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Role of Cyclophilin A in HIV Type 1 Replication

M.D. Bobardt, P.A. Gallay

Assembly of retroviral virions is orchestrated by proteins encoded by the gene gag. The proteins are synthesized as a precursor that is cleaved during particle maturation by a virally encoded protease. The protein Gag not only carries all the information necessary for the formation and budding of retroviral particles but also mediates virion incorporation of the viral envelope and genomic RNA. In addition, functional and genetic analyses have indicated that Gag plays a crucial role during the early steps of replication, such as uncoating and the nuclear targeting of the viral preintegration complex.

Although crucial interactions with various components of the cell machinery most likely underlie the completion of these steps, only a few of the host cellular partners of Gag have been determined. Of these, the ubiquitous and abundant cytoplasmic protein cyclophilin A, best known as the receptor for the immunosuppressant cyclosporin A, specifically associates with a region of Gag, the capsid responsible for the formation of the mature virion core. This specific interaction between 2 critical residues of the capsid allows incorporation of cyclophilin A into the viral particles. Virions made deficient in cyclophilin A, either by mutations of these capsid residues or by producing virions in the presence of cyclosporin A, which is a competitive inhibitor of the interaction between cyclophilin A and the capsid, have attenuated infectivity.

Despite intensive research, the precise role of cyclophilin A during infection with HIV type 1 (HIV-1) remains completely unknown. Recent data obtained in our laboratory might shed light on the mechanisms of action of cyclophilin A. We found that noninfectious cyclophilin A--deficient viruses efficiently formed in viral producer cells and released into the extracellular medium were indistinguishable from wild-type viruses by standard biochemical criteria. However, we discovered that disruption of cyclophilin A incorporation caused a dramatic reduction in viral entry into target cells. We are currently using a variety of immunologic, biochemical and genetic approaches to experimentally define what role cyclophilin A plays in early events of the HIV-1 life cycle. It is hoped that understanding the precise role of cyclophilin A in HIV-1 infectivity will lead to the development of novel anti-viral therapies.

PUBLICATIONS

Camaur, D., Gallay, P., Swingler, S., Trono, D. Human immunodeficiency virus matrix tyrosine phosphorylation: Characterization of the kinase and its substrate requirements. J. Virol. 71:6834, 1997.

Gallay, P., Hope, T., Chin, D., Trono, D. HIV-1 infection of nondividing cells mediated through the recognition of integrase by the importin/karyopherin pathway. Proc. Natl. Acad. Sci. U.S.A. 94:9825, 1997.

Swingler, S., Gallay, P., Camaur, D., Song, J., Abo, A., Trono, D. The Nef protein of human immunodeficiency virus type 1 enhances serine phosphorylation of the viral matrix. J. Virol. 71:4372, 1997.