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Journal of Virology, March 2006, p. 2855-2862, Vol. 80, No. 6
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.6.2855-2862.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Cyclophilin A and TRIM5{alpha} Independently Regulate Human Immunodeficiency Virus Type 1 Infectivity in Human Cells

Elena Sokolskaja,1 Lionel Berthoux,1 and Jeremy Luban1,2*

Departments of Microbiology,1 Medicine, Columbia University, New York, New York2

Received 23 March 2005/ Accepted 7 December 2005

Cyclophilin A (CypA), a cytoplasmic, human immunodeficiency virus type 1 (HIV-1) CA-binding protein, acts after virion membrane fusion with human cells to increase HIV-1 infectivity. HIV-1 CA is similarly greeted by CypA soon after entry into rhesus macaque or African green monkey cells, where, paradoxically, the interaction decreases HIV-1 infectivity by facilitating TRIM5{alpha}-mediated restriction. These observations conjure a model in which CA recognition by the human TRIM5{alpha} orthologue is precluded by CypA. Consistent with the model, selection of a human cell line for decreased restriction of the TRIM5{alpha}-sensitive, N-tropic murine leukemia virus (N-MLV) rendered HIV-1 transduction of these cells independent of CypA. Additionally, HIV-1 virus-like particles (VLPs) saturate N-MLV restriction activity, particularly when the CA-CypA interaction is disrupted. Here the effects of CypA and TRIM5{alpha} on HIV-1 restriction were examined directly. RNA interference was used to show that endogenous human TRIM5{alpha} does indeed restrict HIV-1, but the magnitude of this antiviral activity was not altered by disruption of the CA-CypA interaction or by elimination of CypA protein. Conversely, the stimulatory effect of CypA on HIV-1 infectivity was completely independent of human TRIM5{alpha}. Together with previous reports, these data suggest that CypA protects HIV-1 from an unknown antiviral activity in human cells. Additionally, target cell permissivity increased after loading with heterologous VLPs, consistent with a common saturable target that is epistatic to both TRIM5{alpha} and the putative CypA-regulated restriction factor.

* Corresponding author. Mailing address: Department of Microbiology, Columbia University, 701 West 168th Street, New York, NY 10032. Phone: (212) 305-8710. Fax: (212) 305-0333. E-mail: jl45{at}columbia.edu.

Journal of Virology, March 2006, p. 2855-2862, Vol. 80, No. 6
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.6.2855-2862.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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