Abstract
According to the WHO, 38 million individuals were living with human immunodeficiency virus (HIV), 25.4 million of which were using antiretroviral therapy (ART) at the end of 2019. Despite ART-mediated suppression of viral replication, ART is not a cure and is associated with viral persistence, residual inflammation, and metabolic disturbances. Indeed, due to the presence of viral reservoirs, lifelong ART therapy is required to control viremia and prevent disease progression into acquired immune deficiency syndrome (AIDS). Successful ART treatment allows people living with HIV (PLHIV) to achieve a similar life expectancy to uninfected individuals. However, recent studies have illustrated the presence of increased comorbidities, such as accelerated, premature immune aging, in ART-controlled PLHIV compared to uninfected individuals. Studies suggest that both HIV-infection and ART-treatment lead to mitochondrial dysfunction, ultimately resulting in cellular exhaustion, senescence, and apoptosis. Since mitochondria are essential cellular organelles for energy homeostasis and cellular metabolism, their compromise leads to decreased oxidative phosphorylation (OXPHOS), ATP synthesis, gluconeogenesis, and beta-oxidation, abnormal cell homeostasis, increased oxidative stress, depolarization of the mitochondrial membrane potential, and upregulation of mitochondrial DNA mutations and cellular apoptosis. The progressive mitochondrial damage induced by HIV-infection and ART-treatment likely contributes to accelerated aging, senescence, and cellular dysfunction in PLHIV. This review discusses the connections between mitochondrial compromise and cellular dysfunction associated with HIV- and ART-induced toxicities, providing new insights into how HIV and current ART directly impact mitochondrial functions and contribute to cellular senescence and aging in PLHIV. Identifying this nexus and potential mechanisms may be beneficial in developing improved therapeutics for treating PLHIV.
Highlights
human immunodeficiency virus (HIV) infection begins by glycoproteins, such as Env/gp120, on the surface of the HIV virus interacting with CD4 and CCR5/CXCR4 receptors on the surface of a target CD4 T cell, which is inhibited by coreceptor antagonists
There is a current lack of understanding of how antiretroviral therapy (ART) treatments and HIV individually and potentially cooperatively lead to mitochondrial dysfunction, as well as how these processes likely contribute to the progressive immune aging observed in people living with HIV (PLHIV) on ART
Following ART therapy, both cell subsets showed a significant decrease in mitochondrial mass, followed by an increase after three years of treatment. These results indicate a dynamic fluctuation in immune cell response to HIV infection and ARTmediated suppression of infection, which was unique between CD4+ and CD8+ T cells [7]
Summary
HIV lifecycle has seven major steps: binding, fusion, reverse transcription, integration, replication, assembly, and budding (Figure 1) [1,2,3,4,5,6,7,8]. HIV infection begins by glycoproteins, such as Env/gp120, on the surface of the HIV virus interacting with CD4 and CCR5/CXCR4 receptors on the surface of a target CD4 T cell (step 1), which is inhibited by coreceptor antagonists. This facilitates fusion between the HIV membrane and the cell membrane (step 2). The viral DNA is transported into the cell nucleus for integration into the host genome by HIV integrase and transcription (steps 5 and 6). HIV infects target cells, including but not limited to CD4 T cells, macrophages, and lymphoid tissues, and integrates proviral DNA into the host genome to establish reservoirs. Despite ART-mediated viral suppression aiding CD4 T cell recovery, this reversal constitutes an incomplete immune reconstitution, forcing PLHIV to face lifelong challenges with immune failure [27,28]
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