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Short-Lived Infected Cells Support Virus Replication in Sooty Mangabeys Naturally Infected with Simian Immunodeficiency Virus: Implications for AIDS Pathogenesis

Shari N. Gordon,^1,2 Richard M. Dunham,^1,2 Jessica C. Engram,^1,2 Jacob Estes,^3, Zichun Wang,⁴ Nichole R. Klatt,^1,2 Mirko Paiardini,¹ Ivona V. Pandrea,⁵ Cristian Apetrei,⁵ Donald L. Sodora,⁶ Ha Youn Lee,^7,8 Ashley T. Haase,³ Michael D. Miller,⁹ Amitinder Kaur,⁴ Silvija I. Staprans,^2,10 Alan S. Perelson,⁷ Mark B. Feinberg,^2,10 and Guido Silvestri^1,2*

Department of Pathology, University of Pennsylvania, Philadelphia, Pennsylvania,¹ Emory Vaccine Center and Yerkes National Primate Research Center, Atlanta, Georgia,² Department of Microbiology, University of Minnesota, Minneapolis, Minnesota,³ New England Primate Research Center, Harvard Medical School, Southborough, Massachusetts,⁴ Tulane National Primate Research Center, Covington, Louisiana,⁵ Seattle Biomedical Research Institute, Seattle, Washington,⁶ Los Alamos National Laboratory, Los Alamos, New Mexico,⁷ University of Rochester, Rochester, New York,⁸ Gilead Sciences, Inc., Foster City, California,⁹ Merck Vaccine Division, Merck & Co., Inc., West Point, Pennsylvania,¹⁰

Received 7 November 2007/ Accepted 15 January 2008

Sooty mangabeys (SMs) naturally infected with simian immunodeficiency virus (SIV) 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 human immunodeficiency virus (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 SMs naturally infected with SIV also present a two-phase decay of viremia following ART, with the bulk (92 to 99%) of virus replication sustained by short-lived cells (average life span, 1.06 days), and only 1 to 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 type 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 life span of infected cells is a common feature of both pathogenic and nonpathogenic 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.

Published ahead of print on 23 January 2008.

Current address: AIDS Vaccine Program, SAIC-Frederick, Inc., National Cancer Institute, Frederick, MD.

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