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AIDS is characterized by CD4+ T lymphocyte depletion, yet the mechanisms underlying this central aspect of HIV pathogenesis are still poorly understood. In this issue of the JCI, Espert et al. identify a mechanism by which the HIV envelope glycoprotein can induce death in uninfected CD4+ T cells (see the related article beginning on page 2161). The HIV envelope glycoprotein interacts with CXC chemokine receptor 4 to activate the lysosomal degradation pathway of autophagy, which is necessary for both apoptotic and nonapoptotic cell death.