The role of extracellular ATP and P2X receptors in the pathogenesis of HIV-1

Abstract

Human Immunodeficiency Virus Type 1 (HIV-1) causes a chronic, incurable infection associated with chronic inflammation despite virologic suppression on antiretroviral therapy (ART). This chronic inflammation underlies significant comorbidities, including cardiovascular disease, neurocognition decline, and malignancies. The mechanisms of chronic inflammation have been attributed, in part, to the role of extracellular ATP and P2X-type purinergic receptors that sense damaged or dying cells and undergo signaling responses to activate inflammation and immunomodulation. This review describes the current literature on the role of extracellular ATP and P2X receptors in HIV-1 pathogenesis, describing the known intersection with the HIV-1 life cycle in mediating immunopathogenesis and neuronal disease. The literature supports key roles for this signaling mechanism in cell-to-cell communication and in activating transcriptional changes that impact the inflammatory state leading to disease progression. Future studies must characterize the numerous functions of ATP and P2X receptors in HIV-1 pathogenesis to inform future therapeutic targeting.

Keywords: Extracellular ATP; HIV-1; Inflammation; P2X receptors; Purinergic receptors.

Figure 1.. HIV-1 life cycle and the role of extracellular and P2X receptors in inflammatory signaling.

A CD4+ T lymphocyte is shown to be infected with HIV-1 by binding to CD4+, recruitment of co-receptor (CCR5) in binding (1) which leads to viral membrane fusion (2). RNA transcripts are reverse transcribed (3) into viral DNA, which integrates (4) into the host genome, which can then remain latent or can be transcribed (5) and translated (6). Virus particles are then assembled (7) and budded (8) with the release and maturation (9) of mature virus particles that are capable of productive infection. Alongside the viral life cycle, extracellular ATP is shown to signal through P2RX7 to activation of cation flux (calcium and potassium) to activate Rho, which activates phospholipase D, which activates the phagolysosome; calcium flux can activate NFkB-dependent transcription via p38 which can activate NLRP3 inflammasome gene transcription and activation of the NLRP3 inflammasome via caspase-1 can result in maturation and secretion of IL-18 and IL-1β and pyroptosis. P2RX7 signaling can also result in potassium flux that can activate apoptosis via SAPK/JNK. These pathways can lead to HIV-1-associated inflammation, including neurocognitive impairment, cardiovascular disease, and thromboembolic events. Created with Biorender.