Cyclophilin A Renders Human Immunodeficiency Virus Type 1 Sensitive to Old World Monkey but Not Human Trim5 Alpha Antiviral Activity.
From: Department of Infection, Royal Free and University College Medical School, University College London, Windeyer Building, 46 Cleveland Street, London W1T4JF, United Kingdom.
Journal of virology
- Publish Date: May 2006
- ISSN: 0022-538X
- Volume: 80
- Issue: 10
- Pages: 4683-90
- Medium: Print
- Language: English
- Citation (JAMA): Keckesova Zuzana, Ylinen Laura M J, Towers Greg J, et al. Cyclophilin A Renders Human Immunodeficiency Virus Type 1 Sensitive to Old World Monkey but Not Human Trim5 Alpha Antiviral Activity.. J. Virol. May 2006;80:4683-90
Abstract
TRIM5alpha 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 TRIM5alpha 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 TRIM5alpha 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 TRIM5alpha-restricted HIV-1 infectivity. The effect of cyclosporine A on HIV-1 infectivity is dependent on TRIM5alpha expression, and expression of simian TRIM5alpha 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 TRIM5alpha and owl monkey TRIM-Cyp. TRIM-Cyp, but not TRIM5alpha, recruits its tripartite motif to HIV-1 capsid via cyclophilin A and, therefore, HIV-1 G89V is insensitive to TRIM-Cyp but sensitive to TRIM5alpha. We propose that cyclophilin A isomerization of a proline residue in the TRIM5alpha sensitivity determinant of the HIV-1 capsid sensitizes it to restriction by Old World monkey TRIM5alpha. In humans, where HIV-1 has adapted to bypass TRIM5alpha activity, the effects of cyclosporine A are independent of TRIM5alpha. We speculate that cyclophilin A alters HIV-1 sensitivity to a TRIM5alpha-independent innate immune pathway in human cells.
Mesh Headings (Keywords): Animals, Anti-HIV Agents, Carrier Proteins, Cats, Cell Line, Cercopithecidae, Cyclophilin A, Cyclosporine, Drug Resistance, Viral, HIV Infections, HIV-1, Humans, Leukemia Virus, Murine, Simian immunodeficiency virus
Check for Full Text / PubMed Unique Identifier (PMID): 16641261
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