Abstract
The host protein TRIM5α inhibits retroviral infection at an early post-penetration stage by targeting the incoming viral capsid. While the detailed mechanism of restriction remains unclear, recent studies have implicated the activity of cellular proteasomes in the restriction of retroviral reverse transcription imposed by TRIM5α. Here, we show that TRIM5α is rapidly degraded upon encounter of a restriction-susceptible retroviral core. Inoculation of TRIM5α-expressing human 293T cells with a saturating level of HIV-1 particles resulted in accelerated degradation of the HIV-1-restrictive rhesus macaque TRIM5α protein but not the nonrestrictive human TRIM5α protein. Exposure of cells to HIV-1 also destabilized the owl monkey restriction factor TRIMCyp; this was prevented by addition of the inhibitor cyclosporin A and was not observed with an HIV-1 virus containing a mutation in the capsid protein that relieves restriction by TRIMCyp IVHIV. Likewise, human TRIM5α was rapidly degraded upon encounter of the restriction-sensitive N-tropic murine leukemia virus (N-MLV) but not the unrestricted B-MLV. Pretreatment of cells with proteasome inhibitors prevented the HIV-1-induced loss of both rhesus macaque TRIM5α and TRIMCyp proteins. We also detected degradation of endogenous TRIM5α in rhesus macaque cells following HIV-1 infection. We conclude that engagement of a restriction-sensitive retrovirus core results in TRIM5α degradation by a proteasome-dependent mechanism.
Highlights
Retroviruses exhibit a restricted host range due to the requirement for specific interactions between viral and host proteins to complete the viral life cycle
Exposure of Cells to HIV-1 Destabilizes TRIM5a We hypothesized that TRIM5a itself might be degraded as a consequence of the post-entry restriction process
TRIM5a can associate with assemblies of HIV-1 CA-NC protein in vitro, and genetic evidence indicates that TRIM5a and TRIMCyp require an intact or semiintact viral capsid for binding [60,61]
Summary
Retroviruses exhibit a restricted host range due to the requirement for specific interactions between viral and host proteins to complete the viral life cycle. The prototypical restriction activity, Fv1, was first detected in the 1970s as differential susceptibility of inbred mice strains to the Friend leukemia virus [11,12,13]. Fv1 blocks infection of murine leukemia viruses (MLV) at a stage following fusion but prior to integration [14,15]. The block to infection can be overcome at high multiplicities of infection (m.o.i.) or by pretreatment of target cells with non-infectious virus like particles (VLPs) [11,16]. Susceptibility to Fv1 restriction is determined by the sequence of the viral capsid protein (CA) [17,18,19]. The gene encoding Fv1 was identified in 1996 by positional cloning [1]; yet the molecular mechanism by which Fv1 inhibits MLV infection remains poorly defined
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