNA recombination as well as the mechanism of clinical INSTI action. source

In the paper

“The CIC contains two IN CCD dimers (painted cyan and green in Figs. 2–4), each of which contributes one active site for catalysis.”

What the sources say

• Supported

  The Overall architecture of the PFV intasome section describes a tetramer with a conserved CCD dimeric interface between inner and outer integrase subunits. The Active site of the functional intasome section locates the catalytic active sites in the two inner subunits, consistent with one active site from each CCD dimer. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  cites [25] Hare, S., Gupta, S. S., Valkov, E., Engelman, A. & Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464, 232–236 (2010). The first high-resolution structure of a retroviral intasome reveals the IN–viral DNA architecture underlying DNA recombination as well as the mechanism of clinical INSTI action. source

In the paper

“The observed integration target site preference accordingly supports the large target DNA distortion required to accommodate scissile phosphodiester bonds at opposing IN active sites, as observed in the PFV structure29.”

What the sources say

• Supported

  The passage discussing integration-site sequences (Supplementary Fig. 6) reports a preference for flexible YR dinucleotide steps, consistent with the severe target-DNA bending described for the structures (Fig. 2a). The structural passage states that this bending gives the opposing integrase active sites direct access to the target DNA’s scissile phosphodiester bonds. Together, these passages support the attributed interpretation. (LLM, conf=0.91)

  cites [29] Maertens, G. N., Hare, S. & Cherepanov, P. The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature 468, 326–329 (2010). The first high-resolution structures of retroviral target capture and strand transfer intasome complexes reveal the requirement for target DNA distortion during integration. sourceExperimental — accuracy not yet measured

In the paper

“The active site of retroviral IN is fully structured only upon engagement of the vDNA end in the context of the intasome25.”

What the sources say

• Partly supported

  The introduction (page unavailable in our copy) says the active site is *believed* to adopt its functional state only upon viral-DNA binding. The section “The active site of the functional intasome” describes an assembled active site engaged with viral DNA, but does not establish the unqualified claim that it becomes fully structured only then. (LLM, conf=0.83)

  cites [25] Hare, S., Gupta, S. S., Valkov, E., Engelman, A. & Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464, 232–236 (2010). The first high-resolution structure of a retroviral intasome reveals the IN–viral DNA architecture underlying DNA recombination as well as the mechanism of clinical INSTI action. sourceExperimental — accuracy not yet measured

In the paper

“Brief incubation of the crystals in the presence of Mn2+ ions prior to snap-freezing in liquid nitrogen trapped the active site prior to strand transfer.”

What the sources say

• Supported

  In “Target DNA binding and strand transfer” (page not supplied), the paper reports that a 1.5-minute Mn²⁺ soak yielded a metal-occupied active site poised for strand transfer, after efforts to optimize soaking and snap-freezing. “Reactions in crystallo” states that soaked crystals were flash-frozen for X-ray diffraction. (LLM, conf=0.93)

  cites [28] Hare, S., Maertens, G. N. & Cherepanov, P. 3′-processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J. 31, 3020–3028 (2012). This study visualizes the 3′-processing and strand transfer reactions in crystals of PFV intasomes, which defined the roles of chemical nucleophiles and divalent metal ions in catalysis, and reveals substrate mimicry by INSTIs. source

In the paper

“Sharp bending of the target DNA duplex substantially widened the major groove at the site of integration, permitting the insertion of opposing strand phosphodiester bonds into the intasome active sites (Fig. 2A).”

What the sources say

• Partly supported

  The Introduction (page unavailable) says target DNA binds in a severely bent conformation that forces its phosphodiesters toward the integrase active sites. Our copy does not say that the bending substantially widens the DNA major groove at the integration site; the groove it mentions is between integrase subunits. (LLM, conf=0.84)

  cites [28] Hare, S., Maertens, G. N. & Cherepanov, P. 3′-processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J. 31, 3020–3028 (2012). This study visualizes the 3′-processing and strand transfer reactions in crystals of PFV intasomes, which defined the roles of chemical nucleophiles and divalent metal ions in catalysis, and reveals substrate mimicry by INSTIs. sourceExperimental — accuracy not yet measured

In the paper

“Furthermore, while the intasome structure covers only ~20 bp of vDNA, footprinting studies suggested that as much as 200–250 bp at each vDNA end are protected by a stable protein complex within retroviral PICs45,46.”

What the sources say

• Partly supported

  The Footprinting by Mu-mediated PCR section reports protection at each viral DNA end in pre-integration complexes and associates it with a nucleoprotein structure. But it says protection extends approximately 500 bp, with no sharply defined border, rather than only as much as 200–250 bp. No page number is available in our copy. (LLM, conf=0.88)

  cites [45] Wei, S. Q., Mizuuchi, K. & Craigie, R. A large nucleoprotein assembly at the ends of the viral DNA mediates retroviral DNA integration. EMBO J. 16, 7511–7520 (1997). sourceExperimental — accuracy not yet measured
• Supported

  The MM-PCR analysis of wild-type HIV-I preintegration complexes reports a footprint of approximately 250 bp at the U3 end and 200 bp at the U5 end. The Discussion describes these as regions of protein binding detected by footprinting. Page numbers are not provided in our copy. (LLM, conf=0.93)

  cites [46] Chen, H., Wei, S. Q. & Engelman, A. Multiple integrase functions are required to form the native structure of the human immunodeficiency virus type I intasome. J. Biol. Chem. 274, 17358–17364 (1999). source

In the paper

“Relocation of the new phosphodiester bond that joins vDNA to the target protects it from a nucleophilic attack by the 3’ hydroxyl of the target DNA28,29.”

What the sources say

• Partly supported

  The “Target DNA binding and strand transfer” section reports that the newly formed viral–target DNA phosphodiester bond moves out of the active site and says this was postulated to make strand transfer irreversible. It does not specifically identify prevention of attack by the target DNA 3′ hydroxyl as the mechanism, and the claim states the proposed protective effect as fact. (LLM, conf=0.82)

  cites [28] Hare, S., Maertens, G. N. & Cherepanov, P. 3′-processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J. 31, 3020–3028 (2012). This study visualizes the 3′-processing and strand transfer reactions in crystals of PFV intasomes, which defined the roles of chemical nucleophiles and divalent metal ions in catalysis, and reveals substrate mimicry by INSTIs. sourceExperimental — accuracy not yet measured
• Supported

  The passage discussing Fig. 2b (page not supplied) says the newly formed viral DNA–target DNA phosphodiester shifts 2.3 Å and is ejected from the active site, preventing reversal of strand transfer. The claim describes that reversal as attack by the target DNA 3′ hydroxyl, consistent with the passage’s account of the strand-transfer reaction. (LLM, conf=0.88)

  cites [29] Maertens, G. N., Hare, S. & Cherepanov, P. The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature 468, 326–329 (2010). The first high-resolution structures of retroviral target capture and strand transfer intasome complexes reveal the requirement for target DNA distortion during integration. source

In the paper

“Within the CIC, the vDNA duplex is split at the invariant dCdA dinucleotide: while dC remains paired to its dG mate from the opposing vDNA strand, 3’ dA and the scissile dinucleotide are unpaired.”

What the sources say

• Partly supported

  The 'IN-DNA interactions within the PFV intasome' section says the cytosine of the invariant CA dinucleotide remains in a distorted base pair, while the terminal adenine is isolated from its complement. It describes separation of the viral DNA strands, but does not say that a scissile dinucleotide is unpaired. No page number is provided in our copy. (LLM, conf=0.85)

  cites [25] Hare, S., Gupta, S. S., Valkov, E., Engelman, A. & Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464, 232–236 (2010). The first high-resolution structure of a retroviral intasome reveals the IN–viral DNA architecture underlying DNA recombination as well as the mechanism of clinical INSTI action. sourceExperimental — accuracy not yet measured

In the paper

“The PFV intasome crystallised with blunt-ended vDNA underwent catalysis upon incubation of the crystals in the presence of Mg2+ or Mn2+ salts.”

What the sources say

• Supported

  The ‘Detection of 3′-processing and strand transfer in crystallo’ section reports that crystals of the PFV intasome assembled with unprocessed viral DNA produced 3′-processing products after soaking in MnCl₂. It also states that both Mn²⁺ and Mg²⁺ supported integrase-catalysed reactions in the crystals (Figure 1B–C). (LLM, conf=0.94)

  cites [28] Hare, S., Maertens, G. N. & Cherepanov, P. 3′-processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J. 31, 3020–3028 (2012). This study visualizes the 3′-processing and strand transfer reactions in crystals of PFV intasomes, which defined the roles of chemical nucleophiles and divalent metal ions in catalysis, and reveals substrate mimicry by INSTIs. sourceExperimental — accuracy not yet measured

In the paper

“The target DNA bound a groove between the active sites of the intasome, nestling on the synaptic CTDs.”

What the sources say

• Partly supported

  The Introduction (page unavailable) says target DNA binds in a groove between the inner integrase subunits and presents its phosphodiesters to the active sites. It does not specify that the DNA nestles on the synaptic C-terminal domains, so that part of the claim is unsupported by our copy. (LLM, conf=0.84)

  cites [28] Hare, S., Maertens, G. N. & Cherepanov, P. 3′-processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J. 31, 3020–3028 (2012). This study visualizes the 3′-processing and strand transfer reactions in crystals of PFV intasomes, which defined the roles of chemical nucleophiles and divalent metal ions in catalysis, and reveals substrate mimicry by INSTIs. sourceExperimental — accuracy not yet measured

In the paper

“Thus, the metal ions in the IN active site swap their roles during 3’-processing versus strand transfer.”

What the sources say

• Supported

  The Target DNA binding and strand transfer section (page unavailable) explicitly states that the roles of the metal ion cofactors switch between 3′-processing and strand transfer. (LLM, conf=0.95)

  cites [28] Hare, S., Maertens, G. N. & Cherepanov, P. 3′-processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J. 31, 3020–3028 (2012). This study visualizes the 3′-processing and strand transfer reactions in crystals of PFV intasomes, which defined the roles of chemical nucleophiles and divalent metal ions in catalysis, and reveals substrate mimicry by INSTIs. source

In the paper

“Intasomes from several retroviral species as well as prokaryotic and eukaryotic transpososomes have been visualised as post-catalytic strand transfer complexes, all of which display sharp deformations of target DNA29,30,32,33,37,51–54.”

What the sources say

• Partly supported

  The paper reports a post-catalytic strand transfer structure of the prototype foamy virus intasome and severe bending of its target DNA (Abstract; page unavailable). It does not establish the sentence’s broader claim about structures from several retroviral species and prokaryotic and eukaryotic transpososomes all displaying sharp target-DNA deformations. (LLM, conf=0.86)

  cites [29] Maertens, G. N., Hare, S. & Cherepanov, P. The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature 468, 326–329 (2010). The first high-resolution structures of retroviral target capture and strand transfer intasome complexes reveal the requirement for target DNA distortion during integration. sourceExperimental — accuracy not yet measured
• Supported

  The RSV intasome preparation section says the crystallized complex used DNA mimicking the product of integration. Extended Data Figure 8 identifies the RSV intasome as a strand-transfer complex, and the target-DNA passage reports a sharp bend of about 90°. This paper supports the RSV example in the collectively cited sentence; it need not document every species listed. (LLM, conf=0.90)

  cites [30] Yin, Z. et al. Crystal structure of the Rous sarcoma virus intasome. Nature 530, 362–366 (2016). Together with Ballandras-Colas et al. (2016), these intasome structures first reveal the requirement for more than four IN protomers for functional integration. source
• Supported

  The passage beginning “To visualize how the lentiviral intasome engages target DNA” (section labelled Abstract; page unavailable) reports a cryo-EM structure of the maedi-visna virus strand transfer complex and describes bending of its target DNA. This supports the paper’s role as an example of a visualized lentiviral complex with deformed target DNA; the other species in the citing sentence are covered by its other citations. (LLM, conf=0.88)

  cites [32] Ballandras-Colas, A. et al. A supramolecular assembly mediates lentiviral DNA integration. Science 355, 93–95 (2017). Cryo-EM structures of intasomes derived from the sheep lentivirus MVV reveal a higher-order macromolecular machine composed of 16 IN protomers and define the conserved intasome core shared by all retroviral intasome structures. source
• ?Not checked — no full text of the sourcecites [33] Passos, D. O. et al. Cryo-EM structures and atomic model of the HIV-1 strand transfer complex intasome. Science 355, 89–92 (2017). Initial cryo-EM structures of HIV-1 strand transfer complex intasomes reveal a higher-order IN dodecamer architecture. source
• Partly supported

  The Results section ('IN tetramer in the HTLV-1 intasome'; page unavailable) reports sharp target-DNA kinks in the HTLV-1 strand-transfer complex and describes a similar target-DNA trajectory in the RSV intasome. The paper does not establish the claim about prokaryotic or eukaryotic transpososomes, or that all the complexes listed display sharp deformations. (LLM, conf=0.86)

  cites [37] Bhatt, V. et al. Structural basis of host protein hijacking in human T-cell leukemia virus integration. Nat. Commun. 11, 3121 (2020). Together with Barski et al. (2020), cryo-EM studies reveal that deltaretrovirus intasomes are composed of IN tetramers and visualize details of the IN–PP2A interface. sourceExperimental — accuracy not yet measured
• Partly supported

  The Results and Discussion (‘The PEC contains a dimeric transposase’; page not available) describe a visualized eukaryotic Mos1 transpososome, supporting that part of the citation. But the structure contains transposon ends positioned as if just cleaved, not a post-catalytic strand-transfer complex. In ‘A model for the target capture complex,’ target DNA is modeled rather than observed, so this paper does not show a sharp deformation of target DNA. (LLM, conf=0.88)

  cites [51] Richardson, J. M., Colloms, S. D., Finnegan, D. J. & Walkinshaw, M. D. Molecular architecture of the Mos1 paired-end complex: the structural basis of DNA transposition in a eukaryote. Cell 138, 1096–1108 (2009). sourceExperimental — accuracy not yet measured
• Partly supported

  The Methods (Overview; page not specified) describe a final strand-transfer complex of Mu, and Overall Architecture (Target DNA; page not specified) reports that its target DNA bends by about 140°. Convergent and divergent evolution also describes bent target DNA in the PFV intasome, but says Mos1 was crystallized without target DNA and bending in Tn5 was inferred by modeling. The paper therefore does not support the claim that all the complexes mentioned were visualized as post-catalytic complexes displaying sharply deformed target DNA, or its reference to several retroviral species. (LLM, conf=0.88)

  cites [52] Montano, S. P., Pigli, Y. Z. & Rice, P. A. The mu transpososome structure sheds light on DDE recombinase evolution. Nature 491, 413–417 (2012). sourceExperimental — accuracy not yet measured
• Supported

  The Results (Architecture of the Mos1 strand transfer complex; page unavailable) describe a crystal structure containing the products of transposon integration and bent target DNA. The Discussion (page unavailable) reports a severe ~147° bend in this eukaryotic transpososome and compares it with target-DNA deformation in bacterial MuA and retroviral PFV complexes. This source supports the Mos1 example within the multiply cited sentence. (LLM, conf=0.92)

  cites [53] Morris, E. R., Grey, H., McKenzie, G., Jones, A. C. & Richardson, J. M. A bend, flip and trap mechanism for transposon integration. eLife 5, e15537 (2016). source
• Supported

  The Results sections on the STC structure and altered target-DNA structure describe a visualized P element strand transfer complex with sharply bent target DNA. The paper also identifies target-DNA bending as a common feature of transposase and retroviral integrase structures. It supports the cited claim as an example of a eukaryotic transpososome, rather than as evidence for every complex listed in the multi-citation sentence. (LLM, conf=0.90)

  cites [54] Ghanim, G. E., Kellogg, E. H., Nogales, E. & Rio, D. C. Structure of a P element transposase-DNA complex reveals unusual DNA structures and GTP-DNA contacts. Nat. Struct. Mol. Biol. 26, 1013–1022 (2019). source

In the paper

“The side chains of these residues serve to coordinate the essential pair of Mg2+ ions, which facilitate 3’-processing and strand transfer reactions.”

What the sources say

• Supported

  The Introduction identifies the D,D-X35-E acidic residues as coordinating two divalent metal ions essential to integrase activity, and identifies Mg²⁺ as the natural cofactor. The paper’s structural experiments use Mn²⁺, but that does not conflict with the claim about Mg²⁺ facilitating 3′-processing and strand transfer. (LLM, conf=0.91)

  cites [28] Hare, S., Maertens, G. N. & Cherepanov, P. 3′-processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J. 31, 3020–3028 (2012). This study visualizes the 3′-processing and strand transfer reactions in crystals of PFV intasomes, which defined the roles of chemical nucleophiles and divalent metal ions in catalysis, and reveals substrate mimicry by INSTIs. sourceExperimental — accuracy not yet measured
• Partly supported

  The Background section says that two metal ions in a transposase active site support consecutive reactions: cleavage to generate a 3′ OH, followed by strand transfer. It also describes a conserved Asp coordinating both ions. It does not identify a D,D-35-E motif or establish that the side chains of all three specified residues coordinate the Mg2+ pair. (LLM, conf=0.85)

  cites [47] Yang, W., Lee, J. Y. & Nowotny, M. Making and breaking nucleic acids: two-Mg2+-ion catalysis and substrate specificity. Mol. Cell 22, 5–13 (2006). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page unavailable) describes active-site carboxylates coordinating two magnesium ions in RNase H catalysis, and the concluding remarks suggest that a two-metal mechanism may extend to recombinases. The paper does not identify a D,D-35-E motif or establish that its residues coordinate the ions for 3′-processing and strand transfer; those reaction-specific parts of the attributed claim are unsupported. (LLM, conf=0.86)

  cites [48] Nowotny, M. & Yang, W. Stepwise analyses of metal ions in RNase H catalysis from substrate destabilization to product release. EMBO J. 25, 1924–1933 (2006). sourceExperimental — accuracy not yet measured

In the paper

“The latter hydroxyl takes the role of the nucleophile during the strand transfer reaction to attack the phosphodiester backbone of chromosomal DNA, leading to transesterification and covalent joining of vDNA to the chromosome.”

What the sources say

• Supported

  The Introduction states that integrase uses viral DNA’s 3′-hydroxyls to attack phosphodiester bonds in host DNA during strand transfer. The “Target DNA binding and strand transfer” section describes the hydroxyl as poised for nucleophilic attack, and the Figure 4 caption identifies the resulting viral–target DNA phosphodiester bond. Page numbers are unavailable in our copy. (LLM, conf=0.92)

  cites [28] Hare, S., Maertens, G. N. & Cherepanov, P. 3′-processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J. 31, 3020–3028 (2012). This study visualizes the 3′-processing and strand transfer reactions in crystals of PFV intasomes, which defined the roles of chemical nucleophiles and divalent metal ions in catalysis, and reveals substrate mimicry by INSTIs. source

In the paper

“Both of these reactions were visualised in PFV intasome crystals28.”

What the sources say

• Supported

  In “Detection of 3′-processing and strand transfer in crystallo” (page not provided), the paper reports 3′-processing products after soaking PFV intasome crystals and strand-transfer products after soaking target-capture-complex crystals. It also reports structural observations of the crystallized complexes, supporting the paraphrase that both reactions were visualized in crystals. (LLM, conf=0.92)

  cites [28] Hare, S., Maertens, G. N. & Cherepanov, P. 3′-processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J. 31, 3020–3028 (2012). This study visualizes the 3′-processing and strand transfer reactions in crystals of PFV intasomes, which defined the roles of chemical nucleophiles and divalent metal ions in catalysis, and reveals substrate mimicry by INSTIs. source

In the paper

“However, in the context of the intasome, strand transfer results in reconfiguration of the active site followed by dissociation of metal ion B28.”

What the sources say

• Partly supported

  In “Target DNA binding and strand transfer,” the paper reports that the metal ions move closer and the newly formed phosphodiester is ejected from the active site after strand transfer. It reports reduced occupancy at metal position B in later structures, but describes dissociation of metal B as a suggestion rather than an established sequence of events. The claim overstates that inference. (LLM, conf=0.85)

  cites [28] Hare, S., Maertens, G. N. & Cherepanov, P. 3′-processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J. 31, 3020–3028 (2012). This study visualizes the 3′-processing and strand transfer reactions in crystals of PFV intasomes, which defined the roles of chemical nucleophiles and divalent metal ions in catalysis, and reveals substrate mimicry by INSTIs. sourceExperimental — accuracy not yet measured

In the paper

“The placement of the 3’ vDNA end in the active site is afforded by fraying of the vDNA termini by insertion of a CCD 310 helix between vDNA strands.”

What the sources say

• Partly supported

  In “IN-DNA interactions within the PFV intasome” (page unavailable), the paper describes separation of the viral DNA strands at the reactive terminus, and “The active site of the functional intasome” places the 3′ end near the active-site residues. But it attributes strand separation to the active-site loop, not insertion of a CCD 3₁₀ helix; the CCD α4 helix is described as packing into the DNA minor groove. (LLM, conf=0.87)

  cites [25] Hare, S., Gupta, S. S., Valkov, E., Engelman, A. & Cherepanov, P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 464, 232–236 (2010). The first high-resolution structure of a retroviral intasome reveals the IN–viral DNA architecture underlying DNA recombination as well as the mechanism of clinical INSTI action. sourceExperimental — accuracy not yet measured

In the paper

“Briefly soaking the crystals in Mn2+ allowed visualisation of the active site in the Michaelis complex form just prior to 3’-processing28.”

What the sources say

• Supported

  In “Detection of 3′-processing and strand transfer in crystallo” (page not provided), the authors report that a 5-minute Mn²⁺ soak freeze-trapped the Michaelis complex with both metal ions fully occupied and allowed its structure to be refined. The same section describes the UI Mn structure as showing the active site engaged with the viral DNA substrate before 3′-processing. (LLM, conf=0.94)

  cites [28] Hare, S., Maertens, G. N. & Cherepanov, P. 3′-processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J. 31, 3020–3028 (2012). This study visualizes the 3′-processing and strand transfer reactions in crystals of PFV intasomes, which defined the roles of chemical nucleophiles and divalent metal ions in catalysis, and reveals substrate mimicry by INSTIs. source

In the paper

“IN residues that interact with target DNA which, when altered, significantly changed base preferences at integration sites29,55–57.”

What the sources say

• Supported

  The paper identifies Arg329 and Ala188 as residues that contact target DNA (Abstract, passage 5). It reports that altering Arg329 significantly changed integration-site sequence bias and that A188S produced a significant preference for adenosine at target-DNA position 6 (Abstract, passages 2–3). (LLM, conf=0.94)

  cites [29] Maertens, G. N., Hare, S. & Cherepanov, P. The mechanism of retroviral integration from X-ray structures of its key intermediates. Nature 468, 326–329 (2010). The first high-resolution structures of retroviral target capture and strand transfer intasome complexes reveal the requirement for target DNA distortion during integration. source
• Supported

  The Results section on target-DNA binding reports that altering MLV integrase residues R336 or R337 produces a distinct integration-site sequence preference, statistically enhanced over wild type at almost every position. The paper also reports changed base preferences after substituting residues in the target-DNA-binding loop. Page numbers were not provided in our copy. (LLM, conf=0.93)

  cites [55] Aiyer, S. et al. Structural and sequencing analysis of local target DNA recognition by MLV integrase. Nucleic Acids Res. 43, 5647–5663 (2015). source
• Supported

  The Abstract identifies HIV-1 integrase residues corresponding to residues that contact target DNA and reports that mutations at Ser119 and Arg231 altered integration-site base preferences. The Sequence analysis of in vitro integration products section reports statistically significant changes for specific mutants, including S119A and S119T. (LLM, conf=0.91)

  cites [56] Serrao, E. et al. Integrase residues that determine nucleotide preferences at sites of HIV-1 integration: implications for the mechanism of target DNA binding. Nucleic Acids Res. 42, 5164–5176 (2014). source
• ?Not checked — no full text of the sourcecites [57] Demeulemeester, J. et al. HIV-1 integrase variants retarget viral integration and are associated with disease progression in a chronic infection cohort. Cell Host Microbe 16, 651–662 (2014). source

In the paper

“During 3’-processing, a water molecule is used as a nucleophile, and the reaction results in cleavage of a phosphodiester bond to reveal a 3’ dA hydroxyl group.”

What the sources say

• Supported

  In ‘Detection of 3′-processing and strand transfer in crystallo’ (page unavailable), the paper identifies a water molecule poised to attack the scissile phosphodiester and describes formation of the leaving 3′-hydroxyl. The Discussion identifies the deoxyadenosine retained at the viral DNA end after 3′-processing, supporting the claim’s description of the exposed 3′ dA hydroxyl. (LLM, conf=0.90)

  cites [28] Hare, S., Maertens, G. N. & Cherepanov, P. 3′-processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J. 31, 3020–3028 (2012). This study visualizes the 3′-processing and strand transfer reactions in crystals of PFV intasomes, which defined the roles of chemical nucleophiles and divalent metal ions in catalysis, and reveals substrate mimicry by INSTIs. source

In the paper

“The PFV intasome assembled using pre-processed vDNA was co-crystallized with a double-stranded DNA oligonucleotide in the form of the target capture complex28.”

What the sources say

• Supported

  The Introduction defines the cleaved intasome (CI) as the form containing processed viral DNA ends. The section “Detection of 3′-processing and strand transfer in crystallo” states that PFV target capture complex (TCC) crystals were prepared by co-crystallizing the CI with a 30-bp target DNA molecule, matching the claim. (LLM, conf=0.93)

  cites [28] Hare, S., Maertens, G. N. & Cherepanov, P. 3′-processing and strand transfer catalysed by retroviral integrase in crystallo. EMBO J. 31, 3020–3028 (2012). This study visualizes the 3′-processing and strand transfer reactions in crystals of PFV intasomes, which defined the roles of chemical nucleophiles and divalent metal ions in catalysis, and reveals substrate mimicry by INSTIs. source

In the paper

“Cryo-EM structures of the PFV intasome engaged with a mononucleosome revealed that the latter adapts to present the DNA in a conformation optimal for strand transfer64,65.”

What the sources say

• Supported

  The paper describes a single-particle cryo-EM structure of the PFV intasome bound to the D02 nucleosome before strand transfer (Abstract, passage 5). It reports that nucleosomal DNA is deformed and lifted from the histone surface into a conformation closely matching target DNA captured by the PFV intasome (Abstract, passage 1), supporting the claimed adaptation for strand transfer. (LLM, conf=0.93)

  cites [64] Maskell, D. P. et al. Structural basis for retroviral integration into nucleosomes. Nature 523, 366–369 (2015). Together with Wilson et al. (2019), cryo-EM studies elucidate how the PFV intasome engages and locally remodels a nucleosome for integration. source
• Supported

  The Results section, “Structure of Intasome-NCP strand-transfer complex,” reports a cryo-EM structure of the PFV intasome–nucleosome strand-transfer complex. It finds that nucleosomal DNA is lifted and bent at the integration site to allow access to the integrase catalytic centre, supporting the claim that the nucleosome presents DNA in a conformation suitable for strand transfer. (LLM, conf=0.92)

  cites [65] Wilson, M. D. et al. Retroviral integration into nucleosomes through DNA looping and sliding along the histone octamer. Nat. Commun. 10, 4189 (2019). source

In the paper

“During nuclear import, CPSF6 is thought to compete with Nup153 for capsid binding to release the viral core from the nuclear pore complex81.”

What the sources say

• Supported

  The Discussion’s Figure 8 model says CPSF6 competitively binds the capsid-derived structure, displaces Nup153, and ultimately releases the HIV-1 subviral complex from the nuclear pore complex. The claim’s “is thought to” appropriately reflects that this is a proposed model, described for primary macrophages. (LLM, conf=0.94)

  cites [81] Bejarano, D. A. et al. HIV-1 nuclear import in macrophages is regulated by CPSF6-capsid interactions at the nuclear pore complex. eLife 8, e41800 (2019). source

In the paper

“C-terminal proteolytic processing of spumaviral Gag proteins, which is required for infection, occurs adjacent to the chromatin binding sequence (CBS)90.”

What the sources say

• Partly supported

  Section 2 states that FV Gag undergoes C-terminal proteolytic processing and that Gag processing is essential for viral infectivity. Section 2.3 places the chromatin-binding sequence in the C-terminal GRII region, and the Figure 3 caption identifies the primary cleavage site at amino acid 621. The text provided does not establish that the cleavage site is adjacent to the chromatin-binding sequence. (LLM, conf=0.82)

  cites [90] Müllers, E. The foamy virus Gag proteins: what makes them different? Viruses 5, 1023–1041 (2013). sourceExperimental — accuracy not yet measured

In the paper

“The PFV Gag CBS binds nucleosomes via an acidic patch predominantly composed of core histone H2A/H2B heterodimers91,92”

What the sources say

• Partly supported

  The section “The CBS of PFV Gag interacts with core histones H2A/H2B” (p. 6) reports that the PFV Gag CBS associates with H2A and H2B and binds host chromosomes through them. The Discussion (p. 7) cautions that additional factors or other nucleosomal components may be involved. The paper does not identify an acidic patch as the binding site or establish direct binding to an H2A/H2B heterodimer. (LLM, conf=0.88)

  cites [91] Tobaly-Tapiero, J. et al. Chromatin tethering of incoming foamy virus by the structural Gag protein. Traffic 9, 1717–1727 (2008). sourceExperimental — accuracy not yet measured
• Supported

  The passage labeled Significance (p. 2) reports that PFV GAG CBS binds the nucleosome through contacts predominantly involving an H2A–H2B heterodimer: those contacts account for more than 75% of the contact area. It also identifies the H2A–H2B acidic patch as the site engaged by the CBS arginine anchor. (LLM, conf=0.94)

  cites [92] Lesbats, P. et al. Structural basis for spumavirus GAG tethering to chromatin. Proc. Natl Acad. Sci. USA 114, 5509–5514 (2017). source

In the paper

“which is consistent with predicted variations in target DNA conformations required to integrate across 4–6 bp spacings67.”

What the sources say

• Supported

  The “Central flexibility is a conserved feature of retroviral integration sites” section (page not supplied) predicts a severe central target-DNA bend for 4-bp integration spacing and less central flexibility for 6-bp spacing than for 4- or 5-bp spacing. It also discusses how two central dinucleotide steps may produce the bend needed for 5-bp spacing. These passages support the claimed variation in target-DNA conformation across 4–6 bp spacings. (LLM, conf=0.92)

  cites [67] Serrao, E., Ballandras-Colas, A., Cherepanov, P., Maertens, G. N. & Engelman, A. N. Key determinants of target DNA recognition by retroviral intasomes. Retrovirology 12, 39 (2015). source

In the paper

“The lentiviral IN binding protein LEDGF/p75 significantly stimulated IN strand transfer activity in vitro17,43,96,97.”

What the sources say

• ?Could not verify

  The Results describe LEDGF/p75 binding to lentiviral integrase and show that LEDGF/p75-associated preintegration complexes can integrate DNA in vitro. They do not compare integrase strand-transfer activity with and without LEDGF/p75 or report stimulation of that activity (searched: strand transfer, stimulation, and in vitro integration activity). (LLM, conf=0.76)

  cites [17] Llano, M. et al. LEDGF/p75 determines cellular trafficking of diverse lentiviral but not murine oncoretroviral integrase proteins and is a component of functional lentiviral preintegration complexes. J. Virol. 78, 9524–9537 (2004). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [43] Cherepanov, P. et al. HIV-1 integrase forms stable tetramers and associates with LEDGF/p75 protein in human cells. J. Biol. Chem. 278, 372–381 (2003). source
• ?Not checked — no full text of the sourcecites [96] Busschots, K. et al. The interaction of LEDGF/p75 with integrase is lentivirus-specific and promotes DNA binding. J. Biol. Chem. 280, 17841–17847 (2005). source
• Supported

  The Results section, “LEDGF augments enzymatic activity of divergent lentiviral INs,” reports stimulated strand transfer by BIV and EIAV integrases, and the Discussion states that LEDGF robustly stimulated in vitro strand transfer by HIV-1, BIV, and EIAV integrases. This supports the attributed claim. (LLM, conf=0.94)

  cites [97] Cherepanov, P. LEDGF/p75 interacts with divergent lentiviral integrases and modulates their enzymatic activity in vitro. Nucleic Acids Res. 35, 113–124 (2007). sourceExperimental — accuracy not yet measured

In the paper

“In addition to its role in nuclear import, CPSF6 plays a critical role in regulating nuclear PIC incursion.”

What the sources say

• Partly supported

  The Results section (“Relocation outside of NSs diminishes nuclear VRC stability”; page unavailable) suggests that CPSF6 is involved in transporting HIV-1 viral replication complexes to nuclear speckles. The Discussion (page unavailable) is more cautious: it says CPSF6 and/or other factors may tether the complexes there. These passages support a role in intranuclear positioning, but not the stronger assertion that CPSF6 itself plays a critical role in regulating nuclear PIC incursion. (LLM, conf=0.81)

  cites [84] Francis, A. C. et al. HIV-1 replication complexes accumulate in nuclear speckles and integrate into speckle-associated genomic domains. Nat. Commun. 11, 3505 (2020). This study demonstrates that HIV-1 integration favours regions of chromatin that are located close to nuclear speckles. sourceExperimental — accuracy not yet measured
• Supported

  The Introduction (page not provided) states that CPSF6 engagement lets HIV-1 pre-integration complexes bypass peripheral heterochromatin and penetrate the nuclear interior. The Results section (page not provided) also reports that disrupting the capsid–CPSF6 interaction altered the intranuclear distribution of viral DNA. (LLM, conf=0.93)

  cites [85] Achuthan, V. et al. Capsid-CPSF6 interaction licenses nuclear HIV-1 trafficking to sites of viral DNA integration. Cell Host Microbe 24, 392–404.e398 (2018). source

In the paper

“Yet, chromatinized DNA was shown to be a suitable, or even preferred target for retroviral integration in vitro and in vivo59–64.”

What the sources say

• ?Not checked — no full text of the sourcecites [59] Pryciak, P. M. & Varmus, H. E. Nucleosomes, DNA-binding proteins, and DNA sequence modulate retroviral integration target site selection. Cell 69, 769–780 (1992). source
• ?Not checked — no full text of the sourcecites [60] Pruss, D., Bushman, F. D. & Wolffe, A. P. Human immunodeficiency virus integrase directs integration to sites of severe DNA distortion within the nucleosome core. Proc. Natl Acad. Sci. USA 91, 5913–5917 (1994). source
• Supported

  The paper reports that nucleosome-wrapped DNA is favored over naked DNA for integration in vitro. It also describes in vivo evidence that nucleosome-associated DNA is a target and reports a favored pattern of HIV integration on nucleosome-wrapped chromosomal DNA (Abstract; page unavailable). (LLM, conf=0.88)

  cites [61] Wang, G. P., Ciuffi, A., Leipzig, J., Berry, C. C. & Bushman, F. D. HIV integration site selection: analysis by massively parallel pyrosequencing reveals association with epigenetic modifications. Genome Res. 17, 1186–1194 (2007). source
• ?Not checked — no full text of the sourcecites [62] Roth, S. L., Malani, N. & Bushman, F. D. Gammaretroviral integration into nucleosomal target DNA in vivo. J. Virol. 85, 7393–7401 (2011). source
• Supported

  The “Ty1 targets nucleosomes” section states that nucleosomes are preferred targets for retroviruses and describes genomic HIV and gammaretroviral insertions on nucleosomal DNA. The References section identifies studies of retroviral integration into minichromosomes in vitro and in vivo, supporting the claim’s distinction between those settings. (LLM, conf=0.90)

  cites [63] Baller, J. A., Gao, J., Stamenova, R., Curcio, M. J. & Voytas, D. F. A nucleosomal surface defines an integration hotspot for the Saccharomyces cerevisiae Ty1 retrotransposon. Genome Res. 22, 704–713 (2012). source
• Supported

  The paper’s main text (indexed under Abstract; page unavailable) reports robust PFV integration into nucleosomes in vitro and much less efficient integration into deproteinized nucleosomal DNA. It also reports integration events in infected human cells and a bias toward condensed heterochromatin, supporting chromatinized DNA as a suitable in vivo target; it does not establish that nucleosomes are preferred over naked DNA in vivo. (LLM, conf=0.88)

  cites [64] Maskell, D. P. et al. Structural basis for retroviral integration into nucleosomes. Nature 523, 366–369 (2015). Together with Wilson et al. (2019), cryo-EM studies elucidate how the PFV intasome engages and locally remodels a nucleosome for integration. source

In the paper

“In MLV, the chromatin tethering function is accomplished by p12, a small phosphoprotein that is encoded within the gag gene, which acts in a manner seemingly indistinguishable from the PFV Gag CBS93–95.”

What the sources say

• Partly supported

  The Introduction identifies p12 as a cleavage product of MLV Gag, and the Discussion concludes that it tethers MLV pre-integration complexes to mitotic chromosomes. The Discussion does not establish that p12 acts like the PFV Gag chromatin-binding sequence; it says the interactions underlying p12-mediated tethering remain uncertain. Page numbers are unavailable in our copy. (LLM, conf=0.88)

  cites [93] Elis, E., Ehrlich, M., Prizan-Ravid, A., Laham-Karam, N. & Bacharach, E. p12 tethers the murine leukemia virus pre-integration complex to mitotic chromosomes. PLoS Pathog. 8, e1003103 (2012). sourceExperimental — accuracy not yet measured
• Partly supported

  The Abstract and Discussion support a chromatin-tethering role for MuLV Gag p12: a PFV Gag chromatin-binding sequence can rescue a defective p12 mutant, and the authors infer that wild-type p12 tethers to chromosomes. They do not establish that native p12 acts in a manner indistinguishable from the PFV sequence; the Discussion leaves p12’s tethering partner unresolved. The passages provide no page numbers. (LLM, conf=0.84)

  cites [94] Schneider, W. M. et al. Viral DNA tethering domains complement replication-defective mutations in the p12 protein of MuLV Gag. Proc. Natl Acad. Sci. USA 110, 9487–9492 (2013). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports that MLV p12 directly tethers the pre-integration complex to nucleosomes. It also reports competition between p12 and the PFV Gag chromatin-binding sequence and describes their binding as similar, with about 90% overlap in their chromatin interactomes. That supports a similar mode of action, but not the stronger suggestion that they are indistinguishable. (LLM, conf=0.82)

  cites [95] Wanaguru, M., Barry, D. J., Benton, D. J., O’Reilly, N. J. & Bishop, K. N. Murine leukemia virus p12 tethers the capsid-containing pre-integration complex to chromatin by binding directly to host nucleosomes in mitosis. PLoS Pathog. 14, e1007117 (2018). sourceExperimental — accuracy not yet measured

In the paper

“These interactions are thought to offset the energy required to shift nucleosomal DNA along the histone octamer core to create the slack for lifting the target DNA at the site of integration (Fig. 4)65.”

What the sources say

• Supported

  The Discussion says that energy released by formation of the intasome–nucleosome interface offsets DNA rearrangements, and that looping DNA out of the histone core causes a compensatory shift along the octamer. The Results section on nucleosomal DNA register likewise describes sliding that accommodates looping at the integration site. Page numbers are not supplied in our copy. (LLM, conf=0.91)

  cites [65] Wilson, M. D. et al. Retroviral integration into nucleosomes through DNA looping and sliding along the histone octamer. Nat. Commun. 10, 4189 (2019). source

In the paper

“The genic proviruses that did form under these conditions uncharacteristically congregated around transcription start sites87,99–101.”

What the sources say

• Supported

  The Introduction (page not specified) says that without LEDGF/p75, HIV-1 genic integration shifts toward gene 5′ regions. The Results section (page not specified) reports increased TSS-proximal integration in the absence of LEDGF/p75, supporting the description of genic proviruses congregating near transcription start sites. (LLM, conf=0.91)

  cites [87] Li, W. et al. CPSF6-dependent targeting of speckle-associated domains distinguishes primate from nonprimate lentiviral integration. mBio 11, e02254-20 (2020). source
• Partly supported

  In “A critical role for Ledgf in gene-specific HIV-1 integration” (page not available), the paper reports that HIV-1 integration near transcription start sites was about 2.6-fold more frequent in Ledgf-null cells. That analysis covers all proviruses, not specifically the genic proviruses named in the claim. (LLM, conf=0.82)

  cites [99] Shun, M. C. et al. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev. 21, 1767–1778 (2007). sourceExperimental — accuracy not yet measured
• Supported

  The Results section, “LEDGF causes integration to favor the 5′ end of transcription units” (page not available), reports a strong integration bias at the extreme 5′ ends of transcription units in cells lacking LEDGF. That supports the claim that the genic integrations formed without LEDGF/p75 clustered near transcription start sites. (LLM, conf=0.91)

  cites [100] Singh, P. K. et al. LEDGF/p75 interacts with mRNA splicing factors and targets HIV-1 integration to highly spliced genes. Genes Dev. 29, 2287–2297 (2015). sourceExperimental — accuracy not yet measured
• Supported

  The Results report that, although LEDGF/p75 knockout reduced integration into genes, 62.8% of integrations remained genic. They also report strong enrichment of integration near transcription start sites in knockout cells, supporting the claimed positional shift. (LLM, conf=0.93)

  cites [101] Sowd, G. A. et al. A critical role for alternative polyadenylation factor CPSF6 in targeting HIV-1 integration to transcriptionally active chromatin. Proc. Natl Acad. Sci. USA 113, E1054–E1063 (2016). sourceExperimental — accuracy not yet measured

In the paper

“Cleavage and polyadenylation specificity factor 6 (CPSF6), which is a component of the cellular pre-mRNA cleavage and polyadenylation machinery79, binds the same region of capsid as Nup153 (REF.78,80).”

What the sources say

• Supported

  In “Competitors of NUP153-CA binding,” the paper says the capsid residues involved in NUP153 binding overlap those that interact with CPSF6. It also reports that NUP153 competes with CPSF6 for capsid binding. The supplied passages do not give page numbers. (LLM, conf=0.94)

  cites [78] Matreyek, K. A., Yucel, S. S., Li, X. & Engelman, A. Nucleoporin NUP153 phenylalanine-glycine motifs engage a common binding pocket within the HIV-1 capsid protein to mediate lentiviral infectivity. PLoS Pathog. 9, e1003693 (2013). source
• Supported

  The section “Cofactors CPSF6 and NUP153 bind a hexamer-specific interface formed between two adjacent monomers” explicitly says the two cofactors share a common binding site on HIV-1 capsid. It also notes that they make distinct contacts within that region, which does not undermine the claim. (LLM, conf=0.94)

  cites [80] Price, A. J. et al. Host cofactors and pharmacologic ligands share an essential interface in HIV-1 capsid that is lost upon disassembly. PLoS Pathog. 10, e1004459 (2014). source

In the paper

“The well-understood integration preferences of HIV-1 for active transcription units72 and MLV for promoter/enhancer regions73–75 are in large part dictated via specific interactions of the respective IN proteins with chromatin-bound host factors.”

What the sources say

• ?Not checked — no full text of the sourcecites [72] Schroder, A. R. et al. HIV-1 integration in the human genome favors active genes and local hotspots. Cell 110, 521–529 (2002). Enabled by the release of the human genome sequence, this study convincingly demonstrates that HIV-1 integration strongly favours active transcription units within gene-dense regions of chromatin. source
• ?Not checked — no full text of the sourcecites [73] Wu, X., Li, Y., Crise, B. & Burgess, S. M. Transcription start regions in the human genome are favored targets for MLV integration. Science 300, 1749–1751 (2003). This is the first study to reveal that the gammaretrovirus Moloney murine leukaemia virus favours gene promoter regions for integration. source
• ?Not checked — no full text of the sourcecites [74] De Ravin, S. S. et al. Enhancers are major targets for murine leukemia virus vector integration. J. Virol. 88, 4504–4513 (2014). source
• Partly supported

  The Results and Discussion report a strong MLV integration preference for particular strong enhancers and active promoters. The Results do not exclude an integrase–protein tether, and the Discussion describes BET proteins as possible tethers, but neither establishes that such interactions largely dictate MLV integration. The HIV-1 preference is separately cited in the citing sentence and is not assessed here. (LLM, conf=0.87)

  cites [75] LaFave, M. C. et al. MLV integration site selection is driven by strong enhancers and active promoters. Nucleic Acids Res. 42, 4257–4269 (2014). sourceExperimental — accuracy not yet measured

In the paper

“The intasome forms a multivalent interface with the nucleosome, contacting both nucleosomal DNA gyres and the core histones (Fig. 4).”

What the sources say

• Supported

  The passage labeled Abstract describes an extensive intasome–nucleosome interface involving both gyres of nucleosomal DNA and an H2A–H2B histone heterodimer. It also identifies contacts with the H2B helix and the second DNA gyre, directly supporting the claim. (LLM, conf=0.95)

  cites [64] Maskell, D. P. et al. Structural basis for retroviral integration into nucleosomes. Nature 523, 366–369 (2015). Together with Wilson et al. (2019), cryo-EM studies elucidate how the PFV intasome engages and locally remodels a nucleosome for integration. source
• Supported

  The Results section (‘Structure of Intasome-NCP strand-transfer complex’) states that the intasome engages nucleosomal DNA at the strand-transfer site and the opposing gyre. It also describes direct contacts with histone H2B and the H2A tail, supporting the claimed multivalent interface. (LLM, conf=0.94)

  cites [65] Wilson, M. D. et al. Retroviral integration into nucleosomes through DNA looping and sliding along the histone octamer. Nat. Commun. 10, 4189 (2019). source

In the paper

“Depletion of cellular Nup153 or Nup358 also shifted HIV-1 integration away from gene-dense regions of chromatin88,89”

What the sources say

• Supported

  The Results and Discussion (p. 8) report that NUP153 depletion reduced HIV-1 integration into gene-dense regions. The same section compares this effect with a larger reduction following NUP358 depletion reported in earlier work, supporting the claim for both factors. (LLM, conf=0.91)

  cites [88] Koh, Y. et al. Differential effects of human immunodeficiency virus type 1 capsid and cellular factors nucleoporin 153 and LEDGF/p75 on the efficiency and specificity of viral DNA integration. J. Virol. 87, 648–658 (2013). sourceExperimental — accuracy not yet measured
• Partly supported

  The section on HIV integration site selection reports that RanBP2/Nup358 depletion shifted HIV integration toward regions of lower gene density. Our copy does not report the same result for Nup153; the corresponding experiments concern RanBP2 and Transportin-3. (LLM, conf=0.90)

  cites [89] Ocwieja, K. E. et al. HIV integration targeting: a pathway involving transportin-3 and the nuclear pore protein RanBP2. PLoS Pathog. 7, e1001313 (2011). sourceExperimental — accuracy not yet measured

In the paper

“Consequently, the PFV intasome displays highly preferred nucleosomal integration sites at superhelix ±3.5 locations that overlay the H2A-H2B heterodimers64.”

What the sources say

• Supported

  The paper’s indexed text reports common PFV integration hotspots at SHL±3.5. Its cryo-EM description places the preferred integration site in nucleosomal DNA above an H2A-H2B heterodimer. The indexed copy labels these passages “Abstract”; no page number is provided. (LLM, conf=0.94)

  cites [64] Maskell, D. P. et al. Structural basis for retroviral integration into nucleosomes. Nature 523, 366–369 (2015). Together with Wilson et al. (2019), cryo-EM studies elucidate how the PFV intasome engages and locally remodels a nucleosome for integration. source

In the paper

“However, in vitro studies with intasomes of several retroviruses suggested genus-specific modes of chromosomal integration66”

What the sources say

• Supported

  The Discussion and conclusion reports that in vitro tests of HIV-1, PFV, ASV and MLV intasomes found different integration preferences in chromatinized templates. The Background identifies these viruses with distinct retroviral genera, supporting the paraphrase that the studies suggest genus-specific integration modes. (LLM, conf=0.90)

  cites [66] Benleulmi, M. S. et al. Intasome architecture and chromatin density modulate retroviral integration into nucleosome. Retrovirology 12, 13 (2015). source

In the paper

“The same nucleosomal positions are favoured by yeast retrotransposon Ty1 in vivo63.”

What the sources say

• Supported

  The paper’s summary reports that mapping Ty1 insertions in the yeast genome found preferential integration into nucleosome-bound DNA near the H2A/H2B interface. The “Ty1 targets nucleosomes” section likewise reports enrichment at a particular position on the nucleosome, supporting the claim that Ty1 favors specific nucleosomal positions in vivo. (LLM, conf=0.88)

  cites [63] Baller, J. A., Gao, J., Stamenova, R., Curcio, M. J. & Voytas, D. F. A nucleosomal surface defines an integration hotspot for the Saccharomyces cerevisiae Ty1 retrotransposon. Genome Res. 22, 704–713 (2012). source

In the paper

“HIV-1 nuclear import is mediated via the viral capsid, which interacts directly with several components of the cellular nuclear import machinery, including the nuclear pore complex components Nup153 and Nup358 (REF.76–78).”

What the sources say

• Partly supported

  The Discussion says capsid composition influences retroviral nuclear transport, supporting a role for capsid. It does not report direct capsid interactions with Nup153 or Nup358; instead, it says HIV capsid does not appear to act as a nuclear localization signal and that the component recognized by cellular import machinery remains unclear. (LLM, conf=0.87)

  cites [76] Yamashita, M. & Emerman, M. Capsid is a dominant determinant of retrovirus infectivity in nondividing cells. J. Virol. 78, 5670–5678 (2004). sourceExperimental — accuracy not yet measured
• Partly supported

  The Discussion reports direct binding between HIV-1 capsid and the cyclophilin domain of Nup358, supporting a capsid-mediated nuclear-entry pathway. The Nup153-dependent nuclear-entry section shows that Nup153 affects infection, but the Discussion describes interaction with Nup153 as a possibility, not a demonstrated direct capsid–Nup153 interaction. The claim overstates what this paper establishes for Nup153. (LLM, conf=0.88)

  cites [77] Schaller, T. et al. HIV-1 capsid-cyclophilin interactions determine nuclear import pathway, integration targeting and replication efficiency. PLoS Pathog. 7, e1002439 (2011). sourceExperimental — accuracy not yet measured
• Partly supported

  The Author Summary reports direct binding between HIV-1 capsid and NUP153, and the Figure 12 caption says capsid engagement with NUP153 is required for nuclear import. The “Model of NUP153 FG engagement” section describes docking through NUP358 as likely, rather than establishing the claimed direct interaction with NUP358 as fact. (LLM, conf=0.82)

  cites [78] Matreyek, K. A., Yucel, S. S., Li, X. & Engelman, A. Nucleoporin NUP153 phenylalanine-glycine motifs engage a common binding pocket within the HIV-1 capsid protein to mediate lentiviral infectivity. PLoS Pathog. 9, e1003693 (2013). sourceExperimental — accuracy not yet measured

In the paper

“Knockout of the PSIP1 gene, which encodes for LEDGF/p75, similarly suppressed levels of vDNA integration in cells several fold98,99.”

What the sources say

• Supported

  The Results section on murine cells disrupted at LEDGF/p75 (page unavailable) reports that HIV integration fell approximately fivefold and EIAV integration fell more than 50-fold in cells with a homozygous mutation of the LEDGF/p75 locus. This supports the claim that loss of PSIP1 reduced viral DNA integration by several fold. (LLM, conf=0.94)

  cites [98] Marshall, H. M. et al. Role of PSIP1/LEDGF/p75 in lentiviral infectivity and integration targeting. PLoS ONE 2, e1340 (2007). source
• Supported

  The Abstract identifies Psip1 as the gene encoding Ledgf/p75 and reports reduced HIV-1 vector integration in knockout mouse embryo fibroblasts. In “The mechanism of LEDGF/p75 function during HIV-1 integration,” the paper describes approximately 10-fold lower overall integration after Ledgf ablation, supporting the claimed several-fold reduction in cells. (LLM, conf=0.92)

  cites [99] Shun, M. C. et al. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev. 21, 1767–1778 (2007). source

In the paper

“Be this as it may, B56 proteins additionally served as key structural components of the recent δ-retroviral intasome structures37,38.”

What the sources say

• Supported

  The Results (PP2A-B56γ–IN interaction) describe two B56γ molecules bound to the core of the HTLV-1 intasome. The Results (B56γ is important for HTLV-1 integration in cells) explicitly call B56γ an important component of that intasome, supporting the structural-component claim. (LLM, conf=0.92)

  cites [37] Bhatt, V. et al. Structural basis of host protein hijacking in human T-cell leukemia virus integration. Nat. Commun. 11, 3121 (2020). Together with Barski et al. (2020), cryo-EM studies reveal that deltaretrovirus intasomes are composed of IN tetramers and visualize details of the IN–PP2A interface. source
• Supported

  The Architecture of the deltaretroviral intasome section describes two B56γ subunits flanking the STLV-1 intasome in its cryo-EM structure. This supports the claim that a B56 protein is a structural component of the reported deltaretroviral intasome. (LLM, conf=0.93)

  cites [38] Barski, M. S. et al. Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ. Nat. Commun. 11, 5043 (2020). source

In the paper

“LEDGF/p75 appears to function as a bimodal tether in lentiviral integration targeting.”

What the sources say

• ?Not checked — no full text of the sourcecites [103] Llano, M. et al. Identification and characterization of the chromatin-binding domains of the HIV-1 integrase interactor LEDGF/p75. J. Mol. Biol. 360, 760–773 (2006). source
• Supported

  The Introduction identifies LEDGF/p75 as a binding partner of HIV-1 integrase and reports its role in targeting integration to active genes and A/T-rich sequences. The section “DNA-binding activity maps to residues 93–226” distinguishes its DNA-binding region from its integrase-binding domain. Together, these passages support the hedged description of LEDGF/p75 as a two-sided tether in lentiviral integration targeting. (LLM, conf=0.87)

  cites [104] Turlure, F., Maertens, G., Rahman, S., Cherepanov, P. & Engelman, A. A tripartite DNA-binding element, comprised of the nuclear localization signal and two AT-hook motifs, mediates the association of LEDGF/p75 with chromatin in vivo. Nucleic Acids Res. 34, 1653–1665 (2006). source
• Partly supported

  The Discussion (page unavailable) describes LEDGF/p75 as a chromosomal protein that binds lentiviral integrases, supporting the proposed tether mechanism. It calls LEDGF/p75 a candidate targeting factor, however, and says its role in targeting during infection remains to be established; the claim goes further by saying it appears to function as that tether. (LLM, conf=0.85)

  cites [105] Cherepanov, P., Devroe, E., Silver, P. A. & Engelman, A. Identification of an evolutionarily conserved domain in human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) that binds HIV-1 integrase. J. Biol. Chem. 279, 48883–48892 (2004). sourceExperimental — accuracy not yet measured

In the paper

“LEDGF/p75 similarly tethers several cellular proteins to chromatin, including MLL1 and MML2 methyltransferases, via IBD interactions with a linear IBM (for IBD-binding motif) amino acid sequence113.”

What the sources say

• Partly supported

  The Discussion (page not provided) says LEDGF/p75 can tether its binding partners to chromatin through an IBD interface that recognizes the IBM, and identifies MLL1 and MLL2 as partners. It establishes this interaction for MLL1 but says MLL2 most likely uses the same interface; the citing sentence presents MLL2’s mechanism as established. The source spells the protein name MLL2, not MML2. (LLM, conf=0.83)

  cites [113] Tesina, P. et al. Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif. Nat. Commun. 6, 7968 (2015). sourceExperimental — accuracy not yet measured

In the paper

“The CCD is the main IN binding determinant, with the NTD contributing secondary interactions for full binding affinity106,107.”

What the sources say

• Supported

  The paper states that the integrase catalytic core domain plays the dominant role in LEDGF/p75 binding and that the N-terminal zinc-binding domain also contributes. In the section “Mutational Disruption of the Zinc Binding Domain Reduces Affinity of IN for LEDGF/p75” (page unavailable), disrupting that domain impairs binding, supporting its contribution to full affinity. (LLM, conf=0.88)

  cites [106] Maertens, G. et al. LEDGF/p75 is essential for nuclear and chromosomal targeting of HIV-1 integrase in human cells. J. Biol. Chem. 278, 33528–33539 (2003). source
• Supported

  The Introduction describes the established integrase CCD–LEDGF binding interface and says this study extends it to include NTD contacts essential for high-affinity binding. The Results section, “The IN–LEDGF Interface and the Role of the IN NTD,” describes contacts at both interfaces, supporting the CCD as the main binding site with an additional NTD contribution. (LLM, conf=0.90)

  cites [107] Hare, S. et al. A novel co-crystal structure affords the design of gain-of-function lentiviral integrase mutants in the presence of modified PSIP1/LEDGF/p75. PLoS Pathog. 5, e1000259 (2009). source

In the paper

“Similarly, LEDGF/p75 was instrumental to reconstitute lentiviral intasomes for structural characterisation32–36.”

What the sources say

• Supported

  The paper states that intasome formation required LEDGF. It then reports cryo-electron microscopy of the resulting lentiviral intasome, supporting LEDGF/p75’s role in reconstituting it for structural characterization (Abstract; page not provided). (LLM, conf=0.92)

  cites [32] Ballandras-Colas, A. et al. A supramolecular assembly mediates lentiviral DNA integration. Science 355, 93–95 (2017). Cryo-EM structures of intasomes derived from the sheep lentivirus MVV reveal a higher-order macromolecular machine composed of 16 IN protomers and define the conserved intasome core shared by all retroviral intasome structures. source
• ?Not checked — no full text of the sourcecites [33] Passos, D. O. et al. Cryo-EM structures and atomic model of the HIV-1 strand transfer complex intasome. Science 355, 89–92 (2017). Initial cryo-EM structures of HIV-1 strand transfer complex intasomes reveal a higher-order IN dodecamer architecture. source
• Partly supported

  The Introduction (page unavailable) says that fusing a peptide derived from LEDGF to HIV-1 integrase provided a tool for structural studies of HIV-1 intasomes, and that the authors used it to determine an intasome structure. This supports the role of an LEDGF-derived peptide, but not the broader claim that full-length LEDGF/p75 was instrumental in reconstituting lentiviral intasomes generally. (LLM, conf=0.86)

  cites [34] Li, M. et al. A peptide derived from lens epithelium-derived growth factor stimulates HIV-1 DNA integration and facilitates intasome structural studies. J. Mol. Biol. 432, 2055–2066 (2020). sourceExperimental — accuracy not yet measured
• Partly supported

  The passage labeled Abstract (page unavailable) reports that LEDGF/p75 stimulated strand-transfer activity and that the reaction conditions produced stable nucleoprotein complexes examined by electron microscopy. The paper does not say that LEDGF/p75 was instrumental to reconstituting those intasomes for structural characterization. (LLM, conf=0.82)

  cites [35] Cook, N. J. et al. Structural basis of second-generation HIV integrase inhibitor action and viral resistance. Science 367, 806 (2020). High-resolution cryo-EM structures of simian immunodeficiency virus intasomes reveal the mechanism of INSTI resistance. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [36] Passos, D. O. et al. Structural basis for strand-transfer inhibitor binding to HIV intasomes. Science 367, 810 (2020). This study provides high-resolution cryo-EM structures of HIV-1 intasomes with several advanced INSTIs. source

In the paper

“The literature is replete with examples of HIV-1 IN point mutants that retain enzymatic activity yet fail to support viral replication (REF.132 and references therein).”

What the sources say

• Supported

  In Results, under “Characterization of the replication defects of class II IN mutant viruses,” nearly all tested substitutions reduced virus titers at least 100-fold, while many mutant integrases retained catalytic activity in a complementation assay. The same section concludes that the majority retained at least partial catalytic activity but produced non-infectious virions. (LLM, conf=0.92)

  cites [132] Elliott, J. L. et al. Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis. eLife 9, e543111 (2020). source

In the paper

“Alterations that disrupted LEDGF/p75 binding to chromatin or IN ablated its cofactor function during HIV-1 infection99,103,112.”

What the sources say

• Supported

  In “LEDGF/p75 chromatin and IN-binding functions required for HIV-1 infection” (Fig. 2E; page not supplied), the IN-binding mutant D366N and the combined chromatin-binding-domain deletion both failed to support infection. The paper also notes that deleting PWWP alone left residual function, so the finding applies to the binding-disrupting alterations tested, not every alteration to those domains. (LLM, conf=0.93)

  cites [99] Shun, M. C. et al. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev. 21, 1767–1778 (2007). source
• ?Not checked — no full text of the sourcecites [103] Llano, M. et al. Identification and characterization of the chromatin-binding domains of the HIV-1 integrase interactor LEDGF/p75. J. Mol. Biol. 360, 760–773 (2006). source
• Supported

  The introduction states that integrase- or chromatin-binding-defective LEDGF/p75 mutants fail to restore sensitivity to HIV-1 infection in cells depleted of endogenous LEDGF/p75. The Discussion also states that PWWP-domain or integrase-binding-domain mutations can abrogate LEDGF/p75 function during infection. (LLM, conf=0.93)

  cites [112] Shun, M. C. et al. Identification and characterization of PWWP domain residues critical for LEDGF/p75 chromatin binding and human immunodeficiency virus type 1 infectivity. J. Virol. 82, 11555–11567 (2008). source

In the paper

“MLV and other γ-retroviral INs interact directly with bromo- and extra-terminal domain (BET) proteins, including bromodomain proteins 2, 3 and 4 (REF.114–116).”

What the sources say

• Partly supported

  The Discussion (p. 6) states that BRD2, BRD3, and BRD4 interact with MLV integrase, and the binding assays in Figure 2 (p. 4) support a direct interaction with BET protein domains. The passages do not establish direct binding for integrases from other gammaretroviruses; that extension is unsupported by this paper's reported tests. (LLM, conf=0.85)

  cites [114] De Rijck, J. et al. The BET family of proteins targets moloney murine leukemia virus integration near transcription start sites. Cell Rep. 5, 886–894 (2013). sourceExperimental — accuracy not yet measured
• Supported

  The paper’s introductory summary states that the ET domains of BRD2, BRD3, and BRD4 physically interact with gammaretroviral integrases. The Results further show interaction with integrases from MLV and another gammaretrovirus, FeLV. Page numbers are not provided in our copy. (LLM, conf=0.94)

  cites [115] Gupta, S. S. et al. Bromo- and extraterminal domain chromatin regulators serve as cofactors for murine leukemia virus integration. J. Virol. 87, 12721–12736 (2013). source
• ?Not checked — no full text of the sourcecites [116] Sharma, A. et al. BET proteins promote efficient murine leukemia virus integration at transcription start sites. Proc. Natl Acad. Sci. USA 110, 12036–12041 (2013). source

In the paper

“Thus, lentiviruses have leveraged the juxtaposition of independent IN NTDs and CCDs to evolve a functional mimic of the cellular IBM.”

What the sources say

• Supported

  The Structural validation of the consensus motif section reports that the HIV-2 integrase–LEDGF/p75 interface overlaps with the cellular IBM interface: the integrase CCD occupies a hydrophobic pocket, while its NTD recognizes the basic surface. Figure 6 describes these as bipartite interfaces, and the Discussion says HIV-1 integrase evolved to bind a cellular protein similarly to its cellular partners. No page number is available in our copy. (LLM, conf=0.89)

  cites [113] Tesina, P. et al. Multiple cellular proteins interact with LEDGF/p75 through a conserved unstructured consensus motif. Nat. Commun. 6, 7968 (2015). source

In the paper

“The displaced vDNA nucleotide forms a stacking interaction with the metal chelating core of the inhibitor, greatly enhancing the strength of binding35,36,163.”

What the sources say

• Partly supported

  The passage on the DTG- and BIC-bound structures (labeled Abstract; page unavailable) says the displaced 3′ viral DNA nucleotide stacks against the inhibitor’s central body. It does not say that this stacking greatly strengthens binding; a separate passage attributes extraordinarily tight binding partly to interactions with Mg2+ ions. (LLM, conf=0.85)

  cites [35] Cook, N. J. et al. Structural basis of second-generation HIV integrase inhibitor action and viral resistance. Science 367, 806 (2020). High-resolution cryo-EM structures of simian immunodeficiency virus intasomes reveal the mechanism of INSTI resistance. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [36] Passos, D. O. et al. Structural basis for strand-transfer inhibitor binding to HIV intasomes. Science 367, 810 (2020). This study provides high-resolution cryo-EM structures of HIV-1 intasomes with several advanced INSTIs. source
• ?Not checked — no full text of the sourcecites [163] Langley, D. R. et al. The terminal (catalytic) adenosine of the HIV LTR controls the kinetics of binding and dissociation of HIV integrase strand transfer inhibitors. Biochemistry 47, 13481–13488 (2008). source

In the paper

“The latter three, classified as second-generation compounds, are characterized by reduced susceptibility to viral mutations that render the first-generation drugs, raltegravir and elvitegravir, ineffective151–153.”

What the sources say

• Supported

  The Results report that bictegravir, cabotegravir, and dolutegravir retained reasonable activity against raltegravir- and elvitegravir-resistant viruses, supporting the resistance comparison. The paper identifies dolutegravir as second-generation in a cited reference and describes bictegravir and cabotegravir as newer INSTIs, though it does not explicitly apply that label to all three. (LLM, conf=0.86)

  cites [151] Hassounah, S. A. et al. Antiviral activity of bictegravir and cabotegravir against integrase inhibitor-resistant SIVmac239 and HIV-1. Antimicrob. Agents Chemother. 61, e01695–17 (2017). source
• Supported

  The Discussion identifies DTG, BIC, and CAB as second-generation INSTIs and says they are generally much more effective against INSTI-resistant mutants than RAL and EVG. The results section on resistant double mutants likewise reports that all three retained potency where RAL and EVG did not. (LLM, conf=0.94)

  cites [152] Smith, S. J., Zhao, X. Z., Burke, T. R. Jr. & Hughes, S. H. Efficacies of cabotegravir and bictegravir against drug-resistant HIV-1 integrase mutants. Retrovirology 15, 37 (2018). source
• Partly supported

  The Results report that viruses with G140S/Q148H were highly resistant to raltegravir and elvitegravir but had relatively small susceptibility changes to dolutegravir, bictegravir, and cabotegravir. The claim is broader than that finding: the Results also show that additional mutations produced substantial resistance to all three newer inhibitors. (LLM, conf=0.85)

  cites [153] Zhang, W. W. et al. Accumulation of multiple mutations in vivo confers cross-resistance to new and existing integrase inhibitors. J. Infect. Dis. 218, 1773–1776 (2018). sourceExperimental — accuracy not yet measured

In the paper

“Strikingly, recent cross-linking immunoprecipitation experiments demonstrated that HIV-1 IN directly interacts with viral genomic RNA132,141.”

What the sources say

• Supported

  The Introduction states that HIV-1 integrase binds the viral RNA genome in virions. The Materials and methods section (“CLIP experiments”; page not supplied) describes UV-crosslinking virions and immunoprecipitating integrase–RNA complexes, supporting the citing sentence’s reference to cross-linking immunoprecipitation experiments. (LLM, conf=0.94)

  cites [132] Elliott, J. L. et al. Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis. eLife 9, e543111 (2020). source
• ?Not checked — no full text of the sourcecites [141] Kessl, J. J. et al. HIV-1 integrase binds the viral RNA genome and is essential during virion morphogenesis. Cell 166, 1257–1268 e1212 (2016). This study provides evidence that IN binding to viral RNA has a crucial role in RNA encapsidation, virus particle maturation and HIV-1 infection. source

In the paper

“At least in some cases, the class II phenotype was accompanied by premature proteolytic maturation, misfolding or perhaps mislocalisation of the mutant Gag-Pol polyprotein130,135,136.”

What the sources say

• ?Not checked — no full text of the sourcecites [130] Bukovsky, A. & Gottlinger, H. Lack of integrase can markedly affect human immunodeficiency virus type 1 particle production in the presence of an active viral protease. J. Virol. 70, 6820–6825 (1996). source
• Partly supported

  The Results (page unavailable) report abnormal Gag-Pol cleavage products in several class II mutants and suggest dysregulated protease activation as a cause of abnormal intracellular polyprotein processing. They do not establish misfolding or mislocalisation of mutant Gag-Pol; the misfolded-protein pathway discussed there concerns cleaved integrase, not Gag-Pol. (LLM, conf=0.86)

  cites [135] Mohammed, K. D., Topper, M. B. & Muesing, M. A. Sequential deletion of the integrase (Gag-Pol) carboxyl terminus reveals distinct phenotypic classes of defective HIV-1. J. Virol. 85, 4654–4666 (2011). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [136] Hoyte, A. C. et al. Resistance to pyridine-based inhibitor KF116 reveals an unexpected role of integrase in HIV-1 Gag-Pol polyprotein proteolytic processing. J. Biol. Chem. 292, 19814–19825 (2017). source

In the paper

“However, there are many examples of class II HIV-1 IN mutants that incorporated normal levels of mature viral proteins132.”

What the sources say

• Supported

  In Results, under “Characterization of the replication defects of class II IN mutant viruses” (page not provided), the authors report that many of the tested class II substitutions did not appear to affect IN or Gag-Pol levels in virions. They also report similar particle release across WT and mutant viruses, while identifying several mutants with reduced protein levels; the claim does not say all mutants were unaffected. (LLM, conf=0.90)

  cites [132] Elliott, J. L. et al. Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis. eLife 9, e543111 (2020). source

In the paper

“These data suggest that IN may have a role in organising RNA within infectious particles, which is not inconsistent with the proposed co-factor function during reverse transcription138.”

What the sources say

• Supported

  The citing authors present RNA organisation as their own inference; the citation supports the proposed role of integrase during reverse transcription. The IMPORTANCE section (p. 2) reports that disrupting the integrase–reverse transcriptase interaction impairs reverse transcription, and the DISCUSSION (p. 9) proposes that this complex is required in its early steps. (LLM, conf=0.89)

  cites [138] Tekeste, S. S. et al. Interaction between reverse transcriptase and integrase is required for reverse transcription during HIV-1 replication. J. Virol. 89, 12058–12069 (2015). source

In the paper

“Two recent studies described HIV-1 IN mutants with normal reverse transcription and integration, but delayed proviral expression19,21.”

What the sources say

• Partly supported

  The Results section on the transcription defect reports that expression from the QA mutant provirus was severely reduced at two days but reached wild-type levels by four days, supporting delayed expression. However, Fig. 1 in the Results reports approximately threefold fewer reverse-transcription products and a two- to threefold reduction in integrated provirus for some mutants; these steps were functional, not normal in abundance. The paper also found no delay in integration timing. (LLM, conf=0.90)

  cites [19] Winans, S. & Goff, S. P. Mutations altering acetylated residues in the CTD of HIV-1 integrase cause defects in proviral transcription at early times after integration of viral DNA. PLoS Pathog. 16, e1009147 (2020). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section reports that the E212A/L213A integrase mutant did not impair reverse transcription or integration and had reduced luciferase expression. It does not establish that proviral expression was merely delayed: expression remained considerably lower at 72 hours, even after the measured gap-repair efficiency matched wild type. The paper supports the finding for this mutant, but not the claim’s characterization of its expression as delayed. (LLM, conf=0.84)

  cites [21] Knyazhanskaya, E. et al. NHEJ pathway is involved in post-integrational DNA repair due to Ku70 binding to HIV-1 integrase. Retrovirology 16, 30 (2019). sourceExperimental — accuracy not yet measured

In the paper

“The mislocalisation of the viral genomic material provides an attractive explanation as to why class II mutants fail to synthetize normal levels of vDNA upon infection132.”

What the sources say

• Supported

  The Discussion (page unavailable in our copy) states that class II integrase mutants form eccentric virions blocked at reverse transcription and proposes premature degradation of exposed viral RNA and its separation from reverse transcriptase as the mechanism. This supports the citing sentence’s tentative explanation for reduced vDNA synthesis. (LLM, conf=0.94)

  cites [132] Elliott, J. L. et al. Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis. eLife 9, e543111 (2020). source

In the paper

“Examined class II HIV-1 IN mutant proteins failed to engage genomic RNA, though for varying reasons including defects in virion incorporation, tetramerization, and/or RNA binding132.”

What the sources say

• Partly supported

  The Introduction attributes loss of IN–viral RNA interaction to reduced or absent IN in virions, impaired tetramerization, or likely direct interference with RNA binding. However, the Results section “Class II IN mutants abolish IN binding to RNA” says nearly all tested mutants failed to bind viral RNA: E96A reduced binding but did not abolish it. The claim overstates the finding by saying the examined mutants all failed to engage RNA. (LLM, conf=0.88)

  cites [132] Elliott, J. L. et al. Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis. eLife 9, e543111 (2020). sourceExperimental — accuracy not yet measured

In the paper

“Accordingly, a recent report indicated that HIV-1 IN might persist on proviral DNA after integration19.”

What the sources say

• Supported

  In Results (page not supplied), the authors report more integrase associated with integrated proviral DNA than with unintegrated DNA and say their findings support its retention after integration. The Discussion also presents retention on proviral DNA as a possibility, matching the citing sentence’s cautious wording. (LLM, conf=0.94)

  cites [19] Winans, S. & Goff, S. P. Mutations altering acetylated residues in the CTD of HIV-1 integrase cause defects in proviral transcription at early times after integration of viral DNA. PLoS Pathog. 16, e1009147 (2020). source

In the paper

“Consistent with the known role of LEDGF/p75 in HIV-1 integration targeting, genic integration targeting during HIV-1 ingress was suppressed by ALLINIs177,184,185.”

What the sources say

• Supported

  In the comparative analyses section (page not provided), the paper reports that treating target cells with the ALLINI GS-B significantly reduced HIV-1 integration in active genes. This supports the claim about suppressed genic integration targeting during viral ingress. (LLM, conf=0.91)

  cites [177] Sharma, A. et al. A new class of multimerization selective inhibitors of HIV-1 integrase. PLoS Pathog. 10, e1004171 (2014). source
• ?Not checked — no full text of the sourcecites [184] Feng, L. et al. The competitive interplay between allosteric HIV-1 integrase inhibitor BI/D and LEDGF/p75 during the early stage of HIV-1 replication adversely affects inhibitor potency. ACS Chem. Biol. 11, 1313–1321 (2016). source
• Supported

  Section 3.3 reports that LEDGIN treatment shifted HIV-based vector integration out of transcription units in SupT1 cells, reducing the fraction of sites within RefSeq genes from 69.54% to 54.55% at 50 μM. The Fig. 3 caption describes a dose-dependent shift out of transcriptionally active regions when CX014442 was given during infection. The experiment used an HIV-based vector rather than a full HIV-1 infection. (LLM, conf=0.92)

  cites [185] Vranckx, L. S. et al. LEDGIN-mediated inhibition of integrase-LEDGF/p75 interaction reduces reactivation of residual latent HIV. EBioMedicine 8, 248–264 (2016). source

In the paper

“Accordingly, substitutions at these positions exert their effects by destabilizing the coordination spheres of the Mg2+ ion pair, indirectly affecting drug binding35.”

What the sources say

• Partly supported

  The passage on Q148H/G140S (labelled Abstract; no page given) says His148 disturbs the secondary coordination shell of Mg2+ ions and shifts the bound drug, supporting the mechanism for substitutions at Gln148. Our copy does not establish the same mechanism for substitutions at Asn155. (LLM, conf=0.88)

  cites [35] Cook, N. J. et al. Structural basis of second-generation HIV integrase inhibitor action and viral resistance. Science 367, 806 (2020). High-resolution cryo-EM structures of simian immunodeficiency virus intasomes reveal the mechanism of INSTI resistance. sourceExperimental — accuracy not yet measured

In the paper

“MINI compounds moreover were ineffective at inhibiting the early stage of HIV-1 infection177.”

What the sources say

• Supported

  The section headed “KF116 is not effective during early stages of HIV-1 replication” directly supports the claim. The paper reports that KF116 was about 2,000-fold less effective when added to target cells than when added to virus-producer cells; its weak early-stage activity occurred at concentrations well above the clinically relevant range. No page number is available in our copy. (LLM, conf=0.89)

  cites [177] Sharma, A. et al. A new class of multimerization selective inhibitors of HIV-1 integrase. PLoS Pathog. 10, e1004171 (2014). source

In the paper

“ALLINIs engage the LEDGF/p75 binding cleft at the IN CCD dimer interface, which is distal from the IN active site109,171.”

What the sources say

• Partly supported

  The Results and Discussion (page not available) place the LEDGF-binding site at the integrase CCD dimer interface and describe it as a potential small-molecule inhibitor target. The paper does not show that ALLINIs engage that cleft; it speculates about inhibitor binding and reports other compounds at or near the site. It identifies active sites separately but does not explicitly characterize the cleft as distal from them. (LLM, conf=0.88)

  cites [109] Cherepanov, P., Ambrosio, A. L., Rahman, S., Ellenberger, T. & Engelman, A. Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc. Natl Acad. Sci. USA 102, 17308–17313 (2005). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [171] Christ, F. et al. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat. Chem. Biol. 6, 442–448 (2010). source

In the paper

“Many, though not all, of the ensuing compounds effectively inhibit IN-LEDGF/p75 binding in vitro171,173–175.”

What the sources say

• ?Not checked — no full text of the sourcecites [171] Christ, F. et al. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat. Chem. Biol. 6, 442–448 (2010). source
• Partly supported

  The section describing tBPQAs competing with LEDGF for integrase binding reports that all three tested compounds, GS-A, GS-B and GS-C, inhibited the interaction in an in-vitro assay, with IC50 values of 19–228 nM (page unavailable in our copy). This supports effective inhibition by these compounds, but the paper does not establish the claim’s “though not all” qualification for the broader group of compounds. (LLM, conf=0.79)

  cites [173] Tsiang, M. et al. New class of HIV-1 integrase (IN) inhibitors with a dual mode of action. J. Biol. Chem. 287, 21189–21203 (2012). sourceExperimental — accuracy not yet measured
• Supported

  The Development of IN-LEDGF allosteric inhibitors section reports that seven compounds efficiently inhibited IN–LEDGF binding in laboratory assays, and that a subset of 51 compounds was assessed for inhibition of this interaction. This supports the cited sentence’s claim that many such compounds inhibit binding in vitro; the paper does not claim that all do. (LLM, conf=0.90)

  cites [174] Le Rouzic, E. et al. Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage. Retrovirology 10, 144 (2013). source
• Partly supported

  The section “GSK1264 Inhibits Binding of LEDGF(IBD) to IN F185K (CCD)” reports that GSK1264 disrupts the interaction in vitro and notes other compounds with similar activity. The Discussion reports that GSK1264 did not displace LEDGF from preformed complexes in vitro, but the paper does not establish that some ALLINI compounds fail to inhibit binding in the binding assay. No page numbers were available in our copy. (LLM, conf=0.82)

  cites [175] Gupta, K. et al. Allosteric inhibition of human immunodeficiency virus integrase: late block during viral replication and abnormal multimerization involving specific protein domains. J. Biol. Chem. 289, 20477–20488 (2014). sourceExperimental — accuracy not yet measured

In the paper

“Many ALLINIs were co-crystallised with the isolated HIV-1 IN CCD, and the structures revealed the molecules grip onto the LEDGF/p75 IBD binding pocket at the IN CCD dimerization interface171,172,174,175,180,186,187.”

What the sources say

• ?Not checked — no full text of the sourcecites [171] Christ, F. et al. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat. Chem. Biol. 6, 442–448 (2010). source
• ?Not checked — no full text of the sourcecites [172] Fader, L. D. et al. Discovery of BI 224436, a noncatalytic site integrase inhibitor (NCINI) of HIV-1. ACS Med. Chem. Lett. 5, 422–427 (2014). source
• Supported

  The Development of IN-LEDGF allosteric inhibitors section says Mut101 and several related inhibitors were co-crystallized with the IN-CCD dimer, showing that they bind at the LEDGF-binding site. The same section describes ligand-induced changes at the dimerization interface. (LLM, conf=0.91)

  cites [174] Le Rouzic, E. et al. Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage. Retrovirology 10, 144 (2013). source
• Supported

  The Abstract states that GSK1264 was studied with the isolated integrase CCD and bound the LEDGF/p75 binding site. The X-ray crystallography results locate it in a pocket at the CCD dimer interface and note similar positioning for other inhibitors. This paper provides one example of the structures described in the multiply cited sentence. (LLM, conf=0.92)

  cites [175] Gupta, K. et al. Allosteric inhibition of human immunodeficiency virus integrase: late block during viral replication and abnormal multimerization involving specific protein domains. J. Biol. Chem. 289, 20477–20488 (2014). source
• Partly supported

  The Introduction describes ALLINI binding in a pocket on the IN CCD dimer, supporting the general binding-location claim. The X-ray crystallography methods describe crystallization of isolated CCD, but do not say it was co-crystallized with ALLINIs; the cited passages also do not establish that many such structures show binding at the LEDGF/p75 IBD pocket. Pages are not available in our copy. (LLM, conf=0.78)

  cites [180] Koneru, P. C. et al. HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors. eLife 8, e46344 (2019). sourceExperimental — accuracy not yet measured
• Supported

  The Structure description (p. 6) reports crystallographic structures in which the allosteric inhibitors MUT-A and MUT-A03 bind the LEDGF/p75-binding pocket of the integrase CCD. The paper also identifies the inhibitor-binding site as part of the integrase dimer interface (p. 2). (LLM, conf=0.92)

  cites [186] Bonnard, D. et al. Structure-function analyses unravel distinct effects of allosteric inhibitors of HIV-1 integrase on viral maturation and integration. J. Biol. Chem. 293, 6172–6186 (2018). source
• ?Not checked — no full text of the sourcecites [187] Peese, K. M. et al. 5,6,7,8-Tetrahydro-1,6-naphthyridine derivatives as potent HIV-1-integrase-allosteric-site inhibitors. J. Med. Chem. 62, 1348–1361 (2019). source

In the paper

“Compounds of the latter class do not effectively antagonise HIV-1 IN-LEDGF/p75 binding.”

What the sources say

• Supported

  The Rational design of MINIs section states that the pyridine-based MINIs KF115 and KF116 promote integrase multimerization but are not effective inhibitors of IN–LEDGF/p75 binding. This directly supports the attributed claim. (LLM, conf=0.95)

  cites [177] Sharma, A. et al. A new class of multimerization selective inhibitors of HIV-1 integrase. PLoS Pathog. 10, e1004171 (2014). source

In the paper

“The common biochemical consequence of ALLINI binding is aberrant HIV-1 IN hyper-multimerization140,142,174–181.”

What the sources say

• ?Not checked — no full text of the sourcecites [140] Jurado, K. A. et al. Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation. Proc. Natl Acad. Sci. USA 110, 8690–8695 (2013). This is the first study to reveal that ALLINIs potently inhibit HIV-1 maturation. source
• Supported

  The Discussion (page not provided) says NCINIs promote nonproductive integrase multimerization, and the Introduction identifies ALLINIs as members of that inhibitor class. This supports the claimed biochemical consequence of ALLINI binding. (LLM, conf=0.90)

  cites [142] Balakrishnan, M. et al. Non-catalytic site HIV-1 integrase inhibitors disrupt core maturation and induce a reverse transcription block in target cells. PLoS ONE 8, e74163 (2013). source
• Supported

  The IN section says these inhibitors share an increase in integrase–integrase interaction that favors higher-order oligomerization. The Structural studies section also reports that inhibitor binding shifts integrase toward a higher oligomeric state. Page numbers are not provided in our copy. (LLM, conf=0.91)

  cites [174] Le Rouzic, E. et al. Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage. Retrovirology 10, 144 (2013). source
• Supported

  The Discussion identifies GSK1264 as an ALLINI, links this inhibitor group to integrase self-association, and reports that GSK1264 causes concentration- and time-dependent integrase polymerization into aggregates. The paper also describes increased integrase oligomerization with related molecules, supporting the claim as a general biochemical consequence rather than one unique to GSK1264. (LLM, conf=0.87)

  cites [175] Gupta, K. et al. Allosteric inhibition of human immunodeficiency virus integrase: late block during viral replication and abnormal multimerization involving specific protein domains. J. Biol. Chem. 289, 20477–20488 (2014). source
• Partly supported

  The Discussion reports that LEDGINs enhance HIV-1 integrase multimerization, supporting the claim for that inhibitor class. The Background distinguishes LEDGINs from the broader category of ALLINIs, which includes inhibitors with distinct mechanisms; this paper does not establish hyper-multimerization as a common consequence of ALLINI binding generally. No page numbers are available in our copy. (LLM, conf=0.86)

  cites [176] Desimmie, B. A. et al. LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions. Retrovirology 10, 57 (2013). sourceExperimental — accuracy not yet measured
• Supported

  The Introduction states that ALLINIs promote aberrant HIV-1 integrase multimerization as a mechanism of inhibition. The Rational design and structure-activity relationship studies section likewise says these compounds promote aberrant IN multimerization when binding at the integrase dimer interface. Page numbers are not provided in our copy. (LLM, conf=0.91)

  cites [177] Sharma, A. et al. A new class of multimerization selective inhibitors of HIV-1 integrase. PLoS Pathog. 10, e1004171 (2014). source
• Supported

  The Introduction (p. 2) says ALLINIs inhibit HIV-1 primarily by promoting aberrant, higher-order integrase multimers. The Conclusion (p. 6) likewise describes ALLINI binding as driving aberrant integrase multimerization, supporting the cited biochemical consequence. (LLM, conf=0.93)

  cites [178] Deng, N. et al. Allosteric HIV-1 integrase inhibitors promote aberrant protein multimerization by directly mediating inter-subunit interactions: structural and thermodynamic modeling studies. Protein Sci. 25, 1911–1917 (2016). source
• Supported

  The Results (Functional Analysis of the ALLINI-Binding Interface; page not provided) report that three ALLINIs promoted integrase aggregation. The Discussion describes inappropriate integrase polymerization and aggregation as the proposed common mode of ALLINI action. (LLM, conf=0.93)

  cites [179] Gupta, K. et al. Structural basis for inhibitor-induced aggregation of HIV Integrase. PLoS Biol. 14, e1002584 (2016). source
• Supported

  The Discussion describes ALLINI-induced higher-order multimerization of HIV-1 integrase in virions and refers to aberrant packaging of those multimers. The Results also report inhibitor-induced aggregation and higher-order multimerization, supporting the claimed biochemical consequence. The provided passages do not give page numbers. (LLM, conf=0.92)

  cites [180] Koneru, P. C. et al. HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors. eLife 8, e46344 (2019). source
• ?Not checked — no full text of the sourcecites [181] Gupta, K. et al. Allosteric HIV integrase inhibitors promote formation of inactive branched polymers via homomeric carboxy-terminal domain interactions. Structure 29, 213–225.e5 (2021). source

In the paper

“Under these conditions, it became clear that HIV-1 was more susceptible to ALLINIs when exposed to the compounds during egress as compared to ingress140,142,174–176.”

What the sources say

• ?Not checked — no full text of the sourcecites [140] Jurado, K. A. et al. Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation. Proc. Natl Acad. Sci. USA 110, 8690–8695 (2013). This is the first study to reveal that ALLINIs potently inhibit HIV-1 maturation. source
• Supported

  The Results section, “NCINIs Act Predominantly during the Late Stage of HIV Replication Cycle,” directly compares exposure during virus production with exposure during target-cell infection. It reports markedly reduced potency during target-cell infection, while exposure during virus production retained activity similar to the full-cycle assay. (LLM, conf=0.94)

  cites [142] Balakrishnan, M. et al. Non-catalytic site HIV-1 integrase inhibitors disrupt core maturation and induce a reverse transcription block in target cells. PLoS ONE 8, e74163 (2013). source
• Supported

  The Structural studies section (Figure 8; page not provided) states that INLAIs act more strongly after integration, during virus production, than at integration in target cells. It explains that LEDGF competes with the inhibitors in target-cell nuclei but not in the cytoplasm of virus-producing cells. (LLM, conf=0.93)

  cites [174] Le Rouzic, E. et al. Dual inhibition of HIV-1 replication by integrase-LEDGF allosteric inhibitors is predominant at the post-integration stage. Retrovirology 10, 144 (2013). source
• Supported

  The “Potent Inhibition of Late Replication” section reports an IC50 of 12 nM when virus-producing cells were treated with GSK1264, versus 557 nM when target cells were treated during infection. The paper describes this as a 46-fold difference in inhibition of late versus early infection, supporting the egress-versus-ingress comparison for the ALLINI tested. No page number is available in our copy. (LLM, conf=0.94)

  cites [175] Gupta, K. et al. Allosteric inhibition of human immunodeficiency virus integrase: late block during viral replication and abnormal multimerization involving specific protein domains. J. Biol. Chem. 289, 20477–20488 (2014). source
• Partly supported

  The ‘LEDGINs inhibit multiple steps in HIV replication’ section (page unavailable) reports a lower EC50 for CX05045’s late effect on progeny-virion infectivity (1.46 μM) than for its early effect on integration (4.45 μM). This supports greater susceptibility during late-stage exposure for that compound, but the paper does not establish the comparison for ALLINIs as a whole; its Background explicitly distinguishes the broader ALLINI category from LEDGINs. (LLM, conf=0.85)

  cites [176] Desimmie, B. A. et al. LEDGINs inhibit late stage HIV-1 replication by modulating integrase multimerization in the virions. Retrovirology 10, 57 (2013). sourceExperimental — accuracy not yet measured

In the paper

“Although the α-retroviral strand transfer intasome complex structure was solved by X-ray crystallography30, it seems highly doubtful, given their propensities to artificially stack upon one another in solution35,36, that primate lentiviral intasomes would ever crystallize.”

What the sources say

• Supported

  Citation 30 is attached to the claim that an alpharetroviral intasome structure was solved by X-ray crystallography, not to the later claim about primate lentiviral intasomes, which cites 35 and 36. The paper identifies RSV as an alpharetrovirus and reports crystallizing its intasome and determining its structure (Abstract, page unavailable). (LLM, conf=0.94)

  cites [30] Yin, Z. et al. Crystal structure of the Rous sarcoma virus intasome. Nature 530, 362–366 (2016). Together with Ballandras-Colas et al. (2016), these intasome structures first reveal the requirement for more than four IN protomers for functional integration. source
• Partly supported

  The paper reports prominent stacks in SIVrcm intasome preparations and describes how neighboring intasomes form them (Abstract; page not provided). It does not say that this stacking makes primate lentiviral intasomes unlikely to crystallize; that is the citing authors’ inference. (LLM, conf=0.84)

  cites [35] Cook, N. J. et al. Structural basis of second-generation HIV integrase inhibitor action and viral resistance. Science 367, 806 (2020). High-resolution cryo-EM structures of simian immunodeficiency virus intasomes reveal the mechanism of INSTI resistance. sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [36] Passos, D. O. et al. Structural basis for strand-transfer inhibitor binding to HIV intasomes. Science 367, 810 (2020). This study provides high-resolution cryo-EM structures of HIV-1 intasomes with several advanced INSTIs. source

In the paper

“Although highly potent compounds, ALLINIs to date have proven too toxic for in-depth clinical trials183, warranting attempts to develop safer compounds that can hopefully advance to the clinic.”

What the sources say

• Partly supported

  The Introduction and Discussion report that potent GS-9822 had urothelial toxicity in monkeys, halting its further advancement. They do not establish that ALLINIs as a class have proven too toxic for in-depth clinical trials: the Introduction says BI224436 reached a phase Ia trial without safety concerns at the reported doses, and the Discussion describes another candidate with no significant toxicity reported in rats or dogs. Page numbers are unavailable in our copy. (LLM, conf=0.87)

  cites [183] Bruggemans, A. et al. GS-9822, a preclinical LEDGIN candidate, displays a block-and-lock phenotype in cell culture. Antimicrob. Agents Chemother. 65, e02328–20 (2021). sourceExperimental — accuracy not yet measured

In the paper

“By leveraging the resolution revolution, subsequent single-particle cryo-EM structures of α-, β-, δ-retroviral and lentiviral intasomes revealed unexpected diversity among the number of IN molecules required to construct the active CIC30–33,37,38.”

What the sources say

• Partly supported

  The paper’s Abstract reports an octameric RSV intasome and contrasts it with a tetrameric PFV intasome, supporting diversity in integrase-molecule number. But its RSV structure was determined by crystallography, not single-particle cryo-EM; the paper mentions a cryo-EM structure of a beta-retroviral intasome but does not report the claimed subsequent cryo-EM structures across all four groups. (LLM, conf=0.88)

  cites [30] Yin, Z. et al. Crystal structure of the Rous sarcoma virus intasome. Nature 530, 362–366 (2016). Together with Ballandras-Colas et al. (2016), these intasome structures first reveal the requirement for more than four IN protomers for functional integration. sourceExperimental — accuracy not yet measured
• Supported

  This paper supports the β-retroviral part of the multi-citation sentence. Its Abstract describes a single-particle cryo-EM structure of the MMTV intasome with eight integrase molecules and contrasts it with the PFV intasome, for which four suffice. The other retroviral groups in the sentence are not attributed to this citation alone. (LLM, conf=0.91)

  cites [31] Ballandras-Colas, A. et al. Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function. Nature 530, 358–361 (2016). source
• Supported

  The Abstract reports a cryo-EM structure of a lentiviral intasome containing 16 integrase subunits. The passage beginning “Integrase (IN) acts” contrasts this architecture with previously characterized retroviral intasomes containing fewer subunits, supporting the claimed diversity. This source supplies the lentiviral example among the sentence’s multiple citations. (LLM, conf=0.91)

  cites [32] Ballandras-Colas, A. et al. A supramolecular assembly mediates lentiviral DNA integration. Science 355, 93–95 (2017). Cryo-EM structures of intasomes derived from the sheep lentivirus MVV reveal a higher-order macromolecular machine composed of 16 IN protomers and define the conserved intasome core shared by all retroviral intasome structures. source
• ?Not checked — no full text of the sourcecites [33] Passos, D. O. et al. Cryo-EM structures and atomic model of the HIV-1 strand transfer complex intasome. Science 355, 89–92 (2017). Initial cryo-EM structures of HIV-1 strand transfer complex intasomes reveal a higher-order IN dodecamer architecture. source
• Supported

  The Introduction reports that structural studies found markedly different integrase counts in alpha-, beta- and lentiviral intasomes. The Results (Structure determination of the HTLV-1 intasome) add a single-particle cryo-EM structure of a deltaretroviral intasome containing an integrase tetramer, supporting the cited paper’s contribution to the broader claim. (LLM, conf=0.88)

  cites [37] Bhatt, V. et al. Structural basis of host protein hijacking in human T-cell leukemia virus integration. Nat. Commun. 11, 3121 (2020). Together with Barski et al. (2020), cryo-EM studies reveal that deltaretrovirus intasomes are composed of IN tetramers and visualize details of the IN–PP2A interface. source
• Supported

  The Introduction describes tetrameric, octameric, and dodeca-/hexadecameric integrase assemblies across retroviral genera. The Architecture section reports a cryo-EM reconstruction of the deltaretroviral intasome, and the Discussion identifies its tetrameric architecture. This paper thus supports the deltaretroviral example and the stated diversity in integrase numbers. (LLM, conf=0.90)

  cites [38] Barski, M. S. et al. Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ. Nat. Commun. 11, 5043 (2020). source

In the paper

“Some of the residues that line the ALLINI binding pocket are highly polymorphic among circulating HIV-1 strains, inspiring efforts to design molecules that remain active in the face of such amino acid sequence variability186,187.”

What the sources say

• Supported

  The section on MUT-A activity (p. 3) identifies integrase residues 124 and 125 as highly polymorphic and located at the edge of the inhibitor-binding pocket; its Table 2 shows their variation across HIV-1 clades. The discussion (p. 10) says this variation makes it important to test inhibitor sensitivity and describes efforts to address it through compound optimization. (LLM, conf=0.94)

  cites [186] Bonnard, D. et al. Structure-function analyses unravel distinct effects of allosteric inhibitors of HIV-1 integrase on viral maturation and integration. J. Biol. Chem. 293, 6172–6186 (2018). source
• ?Not checked — no full text of the sourcecites [187] Peese, K. M. et al. 5,6,7,8-Tetrahydro-1,6-naphthyridine derivatives as potent HIV-1-integrase-allosteric-site inhibitors. J. Med. Chem. 62, 1348–1361 (2019). source

In the paper

“Resistance to ALLINIs maps to the IN CCD dimer interface in the vicinity of the LEDGF/p75 binding site171,173,179,182,188.”

What the sources say

• ?Not checked — no full text of the sourcecites [171] Christ, F. et al. Rational design of small-molecule inhibitors of the LEDGF/p75-integrase interaction and HIV replication. Nat. Chem. Biol. 6, 442–448 (2010). source
• Supported

  In “IN Inhibitors with Dual Mode of Action,” the paper reports that resistance-associated mutations selected during viral passaging occurred at the integrase dimer interface that forms the LEDGF binding pocket. It also reports that the compounds bind that pocket in the IN catalytic core domain dimer. (LLM, conf=0.94)

  cites [173] Tsiang, M. et al. New class of HIV-1 integrase (IN) inhibitors with a dual mode of action. J. Biol. Chem. 287, 21189–21203 (2012). source
• Partly supported

  The Introduction places the LEDGF/p75 binding site at the integrase catalytic core domain (CCD) dimer interface, and the Discussion identifies some ALLINI-resistance substitutions that likely interfere with inhibitor binding there. But the Discussion also identifies resistance substitutions affecting the CCD–CTD interaction or residing in the N-terminal domain, so the claim overstates where resistance maps. Our copy provides section labels but no page numbers. (LLM, conf=0.86)

  cites [179] Gupta, K. et al. Structural basis for inhibitor-induced aggregation of HIV Integrase. PLoS Biol. 14, e1002584 (2016). sourceExperimental — accuracy not yet measured
• Partly supported

  The Resistance profile and spectrum of activity of MUT-A section reports that most tested resistance mutations lie in the integrase catalytic core domain (CCD), close to the inhibitor binding site; the Background identifies that site as the LEDGF binding pocket. The copy does not locate those mutations specifically at the CCD dimer interface, and it notes an exception, N222K, in the C-terminal domain. (LLM, conf=0.84)

  cites [182] Amadori, C. et al. The HIV-1 integrase-LEDGF allosteric inhibitor MUT-A: resistance profile, impairment of virus maturation and infectivity but without influence on RNA packaging or virus immunoreactivity. Retrovirology 14, 50 (2017). sourceExperimental — accuracy not yet measured
• Supported

  The Discussion reports that resistance variants selected with BI 224436 map near an allosteric pocket in the integrase catalytic core, with A128 at the edge of the LEDGF binding site. The Results locate that pocket at the catalytic-core dimer interface, and the Discussion notes similar mutations reported for related inhibitors. Page numbers were not available in our copy. (LLM, conf=0.89)

  cites [188] Fenwick, C. et al. Preclinical profile of BI 224436, a novel HIV-1 non-catalytic-site integrase inhibitor. Antimicrob. Agents Chemother. 58, 3233–3244 (2014). source

In the paper

“Solution measurements using mass spectrometry footprinting techniques, mutagenesis and computational chemistry strongly support this mode of IN aggregation by ALLINIs178,189.”

What the sources say

• Supported

  The Introduction (p. 2) says the authors incorporated HDX–mass spectrometry measurements into computational docking models that account for experimental observations about ALLINI-induced multimerization. The Results and Discussion (pp. 2, 5) report HDX protection patterns and mutations consistent with the proposed CCD–CTD interface. The paper presents this mode as a supported hypothesis, not a directly observed structure. (LLM, conf=0.88)

  cites [178] Deng, N. et al. Allosteric HIV-1 integrase inhibitors promote aberrant protein multimerization by directly mediating inter-subunit interactions: structural and thermodynamic modeling studies. Protein Sci. 25, 1911–1917 (2016). source
• Partly supported

  The Results and Discussion report MS-based footprinting, tests of integrase mutants, and ALLINI-2-induced higher-order multimerization. The Discussion interprets these findings using structural models, but the passages do not establish that this paper performed computational chemistry; that part of the attributed claim is not supported by our copy. (LLM, conf=0.83)

  cites [189] Shkriabai, N. et al. A critical role of the C-terminal segment for allosteric inhibitor-induced aberrant multimerization of HIV-1 integrase. J. Biol. Chem. 289, 26430–26440 (2014). sourceExperimental — accuracy not yet measured

In the paper

“The carboxylate establishes a bidentate hydrogen bond with main chain amides of IN Glu170 and His171, perfectly recuperating the interactions made by Asp366 of LEDGF/p75 (Fig. 6C)109.”

What the sources say

• Partly supported

  The Results and Discussion section (page unavailable) reports that LEDGF/p75 Asp-366 forms a bidentate hydrogen bond with the main-chain amides of integrase Glu-170 and His-171. It does not establish that an ALLINI carboxylate makes the same bonds; its discussion of a small-molecule inhibitor is speculative. (LLM, conf=0.90)

  cites [109] Cherepanov, P., Ambrosio, A. L., Rahman, S., Ellenberger, T. & Engelman, A. Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc. Natl Acad. Sci. USA 102, 17308–17313 (2005). sourceExperimental — accuracy not yet measured

In the paper

“Recent work uncovered surprising differences between mechanisms involved in targeting retroviral integration, even within a single genus87.”

What the sources say

• Supported

  The Introduction reports that only primate lentiviruses show a marked CPSF6-dependent preference to integrate into speckle-associated domains, while LEDGF/p75 plays a similar role across the lentiviruses studied. The Discussion attributes the difference between primate and nonprimate lentiviruses to the capsid–CPSF6 interaction. Both groups are within the lentivirus genus, supporting the citing sentence. (LLM, conf=0.93)

  cites [87] Li, W. et al. CPSF6-dependent targeting of speckle-associated domains distinguishes primate from nonprimate lentiviral integration. mBio 11, e02254-20 (2020). source

In the paper

“The absence of structural similarity between ALLINIs outside of the common warhead (Fig. 6A) likely contributes to differential IN aggregation mechanisms reported for some of these compounds180, calling for more research and development of this fascinating class of antiviral agents.”

What the sources say

• Supported

  The Introduction identifies a conserved ALLINI pharmacophore alongside structurally distinct pyridine- and quinoline-based compounds. The Discussion links distinct contacts made by KF116 and BI224436 to possible differences in how they assemble integrase multimers, matching the claim’s qualified explanation. (LLM, conf=0.91)

  cites [180] Koneru, P. C. et al. HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors. eLife 8, e46344 (2019). source