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* Division of Experimental Medicine and
HIV/AIDS Division, San Francisco General Hospital, Department of Medicine, and
Department of Epidemiology and Biostatistics, University of California, San Francisco, CA 94110
Infection with HIV usually results in chronic activation of the immune system, with profound quantitative and qualitative changes in the T cell compartment. To better understand the mechanistic basis for T cell dysfunction and to discern whether such mechanisms are reversed after effective antiviral treatment, we analyzed changes in signaling pathways of human CD4+ and CD8+ T cells from 57 HIV-infected subjects in varying stages of disease progression and treatment, including long-term nonprogressors, progressors, and chronically infected subjects provided effective antiretroviral therapy (responders). A previously described PhosFlow method was adapted and optimized so that protein phosphorylation could be visualized in phenotypically defined subpopulations of CD4+ and CD8+ T cells (naive, memory, and effector) by flow cytometry. T cell signaling induced by TCR cross-linking, IL-2, or PMA/ionomycin was found to be blunted within all T cell subpopulations in those with progressive HIV disease compared with long-term nonprogressors and responders. Although alterations in cellular signaling correlated with levels of basal phosphorylation, viral load, and/or expression of programmed death-1, it was the level of basal phosphorylation that appeared to be the factor most dominantly associated with impaired signaling. Notably, provision of effective antiretroviral therapy was associated with a normalization of both basal phosphorylation levels and T cell signaling. These data, in aggregate, suggest that generalized dysfunction of the T cell compartment during progressive HIV disease may be in part dependent upon an increased basal level of phosphorylation, which itself may be due to the heightened state of immune activation found in advanced disease.
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 in part by grants from the University-wide AIDS Research Program (F05-GI-219), the National Institutes of Health (R01 AI40312, AI47062, AI52745, K24 AI69994, and M01 RR00083), American Foundation for AIDS Research (106710-40-RGRL), the University of California Center for AIDS Research (P30 AI27763, P30 MH59037, and CC99-SF-001), and the University of California Clinical and Translational Research Institute (UL1 RR024131), a component of the National Institutes of Health Roadmap for Medical Research. J.M.M. is a recipient of the Burroughs Wellcome Fund Clinical Scientist Award in Translational Research and the National Institutes of Health Director’s Pioneer Award Program, part of the National Institutes of Health Roadmap for Medical Research, through Grant DPI OD00329.
2 Current address: Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
3 Address correspondence and reprint requests to Dr. Joseph M. McCune, University of California, Division of Experimental Medicine, Box 1234, SFGH Building 3, San Francisco, CA 94143. E-mail address: mike.mccune{at}ucsf.edu
4 Abbreviations used in this paper: PROG, progressor; LTNP, long-term nonprogressor; ART, antiretroviral therapy; RESP, chronically infected subjects responding to ART; VL, viral load (plasma HIV RNA copies/ml); PD-1, programmed death-1; p-, phospho-; MFI, median fluorescence intensity; Lck, lymphocyte specific kinase; Lat, linker for activation of T cell; RT, room temperature; GSH, glutathione.
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