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Suppressor of cytokine signaling 1 counteracts rhesus macaque TRIM5?-induced inhibition of human immunodeficiency virus type-1 production.

ABSTRACT: Old world monkey TRIM5? is a host factor that restricts human immunodeficiency virus type-1 (HIV-1) infection. Previously, we reported that rhesus macaque TRIM5? (RhTRIM5?) restricts HIV-1 production by inducing degradation of precursor Gag. Since suppressor of cytokine signaling 1 (SOCS1) is known to enhance HIV-1 production by rescuing Gag from lysosomal degradation, we examined if SOCS1 is involved in RhTRIM5?-mediated late restriction. Over-expression of SOCS1 restored HIV-1 production in the presence of RhTRIM5? to a level comparable to that in the absence of RhTRIM5? in terms of titer and viral protein expression. Co-immunoprecipitation studies revealed that SOCS1 physically interacted with RhTRIM5?. Over-expression of SOCS1 affected RhTRIM5? expression in a dose-dependent manner, which was not reversed by proteasome inhibitors. In addition, SOCS1 and RhTRIM5? were detected in virus-like particles. These results suggest that SOCS1 alleviates RhTRIM5?-mediated regulation in the late phase of HIV-1 life cycle probably due to the destabilization of RhTRIM5?.

SUBMITTER: Sukegawa S

PROVIDER: S-EPMC4195675 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature

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Suppressor of cytokine signaling 1 counteracts rhesus macaque TRIM5α-induced inhibition of human immunodeficiency virus type-1 production.

Sukegawa Sayaka S Sakuma Ryuta R Ohmine Seiga S Takeuchi Hiroaki H Ikeda Yasuhiro Y Yamaoka Shoji S

PloS one 20141013 10

Old world monkey TRIM5α is a host factor that restricts human immunodeficiency virus type-1 (HIV-1) infection. Previously, we reported that rhesus macaque TRIM5α (RhTRIM5α) restricts HIV-1 production by inducing degradation of precursor Gag. Since suppressor of cytokine signaling 1 (SOCS1) is known to enhance HIV-1 production by rescuing Gag from lysosomal degradation, we examined if SOCS1 is involved in RhTRIM5α-mediated late restriction. Over-expression of SOCS1 restored HIV-1 production in th ...[more]

PMID: 25310711

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Project description:Diversification of antiretroviral factors during host evolution has erected formidable barriers to cross-species retrovirus transmission. This phenomenon likely protects humans from infection by many modern retroviruses, but it has also impaired the development of primate models of HIV-1 infection. Indeed, rhesus macaques are resistant to HIV-1, in part due to restriction imposed by the TRIM5? protein (rhTRIM5?). Initially, we attempted to derive rhTRIM5?-resistant HIV-1 strains using two strategies. First, HIV-1 was passaged in engineered human cells expressing rhTRIM5?. Second, a library of randomly mutagenized capsid protein (CA) sequences was screened for mutations that reduced rhTRIM5? sensitivity. Both approaches identified several individual mutations in CA that reduced rhTRIM5? sensitivity. However, neither approach yielded mutants that were fully resistant, perhaps because the locations of the mutations suggested that TRIM5? recognizes multiple determinants on the capsid surface. Moreover, even though additive effects of various CA mutations on HIV-1 resistance to rhTRIM5? were observed, combinations that gave full resistance were highly detrimental to fitness. Therefore, we employed an 'assisted evolution' approach in which individual CA mutations that reduced rhTRIM5? sensitivity without fitness penalties were randomly assorted in a library of viral clones containing synthetic CA sequences. Subsequent passage of the viral library in rhTRIM5?-expressing cells resulted in the selection of individual viral species that were fully fit and resistant to rhTRIM5?. These viruses encoded combinations of five mutations in CA that conferred complete or near complete resistance to the disruptive effects of rhTRIM5? on incoming viral cores, by abolishing recognition of the viral capsid. Importantly, HIV-1 variants encoding these CA substitutions and SIV(mac239) Vif replicated efficiently in primary rhesus macaque lymphocytes. These findings demonstrate that rhTRIM5? is difficult to but not impossible to evade, and doing so should facilitate the development of primate models of HIV-1 infection.

Dataset Information

Suppressor of cytokine signaling 1 counteracts rhesus macaque TRIM5?-induced inhibition of human immunodeficiency virus type-1 production.

Publications

Suppressor of cytokine signaling 1 counteracts rhesus macaque TRIM5α-induced inhibition of human immunodeficiency virus type-1 production.

Similar Datasets

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