Cyclophilin A Renders Human Immunodeficiency Virus Type 1 Sensitive to Old World Monkey but Not Human TRIM5α Antiviral Activity

Abstract

TRIM5α 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 TRIM5α 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 TRIM5α 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 TRIM5α-restricted HIV-1 infectivity. The effect of cyclosporine A on HIV-1 infectivity is dependent on TRIM5α expression, and expression of simian TRIM5α in permissive feline cells renders them able to restrict HIV-1 in a cyclosporine A-sensitive way. We use an HIV-1 cyclophilin A binding mutant (CA G89V) to show that cyclophilin A has different roles in restriction by Old World monkey TRIM5α and owl monkey TRIM-Cyp. TRIM-Cyp, but not TRIM5α, recruits its tripartite motif to HIV-1 capsid via cyclophilin A and, therefore, HIV-1 G89V is insensitive to TRIM-Cyp but sensitive to TRIM5α. We propose that cyclophilin A isomerization of a proline residue in the TRIM5α sensitivity determinant of the HIV-1 capsid sensitizes it to restriction by Old World monkey TRIM5α. In humans, where HIV-1 has adapted to bypass TRIM5α activity, the effects of cyclosporine A are independent of TRIM5α. We speculate that cyclophilin A alters HIV-1 sensitivity to a TRIM5α-independent innate immune pathway in human cells.