The role of CD4 and CXCR4 mediated apoptosis in T cell depletion during HIV-1 infection

AIDS is characterised by a progressive depletion of CD4+ helper T lymphocytes. This process has been shown to involve apoptosis. Several studies have demonstrated that apoptosis can be induced in both infected and non-infected cells by the HIV-1 gpl20 surface glycoprotein. Thus, crosslinking of CD4 by gpl20 and anti-gpl20 antibodies, or specific anti-CD4 antibodies induces apoptosis in uninfected T cells which is partially mediated via sensitization to CD95(Apo-l/Fas) -mediated cell death. It has recently been shown that gpl20 induces a novel type of apoptosis in T cells. This was induced via both the CD4 and CXCR4 receptors and was CD95 and caspase independent. The work described in this thesis investigated the role of CD4 and CXCR4 induced apoptosis as a potential indirect mechanism of T-cell depletion during HIV-1 infection. The relative contribution of the „classical" or „novel“ apoptotic pathways engaged by these receptors, upon cell death induction, were investigated in the in vivo situation. Data in this thesis demonstrate that peripheral blood lymphocytes (PBLs) from a representative cohort of HIV-1 infected individuals show higher sensitivity to CD4 and CXCR4 mediated apoptosis compared to PBLs from healthy controls. Activation of PBLs from healthy individuals rendered, however, these cells susceptible to CD4 and CXCR4 mediated apoptosis. This supports the hypothesis that the sensitivity of PBLs from HIV-1 infected individuals to CD4 and CXCR4 mediated apoptosis is due to the immune hyperactivation occuring during the course of the infection. The signaling mechanism of the novel type of cell death was also investigated focusing primarily on CD4 mediated apoptosis. Studies on CD4 mutant receptors showed that the cytoplasmic tail of CD4 is dispensable for the induction of cell death. Preliminary biochemical analysis also failed to detect recruitment of signaling molecules to the CD4 receptor complex. These findings strongly suggest that a molecule adjacent to the CD4 receptor or the CXCR4 receptor may be responsible for the transmission of the apoptotic signal. Studies on the role of mitochondria during CD4 mediated apoptosis showed release of both cytochrome c and AIF. This suggests a central role for mitochondria in the CD4 induced, caspase independent apoptotic signaling pathway. Improvement of our understanding of the mechanisms of HIV-1 associated lymphocyte apoptosis, as well as the signaling cascades involved, may lead to therapeutic strategies aimed at intervening with the CD4+ T cell depletion in HIV-1 infected individuals