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HIV Envelope Suppresses CD4⁺ T Cell Activation Independent of T Regulatory Cells¹

Division of Infectious Diseases, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104

We previously demonstrated that HIV envelope glycoprotein (Env), delivered in the form of a vaccine and expressed by dendritic cells or 293T cells, could suppress Ag-stimulated CD4⁺ T cell proliferation. The mechanism remains to be identified but is dependent on CD4 and independent of coreceptor binding. Recently, CD4⁺ regulatory T (Treg) cells were found to inhibit protective anti-HIV CD4⁺ and CD8⁺ T cell responses. However, the role of Tregs in HIV remains highly controversial. HIV Env is a potent immune inhibitory molecule that interacts with host CD4⁺ cells, including Treg cells. Using an in vitro model, we investigated whether Treg cells are involved in Env-induced suppression of CD4⁺ T cell proliferation, and whether Env directly affects the functional activity of Treg cells. Our data shows that exposure of human CD4⁺ T cells to Env neither induced a higher frequency nor a more activated phenotype of Treg cells. Depletion of CD25⁺ Treg cells from PBMC did not overcome the Env-induced suppression of CD4⁺ T cell proliferation, demonstrating that CD25⁺FoxP3⁺ Treg cells are not involved in Env-induced suppression of CD4⁺ T cell proliferation. In addition, we extend our observation that similar to Env expressed on cells, Env present on virions also suppresses CD4⁺ T cell proliferation.

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 work was supported by National Institutes of Health Grants R01 AI50484.

² Address correspondence and reprint requests to Dr. Drew Weissman, 522B Johnson Pavilion, 3610 Hamilton Walk, Philadelphia, PA 19104. E-mail address: dreww{at}mail.med.upenn.edu

³ Abbreviations used in this paper: Env, HIV envelope glycoprotein; DC, dendritic cell; Treg, regulatory T; PB, peripheral blood; LN, lumph node; AT-2, Aldrothiol-2; s, soluble.