Cyclophilin A renders human immunodeficiency virus type 1 sensitive to old world monkey but not human TRIM5α antiviral activity

TRIM5 alpha is an important mediator of antiretroviral innate immunity influencing species-specific retroviral replication. Here we investigate the role of the peptidyl prolyl isomerase enzyme cyclophilin A in TRIM5 alpha antiviral activity. Cyclophilin A is recruited into nascent human immunodeficiency virus type 1 (HIV-1) virions as well as incoming HIV-1 capsids, where it isomerizes an exposed proline residue. Here we show that cyclophilin A renders HIV-1 sensitive to restriction by TRIM5 alpha in cells from Old World monkeys, African green monkey and rhesus macaque. Inhibition of cyclophilin A activity with cyclosporine A, or reducing cyclophilin A expression with small interfering RNA, rescues TRIM5 alpha-restricted HIV-1 infectivity. The effect of cyclosporine A on HIV-1 infectivity is dependent oil TRIM5 alpha expression, and expression of simian TRIM5 alpha in permissive feline cells renders them able to restrict HIV-1 in a cyclosporine A-sensitive way. We use all HIV-1 cyclophilin A binding mutant (CA G89V) to show that cyclophilin A has different roles in restriction by Old World monkey TRIM5 alpha and owl monkey TRIM-Cyp. TRIM-Cyp, but not TRIM5 alpha, recruits its tripartite motif to HlV-1 capsid via cyclophilin A and, therefore, HIV-1 G89V is insensitive to TRIM-Cyp but sensitive to TRIM-5 alpha. We propose that cyclophilin A isomerization of a proline residue in the TRIM5 alpha sensitivity determinant of the HIV-1 capsid sensitizes it to restriction by Old World monkey TRIM5 alpha. In humans, where HIV-1 has adapted to bypass TRIM5 alpha activity, the effects of cyclosporine A are independent of TRIM5 alpha. We speculate that cyclophilin A alters HIV-1 sensitivity to a TRIM5 alpha-independent innate immune pathway in human cells.