Telomere Length Shortening in Microglia: Implication for Accelerated Senescence and Neurocognitive Deficits in HIV

Abstract

The widespread use of combination antiretroviral therapy (cART) has led to the accelerated aging of the HIV-infected population, and these patients continue to have a range of mild to moderate HIV-associated neurocognitive disorders (HAND). Infection results in altered mitochondrial function. The HIV-1 viral protein Tat significantly alters mtDNA content and enhances oxidative stress in immune cells. Microglia are the immune cells of the central nervous system (CNS) that exhibit a significant mitotic potential and are thus susceptible to telomere shortening. HIV disrupts the normal interplay between microglia and neurons, thereby inducing neurodegeneration. HIV cART contributes to the inhibition of telomerase activity and premature telomere shortening in activated peripheral blood mononuclear cells (PBMC). However, limited information is available on the effect of cART on telomere length (TL) in microglia. Although it is well established that telomere shortening induces cell senescence and contributes to the development of age-related neuro-pathologies, the effect of HIV-Tat on telomere length in human microglial cells and its potential contribution to HAND are not well understood. It is speculated that in HAND intrinsic molecular mechanisms that control energy production underlie microglia-mediated neuronal injury. TL, telomerase and mtDNA expression were quantified in microglial cells using real time PCR. Cellular energetics were measured using the Seahorse assay. The changes in mitochondrial function were examined by Raman Spectroscopy. We have also examined TL in the PBMC obtained from HIV-1 infected rapid progressors (RP) on cART and those who were cART naïve, and observed a significant decrease in telomere length in RP on cART as compared to RP’s who were cART naïve. We observed a significant decrease in telomerase activity, telomere length and mitochondrial function, and an increase in oxidative stress in human microglial cells treated with HIV Tat. Neurocognitive impairment in HIV disease may in part be due to accelerated neuro-pathogenesis in microglial cells, which is attributable to increased oxidative stress and mitochondrial dysfunction.

HIV-1 Tat Induces Dysregulation of PGC1-Alpha and Sirtuin 3 Expression in Neurons: The Role of Mitochondrial Biogenesis in HIV-Associated Neurocognitive Disorder (HAND)

“…We found that in vivo Tert mRNA levels remain unaffected by HIV-1 Tat, contrary to the findings reported by Hsiao et al in peripheral blood mononuclear cells of individuals with HIV. Interestingly, this research team reported no changes in TERT expression in microglia exposed to HIV-1 Tat [45], aligning with our results in neurons. This suggests that the impact of HIV on telomerase expression may vary depending on cell type and other viral factors, since TERT expression levels and regulatory mechanisms in the CNS differ from those in other tissues [46].…”

The relationship between cognitive clusters and telomere length in bipolar-schizophrenia spectrum disorders

“…Telomere length shortening is thought to contribute to genetic instability of cells, lower levels of cell proliferation and apoptosis. This may lead to neuronal vulnerability, neurodegeneration, and cognitive deficits (Ferron et al, 2009; Hsiao et al, 2021; Palmos et al, 2020). An indirect pathway between peripheral telomere length and cognitive function may also occur via inflammatory processes.…”

Dietary fat, telomere length and cognitive function: unravelling the complex relations

“…Diets high in these fatty acids lead to increased levels of inflammatory biomarkers [87], associated with shorter telomeres. Telomere attrition in microglia may also alter the normal immune functions within the brain and produce neurocognitive deficits [88].…”