Fig. (2) T-cell death during HIV-1 infection. A) Death associated with gp120 binding to CD4 or CCR5. After binding of gp120 to CD4 or CCR5, it activates intracellular signaling pathways that increase CD4+ T-cell susceptibility to Fas-mediated apoptosis. B) Extracellular Nef interacts with CXCR4 surface receptors and induces apoptosis. C) Nef directly stimulates TCR-CD3 complex and upregulates Fas and FasL expression while also inhibiting the antiapoptotic proteins Bcl-2 family. D) Endogenous Nef and Tat upregulate Fas/FasL and induces apoptosis through caspase-8 pathway. E) Tat and Vpr inhibit Bcl-2 and Bcl-xL, and increase mitochondria dysfunctions. Vpr targets the mitochondrial permeability transition pore complex (PTPC) and causes loss of membrane potential, release of cytochrome c, and the activation of caspase-9 and caspase-3. F) Vpr arrests cells at the G2 phase of the cell cycle that results in apoptosis.