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Cited by 39T-cell and Retrovirus StudiesHIV Research and TreatmentVirus-based gene therapy research

Structural basis of host protein hijacking in human T-cell leukemia virus integration

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Bhatt, Veer, Shi, Ke, Salamango, Daniel J., Moeller, Nicholas H., Pandey, Krishan K., Bera, Sibes, Bohl, Heather O., Kurniawan, Fredy +6 more·2020·Nature Communications
DOI 10.1038/s41467-020-16963-6PMC PMC7305164
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Abstract

Integration of the reverse-transcribed viral DNA into host chromosomes is a critical step in the life-cycle of retroviruses, including an oncogenic delta(δ)-retrovirus human T-cell leukemia virus type-1 (HTLV-1). Retroviral integrase forms a higher order nucleoprotein assembly (intasome) to catalyze the integration reaction, in which the roles of host factors remain poorly understood. Here, we use cryo-electron microscopy to visualize the HTLV-1 intasome at 3.7-Å resolution. The structure together with functional analyses reveal that the B56γ (B’γ) subunit of an essential host enzyme, protein phosphatase 2 A (PP2A), is repurposed as an integral component of the intasome to mediate HTLV-1 integration. Our studies reveal a key host-virus interaction underlying the replication of an important human pathogen and highlight divergent integration strategies of retroviruses.

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  • All intasomes incorporate a conserved intasome core assembly, which is the minimal functional unit and is represented by the PFV structure.

    “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).”

    From Structure and function of retroviral integrase (2022) · cites this paper as [37]

    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)

    Experimental — accuracy not yet measured

  • PFV, HTLV-1, and STLV intasomes contain four integrase subunits arranged as a dimer-of-dimers.

    “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”

    From Structure and function of retroviral integrase (2022) · cites this paper as [37]

    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)

    Experimental — accuracy not yet measured

  • All retroviral intasomes have 2-fold symmetry and contain a pair of adjacent active sites bound to 3' viral DNA ends.

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

    From Structure and function of retroviral integrase (2022) · cites this paper as [37]

    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)

    Experimental — accuracy not yet measured

  • Intasomes from several retroviral species and prokaryotic and eukaryotic transpososomes have been visualized as post-catalytic strand transfer complexes, all showing sharp deformations of target DNA.

    “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.”

    From Structure and function of retroviral integrase (2022) · cites this paper as [37]

    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)

    Experimental — accuracy not yet measured

  • Intasomes from different retroviral genera display unexpected architectural diversity.

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

    From Structure and function of retroviral integrase (2022) · cites this paper as [37]

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Authors
Bhatt, V., Shi, K., Salamango, D. J., Moeller, N. H., Pandey, K. K., Bera, S., Bohl, H. O., Kurniawan, F., Orellana, K., Zhang, W., Grandgenett, D. P., Harris, R. S., Sundborger-Lunna, A. C., & Aihara, H.
Affiliations
  • University of Minnesota (US)
  • Saint Louis University (US)
Corresponding author
Aihara, Hideki
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-06-19
Volume
11
Issue
1
Pages
3121-3121
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-16963-6
PMC
PMC7305164
OpenAlex
W3035912978
Cited by
39
References
71
Citations by year
2026: 4 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 7 · 2021: 13 · 2020: 2
FWCI
2.36
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • U.S. Department of Health & Human Services | National Institutes of Health (AI064046, GM118047)
  • Hormel Foundation
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords
HTLV-1, viral integration, intasome, retroviral integrase, host-virus interaction, protein phosphatase 2A, retroviral life cycle, cryo-EM structure
MeSH terms
DNA, Viral, Humans, Models, Molecular, Protein Binding, Viral Proteins, Human T-lymphotropic virus 1, Virus Integration, Point Mutation, Integrases, Cryoelectron Microscopy, Protein Phosphatase 2, Host-Pathogen Interactions, HEK293 Cells

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