HIV-1 envelope induces activation of caspase-3 and cleavage of focal adhesion kinase in primary human CD4(+) T cells

Binding of HIV type 1 (HIV-l) envelope glycoproteins to the surface of a CD 4(+) T cell transduces intracellular signals through the primary envelope r eceptor, CD4, and a coreceptor, either CCR5 or CXCR4. Furthermore, envelope -CD4(+) cell interactions increase rates of apoptosis in peripheral blood m ononuclear cells (PBMCs). We demonstrate that in primary T lymphocytes. rec ombinant HIV-1 envelope proteins induce the activation of caspase-3 and cas pase-6, which belong to a family of cysteine proteases that, upon activatio n, promote programmed cell death. Envelope-mediated activation of caspase-3 and caspase-6 depended on envelope-CD4 receptor interactions; CCR5-utilizi ng as well as CXCR4-utilizing envelopes elicited this response. Focal adhes ion kinase (FAK) is a substrate of both caspase-3 and caspase-6, and inacti vation of FAK by these caspases promotes apoptosis, Envelope treatment of l ymphocytes led to the cleavage of FAK in a manner consistent with caspase-m ediated cleavage.