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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{alpha} Antiviral Activity

Zuzana Keckesova, Laura M. J. Ylinen, and Greg J. Towers*

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{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 on 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 an 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 HIV-1 capsid via cyclophilin A and, therefore, HIV-1 G89V is insensitive to TRIM-Cyp but sensitive to TRIM5{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.

* Corresponding author. Mailing address: Department of Infection, Royal Free and University College Medical School, University College London, Windeyer Building, 46 Cleveland Street, London W1T4JF, United Kingdom. Phone: 44 20 7679 9535. Fax: 44 20 7679 9545. E-mail: g.towers{at}ucl.ac.uk.

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.



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