Two new papers add to the literature demonstrating that the presence of polyfunctional HIV-specific T cell responses correlates with low viral load in HIV infection. In one paper, in the European Journal of Immunology, Rick Koup and colleagues report that virus-specific CD4 and CD8 T cells capable of multiple functions (involving various combinations of IL-2, TNF alpha, interferon gamma and MIP-1 beta production and expression of CD107a, a marker indicating cell-killing ability) are far more frequently detectable in HIV-2 than HIV-1 infection. The study also confirms prior reports that such polyfunctional T cells make 15-20 times more interferon gamma and TNF alpha on a per-cell basis than monofunctional T cells. The authors note that the data do not prove a causative role of the T cell responses in controlling viral load and preventing or slowing disease progression in HIV-2-infected individuals, but cite evidence from other recent studies - including Robert Seder's murine Leishmania vaccine work - as suggesting that polyfunctional T cells do contribute to control of pathogens and are thus unlikely to have arisen simply as a consequence of low viral load in HIV-2 infection.
In a second paper - just published online in J. Virology by Marybeth Daucher from Daniel Douek's laboratory at NIAID - polyfunctional CD8 T cell responses targeting HIV-1 are reported to be associated with maintenance of low viral loads subsequent to antiretroviral therapy interruption. The study only involves six individuals so the authors are appropriately cautious in interpreting the data, but they emphasize that other parameters such as the magnitude and breadth of the HIV-specific CD8 T cell response showed no correlations with post-interruption outcomes. In summing up their work, the researchers state: "Despite the small number of patients and the inherent issues associated with the interpretation of observational studies in humans, these data suggest that functional attributes of the HIV-specific CD8 T-cell response might be important correlates of virological outcome after exposure to SIT regimens and could represent useful biological parameters to measure in the clinical context."
European Journal of Immunology
Volume 38, Issue 2 , Pages 350 - 363
Published Online: 17 Jan 2008
Polyfunctional T cell responses are a hallmark of HIV-2 infection (free access to full text)
Melody G. Duvall 1 2, Melissa L. Precopio 2, David A. Ambrozak 2, Assan Jaye 4, Andrew J. McMichael 1, Hilton C. Whittle 4, Mario Roederer 3, Sarah L. Rowland-Jones 1 4, Richard A. Koup, Dr. 2
1MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
2Immunology Laboratory, Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
3Immuno Technology Section, Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, MD, USA
4MRC Laboratories Fajara, Banjul, The Gambia, West Africa
Funded by:
National Institutes of Health, USA
Medical Research Council, UK
Abstract
HIV-2 is distinguished clinically and immunologically from HIV-1 infection by delayed disease progression and maintenance of HIV-specific CD4+ T cell help in most infected subjects. Thus, HIV-2 provides a unique natural human model in which to investigate correlates of immune protection against HIV disease progression. Here, we report a detailed assessment of the HIV-2-specific CD4+ and CD8+ T cell response compared to HIV-1, using polychromatic flow cytometry to assess the quality of the HIV-specific T cell response by measuring IFN-, IL-2, TNF-, MIP-1, and CD107a mobilization (degranulation) simultaneously following Gag peptide stimulation. We find that HIV-2-specific CD4+ and CD8+ T cells are more polyfunctional that those specific for HIV-1 and that polyfunctional HIV-2-specific T cells produce more IFN- and TNF- on a per-cell basis than monofunctional T cells. Polyfunctional HIV-2-specific CD4+ T cells were generally more differentiated and expressed CD57, while there was no association between function and phenotype in the CD8+ T cell fraction. Polyfunctional HIV-specific T cell responses are a hallmark of non-progressive HIV-2 infection and may be related to good clinical outcome in this setting.
JVI Accepts, published online ahead of print on 30 January 2008
J. Virol. doi:10.1128/JVI.02212-07
Marybeth Daucher*, David A Price, Jason M Brenchley, Laurie Lamoreaux, Julia A Metcalf, Catherine Rehm, Elizabeth Nies-Kraske, Elizabeth Urban, Christian Yoder, Diane Rock, Julie Gumkowski, Michael R Betts, Mark R Dybul, and Daniel C Douek
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
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{gamma}, MIP1{beta}, TNF{alpha} 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.
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