Extracellular adenosine triphosphate (ATP) can activate purinergic receptors of the plasma membrane and modulate multiple cellular functions. We report that ATP is released from HIV-1 target cells through pannexin-1 channels upon interaction between the HIV-1 envelope protein and specific target cell receptors. Extracellular ATP then acts on purinergic receptors, including P2Y2, to activate proline-rich tyrosine kinase 2 (Pyk2) kinase and transient plasma membrane depolarization, which in turn stimulate fusion between Env-expressing membranes and membranes containing CD4 plus appropriate chemokine co-receptors. Inhibition of any of the constituents of this cascade (pannexin-1, ATP, P2Y2, and Pyk2) impairs the replication of HIV-1 mutant viruses that are resistant to conventional antiretroviral agents. Altogether, our results reveal a novel signaling pathway involved in the early steps of HIV-1 infection that may be targeted with new therapeutic approaches.

The present review summarizes recent experimental evidences about the existence of the non-cell-autonomous death entosis in physiological and pathophysiological contexts, discusses some aspects of this form of cell death, including morphological, biochemical and signaling pathways that distinguish non-cell-autonomous demises from other death modalities and propose to define this new modality of death as type IV programmed cell death.

Discussion on the hemichannel PANX1 and associated signaling molecules as new targets for the development of anti-HIV therapeutic strategies.