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Blood, 15 March 2007, Vol. 109, No. 6, pp. 2505-2513.
Prepublished online as a Blood First Edition Paper on November 9, 2006; DOI 10.1182/blood-2006-05-021626.
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Submitted January 20, 2006
Accepted October 30, 2006
Increased mitochondrial mass characterizes the survival
defect of HIV-specific CD8+ T cells
Constantinos Petrovas, Yvonne M. Mueller, Ioannis D. Dimitriou, Susan R. Altork, Anupam Banerjee, Peter A. Sklar, Karam C. Mounzer, John D. Altman, and Peter D Katsikis*
Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA, United States
Department of Medicine, Drexel University College of Medicine, Philadelphia, PA, United States
Philadelphia FIGHT, Philadelphia, PA, United States
Department of Microbiology and Immunology, Emory University, Atlanta, GA, United States
* Corresponding author; email: pdk24{at}drexel.edu.
What governs the increased apoptosis-sensitivity of HIV-specific CD8+ T cells is poorly understood. Here, we examined the involvement of mitochondria in this apoptosis. Remarkably higher mitochondrial mass (MM) was found in HIV- compared to CMV-specific CD8+ T cells from HIV+ patients and this could not be attributed to their different differentiation status. MMHigh phenotype characterized those CD8+ T cells from HIV+ patients that are sensitive to spontaneous and CD95/Fas-induced apoptosis. CD38 expression did not correlate with high MM while Bcl-2 levels were significantly reduced in both CD38+ and CD38- HIV-specific CD8+ T cells. Although CD38+ HIV-specific CD8+ T cells were more susceptible to apoptosis, CD38 expression does not explain on its own the selective apoptosis-sensitivity of HIV-specific CD8+ T cells as CD38- HIV-specific CD8+ T cells were more apoptotic than CD38+ CMV-specific ones. Proapoptotic HIV-specific CD8+ T cells were CD38+Bcl-2LowMMHigh. Copolarization of mitochondria with CD95/Fas-capping, very early in CD95/Fas-induced apoptosis of HIV-specific CD8+ T cells, suggests that mitochondria act as an amplification step for this apoptosis. Thus, an extensive mitochondrial network contributes to apoptosis-sensitivity of CD8+ T cells and when this occurs together with reduced levels of Bcl-2 and chronic activation determines the proapoptotic state of HIV-specific CD8+ T cells.
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