| Human immunodeficiency virus infection leading to acquired immunodeficiency syndrome is characterized by a persistent decline in the number of CD4+ lymphocytes and immune system failure. Induction of lymphocyte apoptosis is one mechanism proposed to explain this loss. Although apoptosis is a well-documented phenomenon in HIV infection, the precise mechanism of apoptosis is not clear. Evidence exists that infection of a lymphocyte by HIV leads to apoptosis mediated by expression of the envelope glycoprotein (gp), gp160. Understanding how Env mediates apoptosis and determining its overall role in HIV-enhanced apoptosis are the goals of these studies.; The studies presented here demonstrate that expression of Env leads to increased FAS- and ceramide-mediated apoptosis and that this effect can be blocked by CaM (CaM) antagonists. In addition, expression of env leads to increased expression of CaM and accelerated activation of caspase 3, a key apoptotic effector molecule. Env is known to bind CaM, and point mutations in the region of the env gene encoding the CaM-binding domain were able to abolish Env effects on apoptosis, CaM up-regulation, and CaM binding. Point mutants of env were expressed in the context of all HIV proteins and shown not to disrupt Env expression or viral production. These mutations did have significant effects on both basal and FAS-mediated apoptosis, verifying that Env plays a dominant role in HIV-enhanced apoptosis and that the CaM-binding domain of Env is essential for this effect. The discovery that Env binding to CaM is a key event in mediating sensitivity to apoptotic stimuli has implications for studies on AIDS pathogenesis, as well as having potential impact on many diverse diseases involving aberrant apoptosis. |
