The Impact of HIV- and ART-Induced Mitochondrial Dysfunction in Cellular Senescence and Aging

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.

Mitochondrial Functions Are Compromised in CD4 T Cells From ART-Controlled PLHIV

“…While our data suggest that HIV infection reduces cell metabolism and fitness, it is possible that HIV preferentially infects target cells based on their metabolic status during acute infection but induces mitochondrial injuries during chronic/persistent infection, as observed in our chronically infected patients. This may be related to the differential regulation of CD4 T cell apoptosis by HIV-encoded proteins under acute versus chronic conditions, given the role of mitochondria in apoptosis (43). Alternatively, HIV-1 may differentially regulate cellular metabolism of target cells to propagate cellular infection and establish viral latency in CD4 T cells (44,45).…”

Mitochondrial Genotoxicity of Hepatitis C Treatment among People Who Inject Drugs

“…Chronic inflammation results in mtDNA damage acceleration, which, in turn, feeds the inflammation, partly explaining the premature ageing observed in chronic diseases. Accelerated ageing has also been reported in chronic infections such as HIV [ 30 ]. HCV itself reduces MCN through the induction of systemic inflammation [ 31 ].…”

A Critical Review of the Biochemical Mechanisms and Epigenetic Modifications in HIV- and Antiretroviral-Induced Metabolic Syndrome

“…The first observed effects of ARVs on the mitochondria were seen with NRTI use ( Figure 3 ). NRTIs inhibit polymerase-γ, which has a role in mitochondrial DNA replication, thus compromising mitochondrial integrity [ 83 ]. Furthermore, NRTIs prevent ATP/ADP translocation.…”