DEATH ASSOCIATED WITH GP120 BINDING TO CXCR4
T tropic or X4 gp120 and virus may bind to and signal through the CXCR4 chemokine receptor alone without infecting the cell. Because the X4 form of the virus is present in the end stages of HIV infection and, therefore, is associated with a more rapid disease progression as well as CD8+ T cell depletion, the mechanism of the CXCR4-mediated death has been closely investigated.
In contrast to CD4- or CCR5-mediated cellular killing, CXCR4 activation by gp120 causes a non-Fas- mediated caspase-independent CD4+ T cell death.9’60 The death signal is independent of G-protein signaling.61 The CXCR4 death is blocked by anti-CXCR4 antibodies; by SDF1α, the natural ligand of CXCR4; and by small molecule inhibitors of gp120 binding. The chemokine SDF1α signals cellular chemotaxis to the T cell but does not cause apoptosis.62’63 The T cell death is independent of caspase activation and, therefore, is not prevented by general caspase inhibitors. Interestingly, direct contact of R5 gp120 with a CD8+ T cell does not kill the cell, but binding of X4 gp120 to the CXCR4 receptors expressed on CD8+ T cells causes a rapid caspase-independent cell death, despite equal expression of CCR5 and CXCR4 on the cell surface.9 Therefore, CD4 and CCR5 activation by HIV gp120 causes a CD4+ T cell apoptosis by a two-step process. In the first step, the gp120 induces cell susceptibility to Fas-mediated apoptosis. In the second step, the cell dies when it engages FasL and signals death through the caspase cascade. In contrast, CXCR4 activation alone by HIV gp120 causes a direct caspase-independent cell death in both CD4+ T cells and CD8+ T cells. The mechanism of this cell death is still being investigated; however, increasing evidence suggests that the mechanism is p38 phosphorylation dependent and requires activation of caspase-9, along with a dissipation of mitochondrial transmembrane potential and, eventually, apoptotic cell death.64’65Not only does HIV envelope gp120 induce cell death in immune cells, but it also does so in nonimmune cells in which the G-protein-coupled chemokine co-receptors are expressed on many cell types.
Specifically, the CXCR4 receptor is expressed on the surface of human neurons. The X4 gp120 signals through the neuron CXCR4 and causes a direct caspase-independent cellular apoptosis.66’67 This death is abrogated by blocking gp120∕CXCR4 binding. It has been proposed that noninfective HIV-induced neuronal apoptosis may contribute to HIV-related dementia or peripheral neuropathy. It is also clear that HIV-infected individuals experience varying degrees of hepatotoxicity that is frequently out of proportion to, or independent of, opportunistic infections or medication-related toxicity. Interestingly, human hepatocytes also express CXCR4 on the cell surface and undergo caspase-independent apoptosis when gp120 binds the hepatocyte via CXCR4.75 Again, this chemokine-mediated death as a result of HIV envelope gp120 signaling may explain some occurrences of liver-related disease during the course of HIV infection.
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