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CD8⁺ Cell Depletion of SHIV89.6P-Infected Macaques Induces CD4⁺ T Cell Proliferation that Contributes to Increased Viral Loads¹

Yvonne M. Mueller,^* Duc H. Do,^* Jean D. Boyer, Muhamuda Kader, Joseph J. Mattapallil, Mark G. Lewis, David B. Weiner, and Peter D. Katsikis^2*

^*Department of Microbiology and Immunology, and Center for Immunology and Vaccine Sciences, Drexel University College of Medicine, Philadelphia, PA, 19129; Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104; Uniformed Services University of the Health Sciences, Bethesda MD 20814; and BIOQUAL, Rockville, MD 20850

Previous studies have shown that depletion of CD8⁺ cells during acute and chronic simian immunodeficiency virus (SIV) infection leads to increased viral replication, morbidity, and mortality, which have been attributed to loss of CD8⁺ T cell-mediated control of SIV. However, these studies did not exclude that CD8⁺ cell depletion increased homeostatic proliferation of CD4⁺ T cells, resulting in increased viral targets and, therefore, viral rebound. Chronically SHIV89.6P-infected cynomolgus macaques were CD8⁺ cell-depleted, and the frequency, cell number, and phenotype of CD4⁺ T cells and viral infection were examined using flow cytometry and quantitative real-time PCR. The frequency and number of Ki-67-expressing CD4⁺ T cells were increased with CD8⁺ cell depletion. This proliferation of CD4⁺ T cells occurred even in animals with no rebound of viral loads. Most of the proliferating cells were effector memory CD4⁺ T cells. Plasma simian HIV (SHIV) RNA copies positively correlated with proliferating CD4⁺ T cells and SHIV DNA copies in Ki-67⁺ CD4⁺ T cells. Although this study does not exclude an important role for virus-specific CD8⁺ T cells in SIV and SHIV infection, our data suggest that homeostatic proliferation is an important contributor to increases in plasma viremia that follow CD8⁺ cell depletion.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by Grants R01 AI62437 and R01 AI46719 (to P.D.K.), Grant R01 A1-071886 (to J.D.B.), and Grants K22 AI07812 and R21 DE018339 (to J.J.M.) all from the National Institutes of Science. D.B.W. was supported in part by grants from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. Peter D. Katsikis, Department of Microbiology and Immunology, and Center for Immunology and Vaccine Sciences, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129. E-mail address: Peter.Katsikis{at}DrexelMed.edu

³ Abbreviations used in this paper: SHIV, simian HIV; PLN, peripheral lymph node; MLN, mesenteric lymph node; GALT, gut-associated lymphoid tissue.