Structure and function of retroviral integrase

In the paper

“Although ALLINIs have yet to advance in clinical trials, several compounds display exquisite low-nM potencies to inhibit HIV-1 replication in vitro172,180,182,183.”

What the sources say

• ?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
• Partly supported

  The Introduction reports low-nanomolar antiviral activity for BI224436 (~14 nM) and racemic KF116 (~24 nM), and the Results report ~7 nM for (-)-KF116 against HIV-1 in cell culture. The Discussion describes translation of ALLINIs from the lab to the clinic as future work, but does not establish that none had advanced to clinical trials. (LLM, conf=0.84)

  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 Background identifies ALLINIs and INLAIs as names for the same inhibitor class and describes it as under preclinical development. The Biochemical and antiretroviral activity section reports low-nanomolar HIV-1 replication EC50 values for MUT-A (12–32 nM); the paper also gives 45 nM for BI-224436 in its resistance-profile data. These passages support the sentence’s characterization of the compounds’ potency and development stage. (LLM, conf=0.85)

  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). source
• Disputed

  The Introduction reports low-nanomolar in vitro antiviral activity for BI224436, supporting the potency portion of the claim. But it also says BI224436 was the first LEDGIN to advance into phase Ia clinical trials, directly contradicting the assertion that none had advanced to clinical trials. No page number is available in our copy. (LLM, conf=0.94)

  Checked by a reasoning model — may be wrong.

  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

“Within the CIC, the IN dimers are bridged via the exchange of associated NTDs and are joined by a pair of CTDs (referred to as the synaptic CTDs), which act as rigid spacers.”

What the sources say

• Partly supported

  In “Crystallization of the PFV intasome” (page unavailable), the paper says the dimer–dimer interface is stabilized by NTD–CCD interactions. “Overall architecture of the PFV intasome” (page unavailable) describes a pair of CTDs interacting with both inner CCDs and a well-constrained assembled structure. Our copy does not describe NTD exchange or call the CTDs rigid spacers. (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

“The expansion of the intasome architecture in these viruses is dictated by three factors.”

What the sources say

• Partly supported

  The discussion passage (indexed as Abstract; page unavailable) links the larger MMTV intasome to its short CCD–CTD linker and the need for flanking integrase dimers to supply CTDs. It also predicts an octamer for α-retroviruses, but treats the architecture of active lentiviral intasomes as uncertain. The paper does not identify the integrase multimeric state before assembly as a determining factor or establish the proposed three-factor rule across all three groups. (LLM, conf=0.86)

  cites [31] Ballandras-Colas, A. et al. Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function. Nature 530, 358–361 (2016). sourceExperimental — accuracy not yet measured
• ?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 section “Structure of the HIV-1 CSC intasome assembled with P5-IN” (page unavailable) describes different intasome assemblies and compares HIV-1 intasomes with those of other retroviruses. It does not identify CCD–CTD linker length, integrase’s pre-assembly multimeric state, and C-terminal domain properties as three factors dictating architectural expansion. (LLM, conf=0.82)

  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 Results and Discussion (pages unavailable) link the integrase C-terminal domain and tail to RSV intasome assembly and describe a transition from tetrameric to octameric complexes. The paper also discusses distal integrase dimers in RSV and MMTV. It does not establish that CCD–CTD linker length or integrase’s pre-assembly multimeric state dictates architectural expansion across alpha-, beta-retroviruses and lentiviruses, or present those features as a definitive three-factor account. (LLM, conf=0.85)

  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). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [40] McCord, M. et al. Purification of recombinant Rous sarcoma virus integrase possessing physical and catalytic properties similar to virion-derived integrase. Protein Expr. Purif. 14, 167–177 (1998). source
• ?Could not verify

  The Introduction discusses flexible linkers between integrase domains, and the Discussion proposes that integrase monomers may be intermediates in intasome assembly. Neither passage addresses expansion of intasome architecture or says it is dictated by CCD–CTD linker length, pre-assembly multimeric state, and C-terminal domain properties. Searches for those architectural factors found no passage establishing the claim. (LLM, conf=0.72)

  cites [41] Ballandras-Colas, A., Naraharisetty, H., Li, X., Serrao, E. & Engelman, A. Biochemical characterization of novel retroviral integrase proteins. PLoS ONE 8, e76638 (2013). sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Introduction discusses integrase domains and multimerization, while the Discussion describes CCD–CTD linker flexibility and says CTD positions in the tetramer cannot be inferred from the available partial structures. Neither section identifies the three proposed determinants of intasome architecture or compares architectural expansion across alpha-, beta-retroviruses and lentiviruses. Searched for the three factors, linker length, pre-assembly multimeric state, and intasome expansion. (LLM, conf=0.72)

  cites [42] Hare, S. et al. Structural basis for functional tetramerization of lentiviral integrase. PLoS Pathog. 5, e1000515 (2009). 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 [44] Lodi, P. J. et al. Solution structure of the DNA binding domain of HIV-1 integrase. Biochemistry 34, 9826–9833 (1995). source

In the paper

“The intasome from maedi-visna virus (MVV, a lentivirus), containing sixteen IN subunits (a tetramer-of-tetramers), is the largest characterized to date32.”

What the sources say

• Supported

  The Abstract describes the MVV intasome as a homo-hexadecamer of integrase with a tetramer-of-tetramers architecture. It also says the assembly is much larger than any previously characterized retroviral intasome. (LLM, conf=0.93)

  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

In the paper

“It is estimated that a mature HIV-1 virion contains about 120 copies of IN protein8,9.”

What the sources say

• ?Not checked — no full text of the sourcecites [8] Jacks, T. et al. Characterization of ribosomal frameshifting in HIV-1 gag-pol expression. Nature 331, 280–283 (1988). source
• Supported

  The Discussion estimates approximately 120 integrase molecules for a virion with a 66 nm radius. It also notes that the estimate depends on virion size, giving approximately 150 for a 73 nm radius. (LLM, conf=0.91)

  cites [9] Carlson, L. A. et al. Three-dimensional analysis of budding sites and released virus suggests a revised model for HIV-1 morphogenesis. Cell Host Microbe 4, 592–599 (2008). source

In the paper

“Despite these differences, all intasomes incorporate the conserved intasome core (CIC) assembly, which is the minimal functional unit and is represented by the PFV structure (Figs. 2A, 3).”

What the sources say

• Partly supported

  The Crystallization and Overall architecture sections describe the PFV intasome structure, and the latter suggests that the HIV-1 intasome could have a similar architecture. But the paper does not establish that all intasomes contain a conserved core assembly or that the PFV structure represents a universally minimal functional unit; it calls the integrase–viral DNA complex the minimal functional complex. (LLM, conf=0.84)

  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 (page unavailable) reports crystal structures of the PFV intasome and describes its integrase tetramer assembled on viral DNA ends. It does not establish that all intasomes contain a conserved intasome core or that this core is the minimal functional unit. (LLM, conf=0.85)

  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 section comparing RSV and PFV intasomes (page not provided) says the four-integrase PFV intasome corresponds to the core tetramer of the eight-integrase RSV intasome. It does not establish that all intasomes contain this assembly or explicitly identify it as the minimal functional unit. (LLM, conf=0.84)

  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
• Partly supported

  The paper’s Abstract says the MMTV intasome has a core that structurally mimics the PFV tetramer, supporting the shared-core comparison. But it also says the flanking dimers are necessary for MMTV integrase activity, so the core alone is not a minimal functional unit for MMTV. The copy does not establish the claim for all intasomes; page numbers are not provided. (LLM, conf=0.90)

  cites [31] Ballandras-Colas, A. et al. Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function. Nature 530, 358–361 (2016). sourceExperimental — accuracy not yet measured
• Supported

  The Abstract (page not supplied) describes the conserved intasome core as minimally comprising a pair of integrase dimers, as in the PFV intasome. It also identifies that core in the lentiviral intasome, supporting the claim despite differences in overall architecture. (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 section “Structure of the HIV-1 CSC intasome assembled with P5-IN” (page not provided) says the CIC is conserved among all intasome structures determined to date. It does not identify the CIC as the minimal functional unit or say that the PFV structure represents it; its mention of prototype foamy virus concerns drug-interaction modeling. (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 passage labeled Abstract describes a conserved intasome core in the SIVrcm structure and refers to PFV intasome crystals. It does not state that every intasome contains that assembly, that the core is the minimal functional unit, or that the PFV structure represents it. (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
• Partly supported

  The Results section (“IN tetramer in the HTLV-1 intasome”; page unavailable) says the HTLV-1 intasome shares a conserved intasome core with assemblies from other retroviral genera. The Introduction describes the PFV intasome as tetrameric, but the paper does not identify the PFV structure as the representation of that core or call the core the minimal functional unit. (LLM, conf=0.82)

  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

In the paper

“Consistent with their function, all intasomes feature 2-fold symmetry and harbour a pair of juxtaposed active sites engaged with 3’ vDNA ends.”

What the sources say

• Partly supported

  The sections on PFV intasome crystallization and target-DNA binding describe symmetry-related integrase dimers and two active sites engaged with viral-DNA 3′ ends. But the paper determines the structure of a prototype foamy virus intasome; its discussion of a similar HIV-1 architecture is based on modeling. It does not establish that all retroviral intasomes have this architecture. (LLM, conf=0.86)

  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 Methods Summary (page unavailable) describes the crystallized prototype foamy virus (PFV) intasome as a two-fold symmetric assembly. The paper’s main text (indexed under Abstract; page unavailable) places the viral DNA 3′-hydroxyl at an active site and describes the two inner integrase active sites. These observations support the description for PFV, but the paper does not establish that all retroviral intasomes have this architecture. (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
• Partly supported

  The RSV structure description (section labeled Abstract; page unavailable) reports an approximately two-fold symmetrical arrangement, with catalytic subunits engaging viral DNA ends. The paper also compares RSV with PFV, but it does not establish that every retroviral intasome has this arrangement; the claim’s “all” is broader than the evidence. (LLM, conf=0.84)

  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
• Partly supported

  The paper’s structure comparison (section labelled Abstract; no page given) describes two catalytic integrase dimers contacting two viral DNA molecules and reports that the active sites in the MMTV and PFV intasomes align closely. Our copy does not state that all retroviral intasomes have twofold symmetry or that their active sites engage specifically the 3′ viral DNA ends, so those universal and positional details are not established by this source. (LLM, conf=0.78)

  cites [31] Ballandras-Colas, A. et al. Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function. Nature 530, 358–361 (2016). sourceExperimental — accuracy not yet measured
• Partly supported

  The copy describes the maedi-visna virus intasome as two-fold symmetric and places each recessed 3′ viral-DNA end in an integrase active site (Abstract; page not given). It also describes a conserved core in several characterized retroviral intasomes, but does not establish that every retroviral intasome has this symmetry and active-site arrangement. (LLM, conf=0.82)

  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. sourceExperimental — accuracy not yet measured
• ?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 describes intasomes as complexes involving a pair of viral DNA ends, and the structural-results section says a conserved core occurs in all intasome structures determined to date. The Methods report imposing C2 symmetry when refining this HIV-1 intasome, but the copy does not establish that all retroviral intasomes have 2-fold symmetry or explicitly describe a pair of juxtaposed active sites engaged with the 3′ ends. Page numbers are unavailable in our copy. (LLM, conf=0.78)

  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 labelled Abstract (page not provided) describes a SIVrcm intasome model with two IN tetramers and associated viral DNA ends, and another passage describes DNA-bound integrase active sites. These support the claim’s structural context, but our copy does not state that all retroviral intasomes have 2-fold symmetry or explicitly describe a pair of juxtaposed active sites. (LLM, conf=0.78)

  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
• Partly supported

  The Results section (‘IN tetramer in the HTLV-1 intasome’; page unavailable) describes a twofold-symmetric HTLV-1 intasome with two catalytic subunits engaging viral DNA junctions and says it shares a conserved core with intasomes from other retroviral genera. It does not establish that all retroviral intasomes have this symmetry or explicitly describe their active sites as engaged with 3′ viral DNA ends. (LLM, conf=0.82)

  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

In the paper

“HIV-1 IN cuts target DNA with a 5-bp spacing, and subsequent analyses revealed the RYNRY consensus at the centre of these sites, which would secure a malleable YR dinucleotide close to the middle of the integration site regardless of the central nucleotide’s identity56.”

What the sources say

• Supported

  The Introduction describes a staggered target-DNA cut that produces a 5-bp duplication in HIV-1. The Abstract and Sequence analysis of in vitro integration products report a central RYXRY preference; the sequence analysis explains that it places a flexible YR dinucleotide on one side or the other of the central base, depending on that base’s identity. Page numbers are unavailable in our copy. (LLM, conf=0.92)

  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

In the paper

“PFV and MLV INs cut the target DNA major groove with 4-bp spacings and strongly disfavour rigid purine/pyrimidine (RY) dinucleotides at the centres of their integration sites29,55.”

What the sources say

• Partly supported

  The paper’s PFV results describe a widened target-DNA major groove and enrichment of flexible YR steps at the integration-site centre; the Methods report a 4-bp target-site duplication. But the explicit increased bias against rigid RY steps is for an R329S PFV integrase mutant, not wild-type PFV, and the cited passages do not establish the same RY preference or cutting geometry for MLV. Page numbers are unavailable in our copy. (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
• Partly supported

  The Results section on target-DNA binding and Figure 8 state that PFV and MLV produce 4-bp target-site duplications, classify RY dinucleotides as rigid, and report a flexible central dinucleotide preference for wild-type MLV. The passages do not establish that both integrases strongly disfavor central RY dinucleotides, and they do not describe cleavage as occurring in the target DNA major groove. No page numbers are available in our copy. (LLM, conf=0.85)

  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). sourceExperimental — accuracy not yet measured

In the paper

“The IN active site contains three acidic residues comprising the essential D,D-35-E motif, and even conservative substitutions of these residues ablate the enzymatic functions.”

What the sources say

• Partly supported

  The Introduction identifies three invariant acidic residues as the D,D-35-E motif and says their carboxylates coordinate metal ions essential for both enzymatic activities. Our copy does not state that conservative substitutions of those residues abolish enzymatic function; searches for that assertion and for mutations of Asp128, Asp185, and Glu221 did not find it. (LLM, conf=0.88)

  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

“In this pre-reaction state, both active site metal ions (designated A and B, Fig. 2B) interact with the scissile phosphodiester bond. While Mn2+ ion A, which interacts with the water nucleophile, exists in a near perfect coordination geometry, the coordination of metal B deviates significantly from the ideal, potentially promoting destabilization of the scissile phosphodiester28,47,48.”

What the sources say

• Supported

  Split into 2 atoms — 2 confirmed, 0 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  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
• Partly supported

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  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

  Split into 2 atoms — 1 confirmed, 1 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  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

“A pair of metal ions interact with the scissile phosphodiester, and it is metal B that coordinates the vDNA 3’-hydroxyl nucleophile for in-line nucleophilic substitution (Fig. 2B).”

What the sources say

• Supported

  In “Target DNA binding and strand transfer,” the paper says the target phosphodiester’s pro-S oxygen is shared between the two metal ions, metal B binds the viral DNA 3′-hydroxyl, and that hydroxyl is poised for in-line attack. This supports the claim for the strand-transfer reaction. (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

“In CPSF6 knockout cells, PICs congregated at the nuclear periphery and uncharacteristically targeted LADs for integration while losing the preference for SPADs84,85.”

What the sources say

• Partly supported

  The Results section ('HIV-1 integrates into speckle-associated genomic DNA'; page unavailable) reports that HIV-1 disfavored SPAD integration in CPSF6-knockout cells. The Discussion (page unavailable) says CPSF6-negative recurrent integration genes associate with LADs at the nuclear periphery, citing a prior report. These passages do not establish that pre-integration complexes congregated at the nuclear periphery in knockout cells or that knockout cells broadly targeted LADs for integration. (LLM, conf=0.84)

  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
• Partly supported

  The Results sections on intranuclear localization and LAD integration report that PIC-associated signals were enriched at the nuclear periphery in CPSF6-knockout cells and that LADs became preferred integration targets. Our copy does not report SPAD integration targeting or establish a loss of SPAD preference; its Discussion mentions trafficking to speckles but not that specific result. Page numbers are unavailable in the indexed copy. (LLM, conf=0.88)

  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). sourceExperimental — accuracy not yet measured

In the paper

“Under normal infection conditions, HIV-1 PICs colocalized with nuclear speckles and strongly favoured SPADs for integration while avoiding LADs84.”

What the sources say

• Partly supported

  The Results section (‘HIV-1 integrates into speckle-associated genomic DNA’; page unavailable) reports that HIV-1 replication complexes accumulate in nuclear speckles and that integration strongly favors SPADs across cell types. The Discussion mentions LAD association for recurrent integration genes in the absence of CA–CPSF6 interaction, but does not establish that HIV-1 avoids LADs under normal infection conditions. (LLM, conf=0.86)

  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

In the paper

“The R540Q substitution in PFV Gag, which altered an Arg residue conserved across this group of H2A/H2B binding proteins, decoupled CBS-nucleosome binding in vitro and redirected a large portion of PFV integration events into centromeres92.”

What the sources say

• Supported

  The in vitro nucleosome-binding experiments (p. 2) report that substituting PFV Gag Arg540 abolished binding by the CBS peptide or full-length protein. The same page identifies R540Q as the PFV Arg-anchor mutation, and the integration-site analysis (p. 3) reports a massive redistribution toward centromeres across all studied cell lines. (LLM, conf=0.90)

  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

“Interestingly, non-primate lentiviruses displayed minimal preferences for integrating into SPADs, and the respective capsid proteins did not bind CPSF6 (REF.87).”

What the sources say

• Supported

  The Discussion reports that the nonprimate lentiviruses studied targeted SPADs at comparatively low frequencies. It also says CPSF6 did not meaningfully interact with FIV, BIV, or EIAV capsids, supporting the claim's binding paraphrase for those viruses. (LLM, conf=0.90)

  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 LEDGF/p75 PWWP domain can bind nucleosomes in vitro that are modified to carry a chemical mimic of trimethylated lysine at position 36 of the histone H3 tail (H3K36me3)110,111, and spatial distribution of LEDGF/p75 on chromatin coincided with H3K36me2 and H3K36me3 epigenetic marks102.”

What the sources say

• Supported

  The Methods describe preparing mononucleosomes with a trimethyl-lysine analogue at H3 position 36. The Results section ‘LEDGF PWWP tightly binds H3KC36me3 MNs’ reports that the LEDGF PWWP domain bound those reconstituted nucleosomes in vitro. The chromatin-distribution statement is attached to citation 102, not this source, so it is not part of this verdict. (LLM, conf=0.94)

  cites [110] Eidahl, J. O. et al. Structural basis for high-affinity binding of LEDGF PWWP to mononucleosomes. Nucleic Acids Res. 41, 3924–3936 (2013). source
• Supported

  The Results (‘Linker DNA stabilizes LEDGF binding to a modified nucleosome’) report binding to recombinant nucleosomes carrying a chemical H3K36me3 mimic. The cryo-EM Results identify the bound LEDGF PWWP domain. The separate claim about chromatin distribution is attached to citation 102, not this source, and is not part of this verdict. (LLM, conf=0.93)

  cites [111] Wang, H., Farnung, L., Dienemann, C. & Cramer, P. Structure of H3K36-methylated nucleosome-PWWP complex reveals multivalent cross-gyre binding. Nat. Struct. Mol. Biol. 27, 8–13 (2020). source
• Partly supported

  The citation to this paper is attached to the chromatin-distribution clause, not the preceding in-vitro binding clause. In the Results (page not provided), LEDGF localization is reported to correlate with H3K36me2; the paper does not report the same spatial correlation with H3K36me3, and its ChIP-MS results identify H3K36me3 enrichment for HDGF2 rather than LEDGF. (LLM, conf=0.84)

  cites [102] LeRoy, G. et al. LEDGF and HDGF2 relieve the nucleosome-induced barrier to transcription in differentiated cells. Sci. Adv. 5, eaay3068 (2019). sourceExperimental — accuracy not yet measured

In the paper

“LEDGF/p75 has been shown to bind several pre-mRNA splicing factors and to assist transcriptional elongation on chromatinized DNA in vitro100,102.”

What the sources say

• Partly supported

  The Results section (‘LEDGF interacts with mRNA splicing machinery’; page unavailable) reports that several splicing factors bind LEDGF/p75. The passages in our copy do not establish that LEDGF/p75 assists transcriptional elongation on chromatinized DNA in vitro; searches for ‘chromatinized’ and ‘elongation’ did not locate that finding. (LLM, conf=0.86)

  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
• Partly supported

  The Results (page not specified) report that purified LEDGF/p75 enabled RNA polymerase II to transcribe through nucleosomes in a reconstituted in vitro assay. The paper does not report p75 binding pre-mRNA splicing factors; its References instead list a study about splicing-factor binding by the distinct p52 isoform. (LLM, conf=0.88)

  cites [102] LeRoy, G. et al. LEDGF and HDGF2 relieve the nucleosome-induced barrier to transcription in differentiated cells. Sci. Adv. 5, eaay3068 (2019). sourceExperimental — accuracy not yet measured

In the paper

“B56 (also called B’ or PR61), a regulatory subunit of protein phosphatase 2A, significantly stimulated δ-retroviral IN124, while purified histone chaperone FACT complex facilitated ASLV IN activity in vitro125.”

What the sources say

• Supported

  The citation to this paper is attached to the B56/PP2A clause, not the separate FACT/ASLV clause. The Abstract identifies B′ as a PP2A regulatory-subunit family and reports that it stimulates δ-retroviral integrase activity in vitro; the Results section reports significant stimulation of HTLV integrase by B′γ. (LLM, conf=0.93)

  cites [124] Maertens, G. N. B′-protein phosphatase 2A is a functional binding partner of delta-retroviral integrase. Nucleic Acids Res. 44, 364–376 (2016). source
• Supported

  Citation 125 is attached to the FACT clause, not the separate B56 clause cited to 124. The Results report that purified FACT components together stimulated ALV integrase activity in vitro; the Discussion identifies FACT as a histone chaperone. The source uses ALV rather than ASLV. (LLM, conf=0.93)

  cites [125] Winans, S. et al. The FACT complex promotes avian leukosis virus DNA integration. J. Virol. 91, e00082–17 (2017). source

In the paper

“BET proteins significantly stimulate γ-retroviral IN strand transfer activities in vitro67,115,116 and appear to act as bimodal tethers to direct PICs to preferred genomic locations74,75,114,117,118.”

What the sources say

• Supported

  This source supports the in-vitro stimulation clause: the section on Rev-A integrase and the BRD4 ET domain reports an approximately fivefold, dose-dependent increase in concerted integration activity. The bimodal-tether clause has a separate citation group in the citing sentence and is not attributed to this source. (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
• Supported

  The Results section reports that BET ET domains augment MLV integrase activity in an in vitro integration assay. The Discussion describes a dual role—integrase activation through ET domains and chromatin tethering through bromodomains—and reports that BET inhibition redirects MLV integration away from transcription start sites. Page numbers are not provided in our copy. (LLM, conf=0.92)

  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
• ?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 Discussion (page unavailable) says BET proteins may serve as tethers guiding MLV integration, which supports the hedged tethering claim. It does not describe them as bimodal tethers or establish that they direct preintegration complexes to preferred locations. The in-vitro strand-transfer clause has separate citations in the citing sentence and is not attributed to this paper. (LLM, conf=0.84)

  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
• Partly supported

  The Discussion (p. 6) reports that a recombinant BRD4 fragment stimulated MLV concerted integration in vitro, but does not establish significant stimulation by BET proteins generally. The Summary (p. 1) and Introduction (p. 1) support the proposed tethering role: BET proteins interact with MLV integrase and help direct integration to preferred genomic locations. (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 Results section reports that Brd4 stimulated MLV integrase strand transfer in vitro. The Discussion describes Brd4 as a bimodal tether linking MLV integrase to mononucleosomes and depicts BET-mediated targeting of the MLV intasome to select chromatin sites. No page numbers are provided in the supplied copy. (LLM, conf=0.93)

  cites [117] Larue, R. C. et al. Bimodal high-affinity association of Brd4 with murine leukemia virus integrase and mononucleosomes. Nucleic Acids Res. 42, 4868–4881 (2014). source
• Partly supported

  The Results section, “Chromosomal locations of Brd- and HP1-bound nucleosomes” (page unavailable), maps BET-family Brd proteins to genomic regions and reports preferential binding on active genes. It does not show that they tether retroviral pre-integration complexes (PICs) or direct integration to those locations. The in-vitro integrase-activity clause carries different citations in the citing sentence. (LLM, conf=0.76)

  cites [118] LeRoy, G. et al. Proteogenomic characterization and mapping of nucleosomes decoded by Brd and HP1 proteins. Genome Biol. 13, R68 (2012). sourceExperimental — accuracy not yet measured

In the paper

“Although PP2A-B56 does not bind chromatin directly, it has a range of chromatin-associated substrates126.”

What the sources say

• Partly supported

  The Discussion (page unavailable) identifies RacGAP1 and FOXO3 as PP2A-B56 substrates and describes recruitment to the outer kinetochore. It does not establish that PP2A-B56 cannot bind chromatin directly or characterize a range of its substrates as chromatin-associated. (LLM, conf=0.79)

  cites [126] Hertz, E. P. T. et al. A conserved motif provides binding specificity to the PP2A-B56 phosphatase. Mol. Cell 63, 686–695 (2016). sourceExperimental — accuracy not yet measured

In the paper

“While LEDGF/p75 interacts primarily with the lentiviral IN CCD dimer interface, BET proteins more simply engage a conserved linear sequence motif located at the C-terminus of γ-retroviral IN proteins114–116,121.”

What the sources say

• Partly supported

  The Discussion (p. 7) states that LEDGF/p75 binds HIV integrase across the catalytic-core-domain dimer interface, whereas BET proteins bind the last 27 amino acids of MLV integrase. The MLV IN C Terminus section (p. 4) identifies W391 as important for BET binding and describes the interaction as gammaretrovirus-specific. These passages do not establish that the C-terminal binding sequence is conserved across gammaretroviral integrases. (LLM, conf=0.84)

  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
• Partly supported

  The Results show that LEDGF’s integrase-binding domain interacts with lentiviral integrases and that BET proteins interact with gammaretroviral integrases. But the paper does not locate LEDGF binding at the CCD dimer interface. Its Results and Discussion identify both the catalytic core and C-terminal domain of MLV integrase as contributing to BET binding, rather than establishing binding to a simple C-terminal linear motif; page numbers are unavailable in our copy. (LLM, conf=0.88)

  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). sourceExperimental — accuracy not yet measured
• ?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
• Partly supported

  The Results (page unavailable) locate BET binding primarily in the C-terminal tail of MLV integrase, and the Discussion describes a conserved C-terminal sequence in several related retroviruses. The Discussion mentions LEDGF/p75 in HIV-1 integration but does not locate its binding site at the lentiviral integrase CCD dimer interface; BET binding across gamma-retroviral integrases beyond MLV is also not established here. (LLM, conf=0.85)

  cites [121] Aiyer, S. et al. Altering murine leukemia virus integration through disruption of the integrase and BET protein family interaction. Nucleic Acids Res. 42, 5917–5928 (2014). sourceExperimental — accuracy not yet measured

In the paper

“Residues Ile356 and Asp366 located on the loop between α-helices 1 and 2 mediate interactions with both IN monomers of the CCD dimer while electropositive residues on the outward face of α-helix 4 interface with electronegative residues of IN NTD α-helix 1 (REF.107,109).”

What the sources say

• Partly supported

  The Introduction and Results section ‘The IN–LEDGF Interface and the Role of the IN NTD’ describe Asp-366 binding at the CCD interface and positively charged LEDGF α4 residues facing acidic residues on integrase NTD α1. They identify the pocket-binding residue as Ile-365, not Ile-356. The cited passages also do not establish that both named residues contact both CCD monomers. (LLM, conf=0.89)

  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). sourceExperimental — accuracy not yet measured
• Partly supported

  The Results and Discussion describe LEDGF Ile-365 contacting both chains of the integrase CCD dimer, while Asp-366 hydrogen-bonds to chain A; the claim instead names Ile-356 and says both residues contact both monomers. The paper suggests that the NTD contributes to binding, but its CCD–IBD structure does not establish the claimed electrostatic contact between LEDGF α-helix 4 and NTD α-helix 1. Page numbers were not available in our copy. (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

“Elements including a PWWP chromatin reader domain and two copies of an AT-hook DNA binding motif in the N-terminal half of the protein mediate its association with chromatin, while the C-terminal IN-binding domain (IBD) confers binding to IN103–105.”

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 an N-terminal PWWP domain and says it works with the NLS and two AT-hook motifs to associate with chromatin in cells. The DNA-binding section places the integrase-binding domain at residues 347–429, in the C-terminal half. The paper supports the domain arrangement and functions, while noting that the PWWP domain is not required on its own for binding condensed mitotic chromosomes. (LLM, conf=0.88)

  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 and Fig. 1 identify an N-terminal PWWP domain, one AT hook-like sequence, and a C-terminal IBD that binds HIV-1 integrase (page numbers unavailable). The paper does not identify two AT-hook motifs or establish that the PWWP domain and AT-hook-like sequence mediate LEDGF/p75 chromatin association; it describes the latter's DNA-binding role as a possibility. (LLM, conf=0.88)

  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

“The mode of action of these compounds was visualized in crystals of the PFV intasome25,161,162 and later refined in HIV-1 and SIV cryo-EM structures35,36.”

What the sources say

• Supported

  The ‘Mechanism for strand transfer inhibitor action’ section reports crystal structures of the PFV intasome bound to strand-transfer inhibitors, showing the drugs in the integrase active sites. This supports the PFV-crystal portion attributed to this paper; the later HIV-1 and SIV cryo-EM structures are attributed to other citations. (LLM, conf=0.93)

  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
• Supported

  The Abstract (page not provided) says PFV intasome–INSTI cocrystal structures established the general INSTI binding mode. The passage describing the structures (passage 2; page not provided) explains how the inhibitors bind and inactivate the intasome. The later HIV-1 and SIV cryo-EM work is attached to different citations in the citing sentence, not attributed to this paper. (LLM, conf=0.92)

  cites [161] Hare, S. et al. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc. Natl Acad. Sci. USA 107, 20057–20062 (2010). sourceExperimental — accuracy not yet measured
• Supported

  The Crystal Structure of the WT PFV Intasome Bound to DTG section describes soaking PFV intasome crystals with an INSTI and resolving how it binds in the active site. This supports the PFV-crystal portion attributed to this source; the later HIV-1 and SIV cryo-EM portion has separate citations. (LLM, conf=0.93)

  cites [162] Hare, S. et al. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol. Pharmacol. 80, 565–572 (2011). source
• Supported

  The passage describing the SIVrcm structures reports cryo-EM reconstructions of intasomes bound to the INSTIs dolutegravir and bictegravir. It also identifies PFV intasome crystals as an earlier visualization. In the citing sentence, this paper supports the SIV cryo-EM part; the HIV-1 structure is cited separately. (LLM, conf=0.91)

  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

“Studies using nuclear magnetic resonance identified amino acid residues within the IN CTD responsible for the interaction, and viruses carrying mutations at these IN positions displayed pronounced defects in reverse transcription138.”

What the sources say

• Supported

  The Discussion (p. 9) says the authors mapped a putative RT-binding surface on the integrase CTD by NMR. It reports that several viruses with substitutions at that surface were replication-incompetent because of defects in early reverse transcription; the Results (p. 8) likewise link substitutions at the RT-binding surface to impaired reverse transcription. (LLM, conf=0.94)

  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

“The second-generation compounds feature extended scaffolds, allowing them to fill the active site more completely, and make additional interactions with the IN backbone35,36,162.”

What the sources say

• Supported

  The Abstract describes expanded scaffolds in second-generation INSTIs that interact with the integrase backbone. It also says dolutegravir and bictegravir extend toward the β4-α2 connector, though substantial space remains in the active site; this is consistent with filling it more completely, not completely. (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. 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
• Partly supported

  The crystal-structure section (p. 567) says second-generation INSTIs extend toward an integrase residue, and the Discussion (p. 570) says dolutegravir’s extended linker lets it reach deeper into the active-site pocket and make closer contacts than raltegravir. The paper describes contacts with an integrase loop, but does not establish the claimed additional interactions specifically with the integrase backbone. (LLM, conf=0.85)

  cites [162] Hare, S. et al. Structural and functional analyses of the second-generation integrase strand transfer inhibitor dolutegravir (S/GSK1349572). Mol. Pharmacol. 80, 565–572 (2011). sourceExperimental — accuracy not yet measured

In the paper

“Class II IN mutations additionally affected viral particle morphology, with the ribonucleoprotein material found outside of the capsid shell, oftentimes in association with the viral membrane131,132,139–142.”

What the sources say

• ?Not checked — no full text of the sourcecites [131] Engelman, A., Englund, G., Orenstein, J. M., Martin, M. A. & Craigie, R. Multiple effects of mutations in human immunodeficiency virus type 1 integrase on viral replication. J. Virol. 69, 2729–2736 (1995). source
• Supported

  The Results section, “Class II IN substitutions generate virions with eccentric morphology” (Figure 6), reports that 70–80% of nearly all tested class II mutant particles had eccentric morphology. Its figure caption locates the electron-dense material between the core and viral membrane, while the Introduction identifies the mislocalized material as vRNPs outside the capsid lattice. (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 [139] Fontana, J. et al. Distribution and redistribution of HIV-1 nucleocapsid protein in immature, mature, and integrase-inhibited virions: a role for integrase in maturation. J. Virol. 89, 9765–9780 (2015). source
• ?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
• ?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
• Partly supported

  The Results section, “Virion Core Morphology is Affected by NCINIs” (page unavailable), reports RNP-like material outside the capsid shell in NCINI-treated particles and independently confirms that phenotype in virus lacking integrase. The Discussion mentions class II integrase mutants in connection with a reverse-transcription block, but our copy does not establish the stated morphology for those mutants or say that the material is associated with the viral membrane. (LLM, conf=0.82)

  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

In the paper

“In the last 14 years, four more INSTIs were approved for treatment of HIV infection: elvitegravir, dolutegravir, bictegravir and cabotegravir147–150.”

What the sources say

• ?Not checked — no full text of the sourcecites [147] Sato, M. et al. Novel HIV-1 integrase inhibitors derived from quinolone antibiotics. J. Med. Chem. 49, 1506–1508 (2006). source
• ?Not checked — no full text of the sourcecites [148] DeJesus, E. et al. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J. Acquir. Immune Defic. Syndr. 43, 1–5 (2006). source
• Partly supported

  The Introduction (page unavailable) says elvitegravir and dolutegravir were approved for HIV treatment, but describes bictegravir as having entered registrational trials. The Discussion (page unavailable) likewise says bictegravir was under phase 3 evaluation; although one Results passage calls it an approved INSTI, that conflicts with those descriptions. The paper does not substantiate cabotegravir’s approval or the four-drug count. (LLM, conf=0.86)

  cites [149] Tsiang, M. et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob. Agents Chemother. 60, 7086–7097 (2016). sourceExperimental — accuracy not yet measured
• ?Not checked — no full text of the sourcecites [150] Markham, A. Cabotegravir plus rilpivirine: first approval. Drugs 80, 915–922 (2020). source

In the paper

“Because retroviral IN active sites are highly conserved, INSTIs are broadly active across the retroviral family32,158,159 save the occasional example when an IN residue, such as Ser150 in ASLV IN, confers baseline resistance, in this case to elvitegravir39,160.”

What the sources say

• Partly supported

  The passage on MVV activity (labeled Abstract in our copy; page unavailable) reports that dolutegravir, an HIV-1 INSTI, inhibited the MVV intasome. Another passage describes a conserved intasome core across several retroviral genera. Neither establishes that highly conserved active sites make INSTIs broadly active across the retroviral family. The ASLV Ser150 exception is attached to different citations in the citing sentence, so it is not assessed against this source. (LLM, conf=0.85)

  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. sourceExperimental — accuracy not yet measured
• Supported

  The Results section reports that two HIV integrase strand-transfer inhibitors also inhibit the divergent PFV integrase. The Discussion identifies active-site features conserved among retroviral genera and links them to inhibitor binding. The Ser150 exception is attached to different citations in the citing sentence, not to this source. (LLM, conf=0.88)

  cites [158] Valkov, E. et al. Functional and structural characterization of the integrase from the prototype foamy virus. Nucleic Acids Res. 37, 243–255 (2009). source
• Partly supported

  The Discussion (page unavailable) reports conserved HIV-1 and HTLV-1 integrase active sites and concludes that HTLV-1 integrase is as sensitive as HIV-1 to the tested INSTIs. That supports activity across these two viruses, but not the broader claim of activity across the retroviral family. The Ser150 exception has separate citations in the citing sentence and is not attributed to this paper. (LLM, conf=0.84)

  cites [159] Barski, M. S., Minnell, J. J. & Maertens, G. N. Inhibition of HTLV-1 infection by HIV-1 first- and second-generation integrase strand transfer inhibitors. Front. Microbiol. 10, 1877 (2019). sourceExperimental — accuracy not yet measured
• Supported

  The Results report that the natural Ser150 residue in RSV integrase confers resistance to elvitegravir, and that changing it to proline increases sensitivity about 74-fold. This supports the exception for which this paper is cited; the sentence cites other sources for the broader claim about INSTI activity. (LLM, conf=0.93)

  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
• Supported

  The paper’s introductory discussion describes conserved integrase active-site residues, and its study summary reports raltegravir activity across the retroviruses tested. The RSV resistance results and Conclusions identify Ser150 as a significant contributor to RSV’s natural resistance to elvitegravir. Page numbers are unavailable in our copy. (LLM, conf=0.90)

  cites [160] Koh, Y., Matreyek, K. A. & Engelman, A. Differential sensitivities of retroviruses to integrase strand transfer inhibitors. J. Virol. 85, 3677–3682 (2011). source

In the paper

“Thus, the dissociation half-times of dolutegravir and bictegravir from the wild-type HIV-1 intasome were reported to be ~100 and 160 h, respectively164,165.”

What the sources say

• Partly supported

  The Abstract and Results (Table 2; page unavailable) report a 71-hour dissociative half-life for dolutegravir from a wild-type integrase–DNA complex, not approximately 100 hours. This paper does not report a bictegravir half-life; the sentence has a separate citation for that value. (LLM, conf=0.88)

  cites [164] Hightower, K. E. et al. Dolutegravir (S/GSK1349572) exhibits significantly slower dissociation than raltegravir and elvitegravir from wild-type and integrase inhibitor-resistant HIV-1 integrase-DNA complexes. Antimicrob. Agents Chemother. 55, 4552–4559 (2011). sourceExperimental — accuracy not yet measured
• Supported

  The passage labeled INTRODUCTION (passage 8; page not provided) reports dissociation half-times from wild-type integrase–DNA complexes of 96 ± 29 h for dolutegravir and 163 ± 31 h for bictegravir. These match the cited approximations of 100 and 160 h. (LLM, conf=0.94)

  cites [165] White, K. L. et al. Long dissociation of bictegravir from HIV-1 integrase-DNA complexes. Antimicrob. Agents Chemother. 65, e02406–e02420 (2021). source

In the paper

“Detailed analysis of virus particles produced in the presence of ALLINIs revealed that although viral RNA and proteins were incorporated properly, IN-RNA binding was disrupted, and the ribonucleoprotein complex was located eccentrically (Fig. 6B)140–142,174–176.”

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
• ?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
• Partly supported

  The Discussion (page unavailable) says NCINI-produced particles appear normal in genomic RNA and major viral-protein content, while electron microscopy shows the ribonucleoprotein complex mislocalized outside the capsid shell. It does not report that integrase–RNA binding was disrupted; the paper instead reports increased integrase oligomerization. It also qualifies the content finding because a detailed proteomic analysis was not performed. (LLM, conf=0.88)

  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
• Partly supported

  The post-integration results section reports normal Gag maturation and CA p24 content in Mut101-produced virions. The discussion reports an eccentric electron-dense HIV core, but does not identify it as the ribonucleoprotein complex. Our copy does not establish proper viral RNA incorporation or disrupted integrase–RNA binding. (LLM, conf=0.86)

  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
• Partly supported

  The Discussion (page unavailable) reports that GSK1264 did not block particle release and that allosteric inhibitors impair particle-core maturation. It does not establish that viral RNA and proteins were incorporated properly, that integrase–RNA binding was disrupted, or that the ribonucleoprotein complex was eccentric. (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
• Partly supported

  In ‘LEDGINs inhibit multiple steps in HIV replication’ (page unavailable), the paper reports unaffected genomic RNA packaging and Gag processing, and frequently observes a mislocalized ribonucleoprotein complex in CX05045-treated particles. It does not establish that all viral proteins were incorporated properly or that integrase–RNA binding was disrupted; instead, the Discussion attributes the maturation defect to enhanced integrase multimerization. (LLM, conf=0.87)

  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

“Resultant proviruses were marginally recalcitrant to transcriptional activation via latency reversal agents183,185, indicating that ALLINIs could potentially be employed as preexposure prophylactic compounds to reduce both the size and reactivation potential of the latent viral reservoir.”

What the sources say

• Partly supported

  The reactivation-results section (page unavailable) reports that proviruses formed during GS-9822 or CX14442 treatment had a dose-dependent reduction in the reactivatable latent fraction after TNFα stimulation. The Discussion proposes early treatment to induce a more latent reservoir, but it does not establish preexposure prophylaxis or show that ALLINIs reduce the size of the latent reservoir. Those parts of the citing sentence go beyond the cell-culture findings. (LLM, conf=0.84)

  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
• Supported

  Section 3.6 reports that LEDGIN treatment reduced reactivation of quiescent HIV with various latency-reversing agents. Section 3.8 reports fewer integrated proviral copies and less reactivation of residual integrants in primary CD4+ T cells. The Discussion explicitly proposes pre-exposure prophylaxis as a potential use, while noting that clinical trials would be needed. (LLM, conf=0.93)

  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

“The oxadiazole group of raltegravir, unique to this inhibitor, stacks with the side chain of Tyr143, explaining why amino acid substitutions such as Y143R/C cause resistance to this drug161.”

What the sources say

• Partly supported

  The passage on raltegravir resistance reports that PFV Tyr212 stacks with raltegravir’s oxadiazole ring and identifies it as the structural equivalent of HIV-1 Tyr143; it also lists Y143R/C among raltegravir-resistance mutations. Our copy does not establish the additional claim that the oxadiazole group is unique to raltegravir. The indexed passage provides no section or page label. (LLM, conf=0.84)

  cites [161] Hare, S. et al. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc. Natl Acad. Sci. USA 107, 20057–20062 (2010). sourceExperimental — accuracy not yet measured

In the paper

“The recent primate lentiviral intasome structures importantly resolved INSTI occupancies in the most relevant retroviral IN active sites and helped to elucidate the structural basis for INSTI drug resistance35,36.”

What the sources say

• Supported

  The passages labeled Abstract describe cryo-EM structures of primate lentiviral SIVrcm intasomes with dolutegravir and bictegravir resolved in their integrase active sites (passages 2 and 4). They also explain how resistance-associated substitutions perturb magnesium-ion coordination and drug binding (passages 5 and 6). (LLM, conf=0.93)

  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

In the paper

“A co-crystal structure of full-length HIV-1 IN with GSK1264 revealed that binding of this ALLINI at the CCD dimer interface contributes to a novel interface for the CTD, leading to formation of linear IN polymers (Fig. 6D)179.”

What the sources say

• Supported

  In Results, “Structure of an HIV IN•GSK1264 Complex” (page unavailable), the paper reports that the protein recovered from the crystals was full length, although its N-terminal domains were disordered. It describes GSK1264 at the catalytic core domain (CCD) dimer interface and CTDs binding to inhibitor-bound CCDs in adjacent dimers, forming an open polymer. This supports the citing sentence’s description of the new CTD interface and linear polymer formation. (LLM, conf=0.91)

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

In the paper

“The PFV intasome crystal structures reported in the early 2010s supercharged the field of retroviral integration structural biology25,29,161.”

What the sources say

• Supported

  The Crystallization of the PFV intasome section reports determining the three-dimensional structure and says its architecture differed drastically from previous models. The Abstract states that the structure enabled the authors to explain strand-transfer inhibitor action, and the Mechanism for strand transfer inhibitor action section reports structures with two clinical inhibitors. The paper thus supports the claim's substance, though “supercharged” is the citing authors’ characterization of its impact. (LLM, conf=0.92)

  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 Abstract (page not provided) reports PFV intasome crystal structures that reveal intermediates of retroviral integration and elucidate its structural basis. This supports the citing sentence’s characterization of the structures as a major advance in the field. The separate INSTI-drug-action wording is not in the verbatim citing sentence assessed here. (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 Introduction describes PFV intasome structures as a proxy for structural studies of HIV integrase inhibitors. The paper also reports new PFV intasome crystal structures and explains how inhibitors bind and inactivate the complex, supporting the claim that these structures advanced structural understanding of integration and INSTI action. (LLM, conf=0.90)

  cites [161] Hare, S. et al. Molecular mechanisms of retroviral integrase inhibition and the evolution of viral resistance. Proc. Natl Acad. Sci. USA 107, 20057–20062 (2010). source

In the paper

“It is becoming increasingly clear that the classification of IN mutants introduced more than 2 decades ago is outdated.”

In the paper

“Prior to 3’-processing, the retroviral IN active site is fully occupied, presenting no available pocket, likely explaining why effective catalytic inhibitors of this step have yet to be found.”

In the paper

“The bulk of chromosomal DNA exists in the form of nucleosomes, and the nucleosomal structure imposes severe constraints on DNA conformation, greatly restricting accessibility of the major groove58.”

What the sources say

• ?Not checked — no full text of the sourcecites [58] Luger, K., Mader, A. W., Richmond, R. K., Sargent, D. F. & Richmond, T. J. Crystal structure of the nucleosome core particle at 2.8 Å resolution. Nature 389, 251–260 (1997). source

In the paper

“The expansion of the intasome structure may allow lentiviruses to form more extensive interactions with chromatin, possibly spanning several nucleosomes.”

In the paper

“Given the key role of IN in mediating integration, it is not surprising that IN-host interactions play fundamental roles in retroviral integration targeting.”

In the paper

“In particular, while HIV-1 PICs are actively transported through nuclear pore complexes69, their MLV and PFV cousins lack this function and require disassembly of the nuclear envelope during the M phase of the cell cycle70,71.”

What the sources say

• ?Not checked — no full text of the sourcecites [69] Bukrinsky, M. I. et al. Active nuclear import of human immunodeficiency virus type 1 preintegration complexes. Proc. Natl Acad. Sci. USA 89, 6580–6584 (1992). source
• ?Not checked — no full text of the sourcecites [70] Roe, T., Reynolds, T. C., Yu, G. & Brown, P. O. Integration of murine leukemia virus DNA depends on mitosis. EMBO J. 12, 2099–2108 (1993). source
• ?Not checked — no full text of the sourcecites [71] Bieniasz, P. D., Weiss, R. A. & McClure, M. O. Cell cycle dependence of foamy retrovirus infection. J. Virol. 69, 7295–7299 (1995). source

In the paper

“On that basis, HIV-1 IN mutants were divided into two groups: class I, which harbours variants specifically defective at the step of integration, and the much larger class II that incorporates variants with a variable degree of reverse transcription defects133.”

What the sources say

• ?Not checked — no full text of the sourcecites [133] Engelman, A. In vivo analysis of retroviral integrase structure and function. Adv. Virus Res. 52, 411–426 (1999). source

In the paper

“N-terminal bromodomains confer binding to acetylated histone H3 and H4 tails, while the C-terminal extraterminal domain interacts with chromatin modifying enzymes such as histone methyltransferase NSD3 (REF.119,120).”

What the sources say

• ?Not checked — no full text of the sourcecites [119] Morinière, J. et al. Cooperative binding of two acetylation marks on a histone tail by a single bromodomain. Nature 461, 664–668 (2009). source
• ?Not checked — no full text of the sourcecites [120] Rahman, S. et al. The Brd4 extraterminal domain confers transcription activation independent of pTEFb by recruiting multiple proteins, including NSD3. Mol. Cell Biol. 31, 2641–2652 (2011). source

In the paper

“The INSTI heteroatoms interact with the essential metal pair in the IN active site, while the halobenzyl sidechain burrows into the vDNA-IN interface, replacing the base of the 3’ adenosine of the processed vDNA end (Fig. 5B).”

In the paper

“The prototypical INSTIs, diketo acids, were discovered over 20 years ago by Merck scientists in a screen for small molecule inhibitors of pre-assembled HIV-1 intasomes155.”

What the sources say

• ?Not checked — no full text of the sourcecites [155] Hazuda, D. J. et al. Inhibitors of strand transfer that prevent integration and inhibit HIV-1 replication in cells. Science 287, 646–650 (2000). This study reports the initial discovery and characterization of INSTIs. source

In the paper

“Pertinently, class I and II HIV-1 IN mutant phenotypes are phenocopied by strand transfer and allosteric IN inhibitors, respectively (see next section).”

In the paper

“However, by contrast to RT and protease, HIV IN inhibitors had to be created without the benefit of prior mechanistic insights or known natural inhibitors144,145.”

What the sources say

• ?Not checked — no full text of the sourcecites [144] Wlodawer, A. & Vondrasek, J. Inhibitors of HIV-1 protease: a major success of structure-assisted drug design. Annu. Rev. Biophys. Biomol. Struct. 27, 249–284 (1998). source
• ?Not checked — no full text of the sourcecites [145] Pattishall, K. H. in The Search for Antiviral Drugs: Case Histories from Concept to Clinic (eds Adams, J. & Merluzzi, V. J.) 23–43 (Birkhäuser, 1993). source

In the paper

“HIV-1 IN can bind RT and stimulate its activity in vitro137.”

What the sources say

• ?Not checked — no full text of the sourcecites [137] Dobard, C. W., Briones, M. S. & Chow, S. A. Molecular mechanisms by which human immunodeficiency virus type 1 integrase stimulates the early steps of reverse transcription. J. Virol. 81, 10037–10046 (2007). source

In the paper

“These compounds bind to the IN active site only when it is engaged with vDNA and compete with target DNA157.”

What the sources say

• ?Not checked — no full text of the sourcecites [157] Espeseth, A. S. et al. HIV-1 integrase inhibitors that compete with the target DNA substrate define a unique strand transfer conformation for integrase. Proc. Natl Acad. Sci. USA 97, 11244–11249 (2000). source

In the paper

“Currently, dolutegravir is recommended by the Word Health Organisation for use in first-line combination antiretroviral therapy154.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [154] WHO. Update of recommendations on first- and second-line antiretroviral regimens. WHO Policy Brief 1–16 (WHO, 2019).

In the paper

“Lead compounds in this class were discovered using two very different high-throughput approaches: a screen for inhibitors of HIV-1 IN 3’-processing activity172, and structure-based design of small molecule inhibitors of the HIV-1 IN-LEDGF/p75 interaction171.”

What the sources say

• ?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
• ?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

“Yet, the most nefarious mutations that contribute to complete or partial loss of INSTI susceptibility involve changes of Gln148 and Asn155, which do not directly contact the drugs.”

In the paper

“The bulky hydrophobic side chain contacts several hydrophobic residues from both subunits of the IN dimer, thus mimicking Ile365 of LEDGF/p75.”