DEATH ASSOCIATED WITH GP120 BINDING TO CD4
The majority of the immune cells that die during HIV infection are, in fact, uninfected bystander cells. This cell death occurs through several mechanisms. When the HIV envelope glycoprotein binds to the CD4 receptor, it frequently attaches and signals the receptor without changing its conformation, binding the chemokine co-receptor and eventually infecting the cell.
In fact, the envelope can bind and signal via CD4 in any of its forms, as part of the whole virion, or as a soluble glycoprotein. After binding CD4, gp120 triggers a complex cascade of intracellular signals increasing CD4+ T cell susceptibility to Fas-mediated apoptosis.52,53 The mechanism of Fas susceptibility is complex, protein synthesis independent, involves protein kinase C activation, and results in decreased FLIP levels.54 Thus, after priming by the HIV gp120, CD4 T cells apoptose when encountering FasL in a caspase-dependent manner that can be inhibited by blocking the caspase cascade, or by preventing the gp120 from physically interacting with the CD4 receptor, with soluble CD4 or anti-CD4 antibodies. This CD4-dependent Fas susceptibility requires CD4 signaling, because deleting the CD4 cytoplasmic tail inhibits the Fas-mediated apoptotic response.55’56 Mutations in the V3 loop of gp120, which binds to CD4, also inhibit CD4+ T cell death.57
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