The Antiviral Spectra of TRIM5α Orthologues and Human TRIM Family Proteins against Lentiviral Production

Background: Rhesus monkey TRIM5 alpha (TRIM5 alpha rh) recognizes the incoming HIV-1 core through its C-terminal B30.2(PRYSPRY) domain and promotes its premature disassembly or degradation before reverse transcription. Previously, we have shown that TRIM5 alpha rh blocks HIV-1 production through the N-terminal RBCC domain by the recognition of Gag polyproteins. Although all TRIM family proteins have RBCC domains, it remains elusive whether they possess similar late-restriction activities. Methodology/Principal Findings: We examined the antiviral spectra of TRIM5 alpha orthologues and human TRIM family members which have a genetic locus proximal to human TRIM5 alpha (TRIM5 alpha hu), against primate lentiviral production. When HIV-1 virus-like particles (VLPs) were generated in the presence of TRIM5 alpha proteins, rhesus, African green and cynomolgus monkey TRIM5 alpha (TRIM5 alpha ag and TRIM5 alpha cy), but not TRIM5 alpha hu, were efficiently incorporated into VLPs, suggesting an interaction between HIV-1 Gag and TRIM5 alpha proteins. TRIM5 alpha rh potently restricted the viral production of HIV-1 groups M and O and HIV-2, but not simian lentiviruses including SIV(MAC)1A11, SIV(AGM)Tan-1 or SIV(AGM)SAB-1. TRIM5 alpha hu did not show notable late restriction activities against these lentiviruses. TRIM5 alpha ag and TRIM5 alpha cy showed intermediate restriction phenotypes against HIV-1 and HIV-2, but showed no restriction activity against SIV production. A series of chimeric TRIM5 alpha constructs indicated that the N-terminal region of TRIM5 alpha ag and TRIM5 alpha cy are essential for the late restriction activity, while the C-terminal region of TRIM5 alpha cy negatively regulates the late restriction activity against HIV-1. When select human TRIM family proteins were examined, TRIM21 and 22 were efficiently incorporated into HIV-1 VLPs, while only TRIM22 reduced HIV-1 titers up to 5-fold. The antiviral activities and encapsidation efficiencies did not correlate with their relative expression levels in the producer cells. Conclusions/Significance: Our results demonstrated the variations in the late restriction activities among closely related TRIM5 alpha orthologues and a subset of human TRIM family proteins, providing further insights into the late restriction activities of TRIM proteins.