| |
The Impact of HIV- and ART-Induced Mitochondrial Dysfunction in Cellular Senescence and Aging
|
| |
| |
Download the PDF here
research shows that PLHIV are more likely to show premature aging, which is linked to increased oxidative stress and damage and shortened telomeres which could further contribute to mitochondrial and metabolic compromise
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.
Alternately, mitochondrial dysfunction is also associated with NNRTIs, PIs, and INSTIs, despite these drug classes not disrupting Pol-γ activity [71,95,106]. Despite ART treatment decreasing HIV-associated comorbidities and improving mortality of PLHIV, mitochondrial functions are disrupted even in clinically stable patients [103].
EFV is correlated with reduced cell growth and increased apoptosis, oxidative stress, mitochondrial mass, and mitochondrial protein expression in Hep3B hepatic cells.
https://www.mdpi.com/2073-4409/10/1/174
INSTIs have become a widely used ART formulation. INSTIs inhibit DNA strand transfer, during which the viral DNA ends are joined into host DNA (step 5 in Figure 1) [21,95,101,106]. In recent years, the most common first-line approach for the treatment of naïve PLHIV has become the administration of an INSTI with NRTIs [101,141]. While extensive research has not yet been completed to identify the potential deregulation of mitochondria by INSTIs, a recent study assessing metabolic and cellular activity in immune cells from treated PLHIV and HIV-negative controls revealed that ART was able to restore the metabolic profile of B cells, NK cells, and CD8+ T cells, but not in CD4+ T cells. Furthermore, CD4 T cells showed a more severe shut down in cellular respiration and a shift to glycolysis from OXPHOS. This was more prevalent in cells from individuals treated with the INSTI dolutegravir (DLG) in triple therapy, compared to non-INSTI ART regimens. Additionally, a comparison of the ex vivo proliferation of CD4+ T cells demonstrated repressed proliferation in CD4 T cells from individuals on treatment with INSTIs versus NNRTI- or PI-regimens. Further evaluation of the effect of INSTIs was completed by treating CD4 T cells from uninfected individuals. Both DLG and elvitegravir (EVG), but not raltegravir (RAL), showed significantly decreased cellular respiration in a dose-dependent manner but did not affect ΔΨm or cellular cytotoxicity. Both drugs induced increased mtDNA copy number and ROS levels, implicating INSTIs as a deregulator of mitochondrial function and immune cell metabolism [64]. While this study highlights potential mitochondrial deregulation by INSTIs, further research is still needed to validate the influence of INSTIs on mitochondria.
Holistically, these findings suggest that regardless of the class of ART treatment, PLHIV using these regimens are at a greater risk of developing premature aging associated with mitochondrial dysfunction, many of which are progressive in nature as treatment time is prolonged. This presents a significant limitation with respect to current HIV treatments due to the need for lifelong treatment adherence. Additionally, the current literature lacks clear evidence for the differential roles of drugs and the relationship between drug mechanism of action and mitochondrial failure due to the profound use of combined HAART. This makes it increasingly difficult to assess and identify mitochondrial deregulation from these drugs independent of additional pharmacological influences.
|
|
| |
| |
|
|
|
