Saturation of TRIM5α-mediated restriction of HIV-1 infection depends on the stability of the incoming viral capsid

HIV-1 infection is restricted at a post-entry stage in some simian cell lines by species-specific variants of TRIM5α. Restriction targets the viral capsid protein (CA) and results in attenuated reverse transcription. TRIM5α restriction can be inhibited by the addition of noninfectious virus-like particles (VLPs), thus rendering cells permissive for infection by an HIV-1 reporter virus. Through the use of HIV-1 VLPs containing Gag cleavage site substitutions and point mutations in CA which alter the stability of the viral capsid, we demonstrate that saturation of TRIM5α restriction depends on the stability of the capsid in the incoming VLPs. Differences in the requirement for cleavage of the specific sites in Gag were observed between distinct African green monkey cell lines. The results strongly suggest that the mechanism of HIV-1 restriction by TRIM5α involves engagement of the viral capsid by the restriction factor prior to completion of uncoating.