Increased mitochondrial mass characterizes the survival defect of HIV-specific CD8+ T cells

Abstract

AbstractWhat 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-specific compared with 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, whereas 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.