14th International AIDS Conference Barcelona, Spain - July 7-12, 2002

Int Conf AIDS 2002 Jul 7-12; 14:(abstract no. WeOrA1260)

Sherman MP, Neidleman JA, Mundt P, Williams SA, de Noronha CM, Grant R, Kreis C, Warmerdam M, Kahn J, Hecht R, Greene WC
Gladstone Institute of Virology &Immunology, San Francisco, United States

BACKGROUND: The HIV-1 accessory protein Vpr enhances HIV replication in macrophages and, when over-expressed in cultured primate cell lines, induces G2 cell cycle arrest. While it is hypothesized that arrest enhances viral replication, the demonstration of such cell cycle perturbation in the absence of Vpr overexpression has not been clearly demonstrated. Furthermore, it is unknown whether HIV-infected target cells in vivo display an abnormal cell cycle progression.

METHODS: We are now able to identify HIV-infected cells expressing viral proteins at the appropriate levels by employing intracellular p24 and flow cytometry. We infected peripheral blood mononuclear cells (PBMC) from sero-negative donors utilizing isogenic NL4-3 molecular clones differing only in Vpr expression. We also stained circulating PBMC isolated directly from patients with primary HIV infection.

RESULTS: We find that cultured PBMC subjected to a spreading infection display G2 cell cycle arrest that is greatly augmented by the presence of Vpr. In the absence of Vpr, these cell cycle changes are markedly diminished and vary from donor to donor. Importantly, a significant proportion of the activated T cells circulating in the peripheral blood of HIV-infected patients are arrested or paused at the G2/M phase of the cell cycle. However, activated but uninfected T cells from these same patients display a normal cell cycle distribution

CONCLUSION: These data thus provide the first evidence that HIV alters cell cycle progression in vivo, likely in a Vpr-dependent fashion. This arrest may play a role in not only virus production, but also in the accelerated T cell turnover observed in HIV-infected individuals.

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WeOrA1260

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