ArticleRetrovirology2013
The V86M mutation in HIV-1 capsid confers resistance to TRIM5α by abrogation of cyclophilin A-dependent restriction and enhancement of viral nuclear import.
Article in Retrovirology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 19 papers.
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19 citing papers in PubMed, 35 citations in OpenAlex.
- A simultaneous knockout knockin genome editing strategy in HSPCs potently inhibits CCR5- and CXCR4-tropic HIV-1 infection.Cell stem cell · 2024Article
- Generation of a bovine cell line for gene engineering using an HIV-1-based lentiviral vector.Scientific reports · 2022Article
- Human TRIM5α: Autophagy Connects Cell-Intrinsic HIV-1 Restriction and Innate Immune Sensor Functioning.Viruses · 2021Review
- Editing of the TRIM5 Gene Decreases the Permissiveness of Human T Lymphocytic Cells to HIV-1.Viruses · 2020Article
- Mutational resilience of antiviral restriction favors primate TRIM5α in host-virus evolutionary arms races.eLife · 2020Article
- Delayed disease progression in HIV-2: the importance of TRIM5α and the retroviral capsid.Clinical and experimental immunology · 2019Review
- Cyclophilin A potentiates TRIM5α inhibition of HIV-1 nuclear import without promoting TRIM5α binding to the viral capsid.PloS one · 2017Article
- Targeting TRIM5α in HIV Cure Strategies for the CRISPR-Cas9 Era.Frontiers in immunology · 2017Article
- Characterization of two distinct early post-entry blocks to HIV-1 in common marmoset lymphocytes.Scientific reports · 2016Article
- Novel mutant human immunodeficiency virus type 1 strains with high degree of resistance to cynomolgus macaque TRIMCyp generated by random mutagenesis.The Journal of general virology · 2016Article
- The interferon-induced antiviral protein PML (TRIM19) promotes the restriction and transcriptional silencing of lentiviruses in a context-specific, isoform-specific fashion.Retrovirology · 2016Article
- Article
- Dynamic allostery governs cyclophilin A-HIV capsid interplay.Proceedings of the National Academy of Sciences of the United States of America · 2015Article
- Preclinical Assessment of Mutant Human TRIM5α as an Anti-HIV-1 Transgene.Human gene therapy · 2015Article
- HIV-1 Resistance to the Capsid-Targeting Inhibitor PF74 Results in Altered Dependence on Host Factors Required for Virus Nuclear Entry.Journal of virology · 2015Article
- Cyclosporin a and rapamycin relieve distinct lentiviral restriction blocks in hematopoietic stem and progenitor cells.Molecular therapy : the journal of the American Society of Gene Therapy · 2015Article
- Cytoplasmic dynein promotes HIV-1 uncoating.Viruses · 2014Article
- HIV-1 B-subtype capsid protein: a characterization of amino acid's conservation and its significant association with integrase signatures.Virus genes · 2014Article
- Assisted evolution enables HIV-1 to overcome a high TRIM5α-imposed genetic barrier to rhesus macaque tropism.PLoS pathogens · 2013Article
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9 authors at 3 institutions in 2 countries.
Funding
Abstract
backgroundHIV-1 is inhibited early after entry into cells expressing some simian orthologues of the tripartite motif protein family member TRIM5α. Mutants of the human orthologue (TRIM5αhu) can also provide protection against HIV-1. The host protein cyclophilin A (CypA) binds incoming HIV-1 capsid (CA) proteins and enhances early stages of HIV-1 replication by unknown mechanisms. On the other hand, the CA-CypA interaction is known to increase HIV-1 susceptibility to restriction by TRIM5α. Previously, the mutation V86M in the CypA-binding loop of HIV-1 CA was found to be selected upon serial passaging of HIV-1 in cells expressing Rhesus macaque TRIM5α (TRIM5αrh). The objectives of this study were (i) to analyze whether V86M CA allows HIV-1 to escape mutants of TRIM5αhu, and (ii) to characterize the role of CypA in the resistance to TRIM5α conferred by V86M.
resultsWe find that in single-cycle HIV-1 vector transduction experiments, V86M confers partial resistance against R332G-R335G TRIM5αhu and other TRIM5αhu variable 1 region mutants previously isolated in mutagenic screens. However, V86M HIV-1 does not seem to be resistant to R332G-R335G TRIM5αhu in a spreading infection context. Strikingly, restriction of V86M HIV-1 vectors by TRIM5αhu mutants is mostly insensitive to the presence of CypA in infected cells. NMR experiments reveal that V86M alters CypA interactions with, and isomerisation of CA. On the other hand, V86M does not affect the CypA-mediated enhancement of HIV-1 replication in permissive human cells. Finally, qPCR experiments show that V86M increases HIV-1 transport to the nucleus of cells expressing restrictive TRIM5α.
conclusionsOur study shows that V86M de-couples the two functions associated with CA-CypA binding, i.e. the enhancement of restriction by TRIM5α and the enhancement of HIV-1 replication in permissive human cells. V86M enhances the early stages of HIV-1 replication in restrictive cells by improving nuclear import. In summary, our data suggest that HIV-1 escapes restriction by TRIM5α through the selective disruption of CypA-dependent, TRIM5α-mediated inhibition of nuclear import. However, V86M does not seem to relieve restriction of a spreading HIV-1 infection by TRIM5αhu mutants, underscoring context-specific restriction mechanisms.
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