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Preservation of T Cell Proliferation Restricted by Protective HLA Alleles Is Critical for Immune Control of HIV-1 Infection¹

Helen Horton^*,, Ian Frank^*, Ruth Baydo^*, Emilie Jalbert^*, Justin Penn^*, Sean Wilson^*, John P. McNevin^*, Matthew D. McSweyn^*, Deborah Lee^*, Yunda Huang, Stephen C. De Rosa^*, and M. Juliana McElrath^2,*,,

^* Program in Infectious Diseases and Statistical Center for HIV/AIDS Research and Prevention, Fred Hutchinson Cancer Research Center, Seattle, WA 98109; and Department of Medicine and Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, WA 98195

HIV-1-infected persons with HLA-B27 and -B57 alleles commonly remain healthy for decades without antiretroviral therapy. Properties of CD8⁺ T cells restricted by these alleles considered to confer disease protection in these individuals are elusive but important to understand and potentially elicit by vaccination. To address this, we compared CD8⁺ T cell function induced by HIV-1 immunogens and natural infection using polychromatic flow cytometry. HIV-1-specific CD8⁺ T cells from all four uninfected immunized and 21 infected subjects secreted IFN- and TNF-. However, CD8⁺ T cells induced by vaccination and primary infection, but not chronic infection, proliferated to their cognate epitopes. Notably, B27- and B57-restricted CD8⁺ T cells from nonprogressors exhibited greater expansion than those restricted by other alleles. Hence, CD8⁺ T cells restricted by certain protective alleles can resist replicative defects, which permits expansion and antiviral effector activities. Our findings suggest that the capacity to maintain CD8⁺ T cell proliferation, regardless of MHC-restriction, may serve as an important correlate of disease protection in the event of infection following vaccination.

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 Grants U01 AI 4674, U01 AI 46725, P01 AI 057005, R01 AI65328-01, and M01-RR-00037 from the National Institutes of Health.

² Address correspondence and reprint requests to Dr. M. Juliana McElrath, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, D3-100, Seattle, WA 98109; E-mail address: jmcelrat{at}fhcrc.org

³ Abbreviations used in this paper: LTNP, long-term nonprogressor; ART, antiretroviral therapy; AINR, activation-induced nonresponsiveness; T_EM, effector memory; T_E, effector; T_CM, central memory.

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