Virological Outcome After Structured Interruption of Antiretroviral Therapy For HIV 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, MD 20892; Graduate Genetics Program, George Washington University, Washington, DC 20522; Human Immunology Section, and Immunology Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892; Department of Medical Biochemistry and Immunology, University of Cardiff, Heath Park, Cardiff CF14 4XN, UK; Department of Microbiology, University of Pennsylvania, Philadelphia, PA 19104; Office of the U.S. Global AIDS Coordinator, U.S. Department of State, Washington, DC 20522

^* To whom correspondence should be addressed. Email: mdaucher{at}niaid.nih.gov.

	Abstract

A clear understanding of the antiviral effects of CD8⁺ T-cells in the context of chronic 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 is 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 (SIT). The magnitude and breadth of the HIV-specific response did not, by itself, explain the changes observed in plasma virus levels after 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, IFN, MIP1, TNF and IL2) reflected the emergent level of plasma virus with multiple functions being elicited in those individuals with lower 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.