Extracellular adenosine triphosphate (ATP) can activate purinergic receptors from the plasma membrane and modulate multiple cellular functions. 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. HIV-1 infection poses a public health problem that is partially controlled by a combination of specific antiretroviral agents. Nonetheless the surge of multiresistant HIV-1 strains will require the development of novel antiviral strategies. Targeting early infection by vaccines and microbicides represents the main challenge to end the AIDS epidemic (Haase 2010 Virgin and Walker 2010 A better understanding of the early steps of HIV-1 infection is critical to achieving this goal. Enveloped viruses must fuse their membranes with host cell membranes to allow productive infection. Major transient changes in the charge and architecture of the host plasma membrane including extreme curvature occur during early steps of infection and facilitate viral replication (Miller et al. 1993 Davis et al. 2004 Nevertheless little is well known about the results of the cell membrane modifications on the first signaling pathway necessary for viral disease. Recent studies exposed that membrane tension induced by mechanised or chemical substance stimuli (shear tension [Wan et al. 2008 osmotic bloating [Darby et al. 2003 and membrane shrinking [Corriden and Insel 2010 stimulates ATP launch. Initially referred to as another messenger in the anxious and vascular systems (Schwiebert et al. 2002 Housley et al. 2009 extracellular ATP could also become a proinflammatory mediator released during severe swelling upon cell harm or infection therefore representing a common marker of harm that may alert P505-15 the disease fighting capability to risk (Gallucci and Matzinger Tpo 2001 Furthermore extracellular ATP inhibits disease by intracellular bacterial pathogens (Lammas et al. 1997 Coutinho-Silva et al. 2003 and modulates immune system responses by taking part in the chemotaxis of immune system cells (eosinophils neutrophils monocytes/macrophages and immature DCs; Chen et al. 2006 Kronlage et al. 2010 by activating the NALP3 inflammasome (Mariathasan et al. 2006 or by mediating costimulatory indicators for antigenic excitement (Schenk et al. 2008 Latest studies exposed that ATP may also be released under basal circumstances and influences a big array of mobile responses. Therefore ATP appears to become an inside-out messenger that good tunes sign transduction pathways (Corriden and Insel 2010 Beyond the P505-15 cell ATP works as an autocrine/paracrine sign modulating a number of mobile features by activating purinergic receptors (Corriden and Insel 2010 These plasma membrane-localized receptors participate in a larger family that can be classified into ionotropic P2X receptor and metabotropic P2Y receptors (Ralevic and Burnstock 1998 Metabotropic receptors are coupled to intracellular signaling pathways through heterotrimeric G proteins (Abbracchio et al. 2006 whereas ionotropic P2X receptors are associated with pores that open upon ATP binding allowing Ca2+ influx and K+ efflux (Ralevic and Burnstock 1998 Seven members of the P2X family P505-15 (P2X1-7; Ralevic and Burnstock 1998 and eight P2Y receptors (P2Y1 P2Y2 P2Y4 P2Y6 P2Y11 P2Y12 P2Y13 and P2Y14) have been characterized (Abbracchio et al. 2003 Upon activation these receptors which are P505-15 widely distributed throughout the body modulate an array of cellular functions like plasma membrane permeabilization Ca2+ influx P505-15 and cell death (Surprenant and North 2009 Purinergic receptors have been extensively involved in the development of innate and/or adaptive immune responses against pathogens (Lammas et al. 1997 Coutinho-Silva et al. 2003 Chen et al. 2006 Mariathasan et al. 2006 Kronlage et al. 2010 but have also been associated with chemotherapy-driven anticancer immune responses.