Volume 69, April 2023, 102358Author links open overlay panel, , , 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.

Section snippetsCRediT author statement

Natalia Rodriguez: Data curation, Writing- Original draft preparation, Trinisia Fortune: Data curation, Writing-Original draft preparation, Thien Vuong: Writing-Original draft preparation Talia Swartz: Conceptualization, Supervision, Writing-Original draft preparation, reviewing and editing.

ATP and P2X receptors in HIV viral life cycle

HIV-1 is a retrovirus that uses its surface envelope glycoprotein (Env) to attach to CD4 on the surface of target CD4+ T lymphocytes to enter and infect cells. Purinergic receptors, P1 and P2, have been implicated in the HIV-1 life cycle [8,17∗∗, 18, 19, 20, 21, 22, 23, 24]. [25] It has been demonstrated in multiple cell types that inhibition of P2X receptors using pharmacological inhibitors can reduce or abrogate HIV-1 infection [17,19,20,23,26, 27, 28].

The activation of P2X receptors via

ATP and P2X receptors in HIV-associated immunopathogenesis

Several studies have shown that immunosenescence is a mediator of chronic inflammation, with HIV infection causing an increase in senescent cells characterized by excessive T cell turnover, leading to CD8+ T lymphocyte accumulation and activation [55,56]. Senescent cells secrete inflammatory mediators, which lead to low-level inflammation and increased cell turnover [55,57, 58, 59]. Desai et al. propose a multifaceted model of accelerated aging in HIV-1 infection [60]. This model includes, but

ATP and P2X receptors in HIV-associated neuronal disease

The central nervous system (CNS) represents a critical reservoir for HIV-1 as a crucial anatomical location of latency, and sites of infection include brain parenchyma, including neuronal and glial cells [36,79]. Penetration of HIV-1 into the CNS can lead to alterations of function, resulting in HIV-associated neurocognitive disorders (HAND) and encephalitis, which are the results of neuroinflammation and neurodegeneration [80,81].

Effective antiretroviral therapy (ART) has decreased the

Conclusions

Extracellular ATP and P2X receptors represent a critical means by which cells communicate with each other and mediate inflammatory signaling in the setting of many infections, specifically in people with HIV. We describe the role of extracellular ATP and P2X receptors as modulators of the HIV-1 life cycle in mediating immunopathogenesis, contributing to the state of HIV-associated chronic inflammation, and mediating neuronal pathogenesis through neuroinflammation. A growing body of literature

Conflict of interest statement

Nothing declared.

Acknowledgments

This work was funded by the NIH K08AI20806 (THS), NIH R21AI152833 (THS), NIH R01DA052255 (THS), and Schneider-Lesser Foundation (THS). NRR contributed substantially to the organization and writing of this manuscript. NRR, TF, TV, and THS contributed to the writing and editing of this manuscript. THS conceived of the approach and oversaw the writing and editing of this manuscript.

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