Strain-Specific Differences in the Impact of Human TRIM5α, Different TRIM5α Alleles, and the Inhibition of Capsid-Cyclophilin A Interactions on the Infectivity of HIV-1

HIV-1 infectivity is strongly restricted by TRIM5 alpha from certain primate species but has been described as being only marginally susceptible to human TRIM5 alpha. In this study, we evaluated the effects of the modulation of human TRIM5 alpha activity (pretreatment of target cells with alpha interferon, expression of a pre-miRNA targeting TRIM5 alpha, and/or overexpression of TRIM5 gamma), the inhibition of cyclophilin A (CypA)-CA interactions, and the expression of different allelic variants of human TRIM5 alpha on the infectivity of a series of recombinant viruses carrying different patient-derived Gag-protease sequences. We show that HIV-1 displays virus-specific differences in its sensitivity to human TRIM5 alpha and in its sensitivity to different TRIM5 alpha alleles. The effect of inhibiting CypA-CA interactions is also strain specific, and blocking these interactions can either inhibit or improve viral infectivity, depending on the isolate studied. The inhibition of CypA-CA interactions also modulates viral sensitivity to human TRIM5 alpha. In the absence of CypA-CA interactions, most viruses displayed increased sensitivity to the inhibitory effects of TRIM5 alpha on viral replication, but one isolate showed a paradoxical decrease in sensitivity to TRIM5 alpha. Taken together, these findings support a model in which three interlinked factors-capsid sequence, CypA levels, and TRIM5 alpha-interact to determine capsid stability and therefore viral infectivity.