Dataset Information

The V86M mutation in HIV-1 capsid confers resistance to TRIM5? by abrogation of cyclophilin A-dependent restriction and enhancement of viral nuclear import.

ABSTRACT:

Background

HIV-1 is inhibited early after entry into cells expressing some simian orthologues of the tripartite motif protein family member TRIM5?. Mutants of the human orthologue (TRIM5?hu) 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 TRIM5?. 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 TRIM5? (TRIM5?rh). The objectives of this study were (i) to analyze whether V86M CA allows HIV-1 to escape mutants of TRIM5?hu, and (ii) to characterize the role of CypA in the resistance to TRIM5? conferred by V86M.

Results

We find that in single-cycle HIV-1 vector transduction experiments, V86M confers partial resistance against R332G-R335G TRIM5?hu and other TRIM5?hu variable 1 region mutants previously isolated in mutagenic screens. However, V86M HIV-1 does not seem to be resistant to R332G-R335G TRIM5?hu in a spreading infection context. Strikingly, restriction of V86M HIV-1 vectors by TRIM5?hu 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 TRIM5?.

Conclusions

Our study shows that V86M de-couples the two functions associated with CA-CypA binding, i.e. the enhancement of restriction by TRIM5? 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 TRIM5? through the selective disruption of CypA-dependent, TRIM5?-mediated inhibition of nuclear import. However, V86M does not seem to relieve restriction of a spreading HIV-1 infection by TRIM5?hu mutants, underscoring context-specific restriction mechanisms.

SUBMITTER: Veillette M

PROVIDER: S-EPMC3598646 | biostudies-literature | 2013 Feb

REPOSITORIES: biostudies-literature

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The V86M mutation in HIV-1 capsid confers resistance to TRIM5α by abrogation of cyclophilin A-dependent restriction and enhancement of viral nuclear import.

Veillette Maxime M Bichel Katsiaryna K Pawlica Paulina P Freund Stefan M V SM Plourde Mélodie B MB Pham Quang Toan QT Reyes-Moreno Carlos C James Leo C LC Berthoux Lionel L

Retrovirology 20130228

<h4>Background</h4>HIV-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 TRIM5 ...[more]

PMID: 23448277

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