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Journal of Virology, May 2006, p. 4683-4690, Vol. 80, No. 10
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.10.4683-4690.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cyclophilin A Renders Human Immunodeficiency Virus Type 1 Sensitive to Old World Monkey but Not Human TRIM5 Antiviral Activity

Department of Infection, Royal Free and University College Medical School, University College London, Windeyer Building, 46 Cleveland Street, London, W1T4JF, United Kingdom

Received 24 November 2005/ Accepted 18 February 2006

TRIM5 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 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 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-restricted HIV-1 infectivity. The effect of cyclosporine A on HIV-1 infectivity is dependent on TRIM5 expression, and expression of simian TRIM5 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 TRIM5 and owl monkey TRIM-Cyp. TRIM-Cyp, but not TRIM5, recruits its tripartite motif to HIV-1 capsid via cyclophilin A and, therefore, HIV-1 G89V is insensitive to TRIM-Cyp but sensitive to TRIM5. We propose that cyclophilin A isomerization of a proline residue in the TRIM5 sensitivity determinant of the HIV-1 capsid sensitizes it to restriction by Old World monkey TRIM5. In humans, where HIV-1 has adapted to bypass TRIM5 activity, the effects of cyclosporine A are independent of TRIM5. We speculate that cyclophilin A alters HIV-1 sensitivity to a TRIM5-independent innate immune pathway in human cells.

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