HIV antiretroviral therapy drugs induce premature senescence and altered physiology in HUVECs

Abstract

Developments in medicine have led to a significant increase in the average human lifespan. This increase in aging is most readily apparent in the case of HIV where antiretroviral therapy has shifted infection from a terminal to a chronic but manageable disease. Despite this advance, patients suffer from co-morbidities best described as an accelerated aging phenotype. A potential contributor is cellular senescence, an aging-associated growth arrest, which has already been linked to other HIV co-morbidities such as lipodystrophies and osteoporosis in response to antiretroviral drugs. We have previously demonstrated that astrocytes senescence in response to antiretroviral drugs. As endothelial cells play a critical role regulating the blood brain barrier (BBB) and senescence could severely impact barrier permeability, we investigate the role of a commonly used combination of HIV reverse transcriptase inhibitors on the senescence program of human umbilical vein endothelial cells (HUVECs). Our studies indicate that HUVECs underwent premature senescence associated with inflammation, oxidative stress and altered eNOS activation. Treated cells had detrimental paracrine effects on astrocytes including paracrine senescence, suggesting that senescent HUVECs could influence astrocytes, which line the other side of the BBB. These results may have implications for HIV-associated neurocognitive disorders (HAND), a set of neurological deficits.

Tenofovir disoproxil fumarate induces peripheral neuropathy and alters inflammation and mitochondrial biogenesis in the brains of mice

“…The question remains as to whether the effect of TDF on neuronal mitochondrial function is direct or mediated through activation of microglia and astroglia. Previous studies suggest that TDF can affect neurons directly 16,72 . Our data clearly show that TDF has robust effects on glial activation both in vivo and in vitro .…”

“…These data are consistent with studies by Cohen et al . that showed ART can induce inflammatory gene expression and cellular senescence in astroglia and endothelial cells 72,73 . Therefore, we hypothesize that TDF affects neuronal mitochondrial function directly and also through activation of glia.…”

Cerebral Vascular Toxicity of Antiretroviral Therapy

“…HIV patients on ART exhibit changes in endothelial functions, such as lower expression levels of von Willebrand Factor or protein S (Chwiki et al 2017 ). A combination of Tenofovir and Emtricitabine can act as cellular stressors, leading to endothelial cell senescence, as demonstrated by a reduction in proliferation, and an increase in inflammatory markers (Cohen et al 2018 ). This results in decreased BBB integrity and impaired endothelial cell functions.…”

Extracellular HIV-1 Tat Mediates Increased Glutamate in the CNS Leading to Onset of Senescence and Progression of HAND

“…Although implementation of ART has decreased the severity of HAND, it still remains prevalent, with over 50% of HIV-1-infected patients exhibiting mild symptoms of HAND (Chai et al, 2017). Because HAND remains prevalent even in the ART era, it has been suggested that viral replication is not a major factor involved in mediating cognitive decline (Zeitler et al, 2015;Berman et al, 2016;Dickens et al, 2017;Cohen et al, 2018). The viral protein HIV-1 Tat therefore, has been highlighted as a potential viral product that may contribute to the development of HAND (Chen et al, 1997;Eugenin et al, 2003).…”

“…Extracellular Tat is biologically active and can cause induction of apoptosis, oxidative stress, and release of pro-inflammatory cytokines and neurotransmitters, all of which may contribute to the development of HAND (Table 1; Henderson et al, 2019;Ajasin and Eugenin, 2020). Additionally, the presence of Tat alone in the CNS of animal models is sufficient to replicate HAND pathologic and behavioral changes (Zeitler et al, 2015;Berman et al, 2016;Dickens et al, 2017;Cohen et al, 2018).…”