T-cell and neuronal apoptosis in HIV infection: implications for therapeutic intervention

The pathogenesis of HIV infection involves the selective loss of CD4+ T cells contributing to immune deficiency. Although loss of T cells leading to immune dysfunction in HIV infection is mediated in part by viral infection, there is a much larger effect on noninfected T cells undergoing apoptosis in response to activation stimuli. In the subset of patients with HIV dementia complex, neuronal injury, loss, and apoptosis are observed. Viral proteins, gp120 and Tat, exhibit proapoptotic activities when applied to T cell and neuronal cultures by direct and indirect mechanisms. The pathways leading to cell death involve the activation of one or more death receptor pathways (i.e., TNF-alpha, Fas, and TRAIL receptors), chemokine receptor signaling, cytokine dysregulation, caspase activation, calcium mobilization, and loss of mitochondrial membrane potential. In this review, the mechanisms involved in T-cell and neuronal apoptosis, as well as antiapoptotic pathways potentially amenable to therapeutic application, are discussed.