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.
Highlights
HIV combination antiretroviral therapy (cART) has dramatically improved survival rates of HIV infected patients, resulting in an aging HIV infected cohort, and viral loads remain suppressed in these patients, HIV-associated neurocognitive disorders (HAND) remain highly prevalent and contribute to significant morbidity
We examined the effect of cART on telomere length (TL) and telomerase activity in peripheral blood mononuclear cells (PBMC) obtained from HIV-1 infected patients who had uncontrolled HIV infection and who were on cART
Accelerated telomere shortening contributes to genetic instability of cells, cellular senescence, cell cycle arrest or apoptosis that may contribute to the neurodegeneration and cognitive deficits typically observed in HAND patients
Summary
HIV cART (combination antiretroviral therapy) has dramatically improved survival rates of HIV infected patients, resulting in an aging HIV infected cohort, and viral loads remain suppressed in these patients, HIV-associated neurocognitive disorders (HAND) remain highly prevalent and contribute to significant morbidity. Microglial activation occurs in HIV-1 infected subjects, and uncontrolled brain inflammation plays a key role in neuronal injury and cognitive dysfunction during HIV infection. Tat is the transactivator of transcription that is essential for transcriptional regulation and replication of the virus, and is the first protein produced after HIV infection. It stimulates transcription of the HIV-1 genes and regulates gene expression in the host [1,2]. HIV-1 Tat protein exerts proinflammatory effects on microglia, astrocytes and neurons that produce key pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), which lead to neuron damage and cognitive deficits.
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