Role of Hydrogen Sulfide Gas in Modulating HIV 1 Latency and Reactivation

Abstract

Human Immunodeficiency Virus 1 (HIV-1) remains a global public health threat, claiming 690 thousand people s lives in 2020 and causing 1.5 million new infections. The advent of combinatorial antiretroviral therapy (ART) have curbed the spread of the HIV-1 epidemic by limiting new infections rate. However, ART is not a curative therapy, and HIV-1 persists in latent reservoirs mainly comprising long-lived memory CD4+ T cells. Notably, low ART treatment coverage and cases of poor therapy adherence lead to replenishment of latent reservoirs and the emergence of drug-resistant variants. Thus, to eradicate HIV-1, it is important to understand how the virus establishes latency, maintains stable cellular reservoirs, and promotes rebound upon interruption of antiretroviral therapy (ART). Cellular redox status has been observed as a key determinant modulating HIV-1 latency and reactivation. HIV-1 patients display the hallmark of oxidative stress with reduced levels of major cellular antioxidants, glutathione (GSH), and thioredoxin (Trx) systems. The current approach to target latent HIV-1 includes a shock and kill approach, which utilizes latency reversing agents (LRAs) to reactivate HIV-1 and kill infected cells by immune-based mechanisms [Chapter 1]. The LRAs belonging to histone deacetylase inhibitors class, when used in combination with GSH biosynthesis inhibitor, BSO, induce robust oxidative stress and heightened HIV-1 reactivation. In this direction, the use of antioxidant molecules, e.g., N-acetyl cysteine (NAC), has been shown to limit HIV-1 reactivation, but the molecular mechanism involved in NAC action remains understudied. Recently, NAC has been shown to exert its effect by inducing the biogenesis of a novel antioxidant gasotransmitter molecule, hydrogen sulfide (H2S). Previously considered as a toxic gas, but literature in the past two decades suggests the cytoprotective and antioxidant role of H2S in several patho-physiological conditions. In this study,...