JVI Accepts, published online ahead of print on 23 January 2008

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J. Virol. doi:10.1128/JVI.02408-07
Copyright (c) 2008, American Society for Microbiology and/or the Listed Authors/Institutions. All Rights Reserved.

Short-lived infected cells support virus replication in naturally SIV-infected sooty mangabeys: implications for AIDS pathogenesis

Shari N. Gordon, Richard M. Dunham, Jessica C. Engram, Jacob Estes, Zichun Wang, Nichole R. Klatt, Mirko Paiardini, Ivona V. Pandrea, Cristian Apetrei, Donald L. Sodora, Ha Youn Lee, Ashley T. Haase, Michael D. Miller, Amitinder Kaur, Silvija I. Staprans, Alan S. Perelson, Mark. B. Feinberg, and Guido Silvestri^*

Department of Pathology, University of Pennsylvania, Philadelphia, PA; Emory Vaccine Center and Yerkes National Primate Research Center, Atlanta, GA; Department of Microbiology, University of Minnesota, Minneapolis, MN; New England Primate Research Center, Harvard Medical School, Southborough, MA; Tulane National Primate Research Center, Covington, LA; Seattle Biomedical Research Institute, Seattle, WA; Los Alamos National Laboratory, Los Alamos, NM; University of Rochester, Rochester, NY; Gilead Sciences, Inc., Foster City, CA; Merck Vaccine Division, Merck & Co., Inc. West Point, PA

^* To whom correspondence should be addressed. Email: gsilvest{at}mail.med.upenn.edu.

Naturally SIV-infected sooty mangabeys (SMs) do not develop AIDS despite high levels of virus replication. At present, the mechanisms underlying this disease-resistance are poorly understood. Here we tested the hypothesis that SIV-infected SMs avoid immunodeficiency as a result of virus replication occurring in infected cells that live significantly longer than HIV-infected human cells. To this end, we treated six SIV-infected SMs with potent antiretroviral therapy (ART) and longitudinally measured the decline in plasma viremia. We applied the same mathematical models used in HIV-infected individuals, and observed that naturally SIV-infected SMs also present a two-phase decay of viremia following ART, with the bulk (92-99%) of virus replication sustained by short-lived cells (average lifespan 1.06 days) and only 1-8% occurring in longer-lived cells. In addition, we observed that ART had a limited impact on CD4+ T cells and the prevailing level of T cell activation and proliferation in SIV-infected SMs. Collectively, these results suggest that in SIV-infected SMs, similar to HIV-1-infected humans, short-lived activated CD4+ T cells, rather than macrophages, are the main source of virus production. These findings indicate that a short in vivo lifespan of infected cells is a common feature of both pathogenic and non-pathogenic primate lentivirus infections, and support a model for AIDS pathogenesis whereby the direct killing of infected cells by HIV is not the main determinant of disease progression.

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