HIV-Specific CD8+ T Cells Exhibit Markedly Reduced Levels of Bcl-2 and Bcl-xL

Abstract

Human immunodeficiency virus-specific CD8+ T cells are highly sensitive to spontaneous and CD95/Fas-induced apoptosis, and this sensitivity may impair their ability to control HIV infection. To elucidate the mechanism behind this sensitivity, in this study we examined the levels of antiapoptotic molecules Bcl-2 and Bcl-xL in HIV-specific CD8+ T cells from HIV-infected individuals. Bcl-2 expression was markedly decreased in HIV-specific CD8+ T cells compared with CMV-specific and total CD8+ T cells from HIV-infected individuals as well as total CD8+ T cells from healthy donors. CD8+ T cell Bcl-2 levels inversely correlated with spontaneous and CD95/Fas-induced apoptosis of CD8+ T cells from HIV-infected individuals. HIV-specific CD8+ T cells also had significantly lower levels of Bcl-xL compared with CMV-specific CD8+ T cells. Finally, IL-15 induces both Bcl-2 and Bcl-xL expression in HIV-specific and total CD8+ T cells, and this correlated with apoptosis inhibition and increased survival in both short- and long-term cultures. Our data indicate that reduced Bcl-2 and Bcl-xL may play an important role in the increased sensitivity to apoptosis of HIV-specific CD8+ T cells and suggest a possible mechanism by which IL-15 increases their survival.

Apoptosis of HIV-specific CD8+ T cells: an HIV evasion strategy

“…A vital issue in the apoptosis field is the relative ratio between proand antiapoptotic factors that critically affect a cell's survival. 151 Similarly, we found downregulated levels of Bcl-2 in SIV-specific CD8 þ T cells from SIV-infected rhesus monkeys, which also exhibit increased apoptosis (YM Mueller, C Petrovas and PD Katsikis, unpublished data).…”

“…153 Our data revealed that such a compensatory mechanism is impaired in HIV-specific CD8 þ T cells, 151 potentially priming them to apoptosis. On the other hand, CMV-specific CD8 þ T cells from HIV-infected patients are characterized by increased levels of Bcl-x L , 151 likely making them less sensitive to apoptosis, in agreement with our previous data. 61 Interestingly, total CD4 þ T cells from HIV-infected patients express comparable Bcl-2 levels with CD4 þ T cells from healthy individuals.…”

“…Unfortunately, most of the studies to date have been carried out in circulating HIVspecific CD8 þ T cells. 61,88,151 As mentioned above, detection of virus-specific CD8 þ T cells at the tissue level and investigation of their apoptosis sensitivity would add significantly to our understanding of their in vivo dynamics and the relationship with other components of the immune system. The study of SIV-specific CD8 þ T cells in rhesus macaques, which share the apoptotic defect of HIV-specific CD8 þ T cells will allow for the study of such in vivo dynamics.…”

“…A remarkably reduced expression of Bcl-2 in HIVspecific CD8 þ T cells compared to CMV-specific and total CD8 þ T cells from HIV-infected individuals were found. 151 Furthermore, the downregulation of Bcl-2 was accompanied by a failure of HIV-specific CD8 þ T cells to upregulate Bcl-x L to the same extent as CMV-specific CD8 þ T cells. A vital issue in the apoptosis field is the relative ratio between proand antiapoptotic factors that critically affect a cell's survival.…”

“…61 Interestingly, total CD4 þ T cells from HIV-infected patients express comparable Bcl-2 levels with CD4 þ T cells from healthy individuals. 151 Therefore, it is possible that Bcl-2 is regulated in a different manner in CD4 þ T cells or alternatively Bcl-2 low CD4 þ T cells primed to apoptosis are rapidly removed from the circulation and cannot be detected ex vivo. Since both CD4 þ and CD8 þ T cells are sensitive to CD95/Fas-induced apoptosis in HIV infection, 26,27 an interesting question is whether these two cell populations employ different intracellular pathways to execute the death process.…”