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Virological Outcome after Structured Interruption of Antiretroviral Therapy for Human Immunodeficiency Virus Infection Is Associated with the Functional Profile of Virus-Specific CD8⁺ T Cells

Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,¹ Graduate Genetics Program, George Washington University, Washington, DC 20522,² Human Immunology Section,³ Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892,⁴ Department of Medical Biochemistry and Immunology, University of Cardiff, Heath Park, Cardiff CF14 4XN, United Kingdom,⁵ Department of Microbiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104,⁶ Office of the U.S. Global AIDS Coordinator, U.S. Department of State, Washington, DC 20522⁷

Received 10 October 2007/ Accepted 19 January 2008

A clear understanding of the antiviral effects of CD8⁺ T cells in the context of chronic human immunodeficiency virus (HIV) infection is critical for the development of prophylactic vaccines and therapeutics designed to support T-cell-mediated immunity. However, defining the potential correlates of effective CD8⁺ T-cell immunity has proven difficult; notably, comprehensive analyses have demonstrated that the size and shape of the CD8⁺ T-cell response are not necessarily indicative of efficacy determined by measures of plasma viral load. Here, we conducted a detailed quantitative and qualitative analysis of CD8⁺ T-cell responses to autologous virus in a cohort of six HIV-infected individuals with a history of structured interruption of antiretroviral therapy (ART) (SIT). The magnitude and breadth of the HIV-specific response did not, by themselves, explain the changes observed in plasma virus levels after the cessation of ART. Furthermore, mutational escape from targeted epitopes could not account for the differential virological outcomes in this cohort. However, the functionality of HIV-specific CD8⁺ T-cell populations upon antigen encounter, determined by the simultaneous and independent measurement of five CD8⁺ T-cell functions (degranulation and gamma interferon, macrophage inflammatory protein 1β, tumor necrosis factor alpha, and interleukin-2 levels) reflected the emergent level of plasma virus, with multiple functions being elicited in those individuals with lower levels of viremia after SIT. These data show that the quality of the HIV-specific CD8⁺ T-cell response, rather than the quantity, is associated with the dynamics of viral replication in the absence of ART and suggest that the effects of SIT can be assessed by measuring the functional profile of HIV-specific CD8⁺ T cells.

Published ahead of print on 30 January 2008.