Organellar stress intersects the astrocyte endoplasmic reticulum, mitochondria and nucleolus in HIV associated neurodegeneration

Nooka, Shruthi; Ghorpade, Anuja

doi:10.1038/s41419-018-0341-3

Cited by 14 publications

(8 citation statements)

References 15 publications

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“…Ischemic injury is associated with increased production of reactive oxygen species and oxidative stress, which can be counteracted by various protective mechanisms including activity of the detoxifying enzyme heme oxygenase-1 (HO-1) and regulation of mitochondrial biogenesis by transcriptional factor A (TFAM) [25,26]. In astrocytes, HIV-associated inflammation and oxidative stress are associated with elevated calcium levels, activation of the unfolded protein response, and mitochondrial dysfunction [27]. To better understand pathways underlying HAND pathogenesis, we assembled a cohort of 58 subjects (34 HIV+ and 24 HIV−) with available postmortem frozen brain tissue and evaluated gene expression patterns (n=933 genes) in frontal lobe subcortical white matter using the NanoString nCounter platform.…”

Section: Introductionmentioning

confidence: 99%

White Matter Abnormalities Linked to Interferon, Stress Response, and Energy Metabolism Gene Expression Changes in Older HIV-Positive Patients on Antiretroviral Therapy

et al. 2019

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Neurocognitive impairment (NCI) remains a significant cause of morbidity in human immunodeficiency virus (HIV)-positive individuals despite highly active antiretroviral therapy (HAART). White matter abnormalities have emerged as a key component of age-related neurodegeneration, and accumulating evidence suggests they play a role in HIV-associated neurocognitive disorders. Viral persistence in brain induces chronic inflammation associated with lymphocytic infiltration, microglial proliferation, myelin loss, and cerebrovascular lesions. In this study, gene expression profiling was performed on frontal white matter from 34 older HIV+ individuals on HAART (18 with NCI) and 24 HIV-negative controls. We used the NanoString nCounter platform to evaluate 933 probes targeting inflammation, interferon and stress responses, energy metabolism, and central nervous system-related genes. Viral loads were measured using single-copy assays. Compared to HIV− controls, HIV+ individuals exhibited increased expression of genes related to interferon, MHC-1, and stress responses, myeloid cells, and T cells, and decreased expression of genes associated with oligodendrocytes and energy metabolism in white matter. These findings correlated with increased white matter inflammation and myelin pallor, suggesting interferon (IRFs, IFITM1, ISG15, MX1, OAS3) and stress response (ATF4, XBP1, Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. http://www.springer.com/gb/openaccess/authors-rights/aam-terms-v1

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Section: Introductionmentioning

confidence: 99%

White Matter Abnormalities Linked to Interferon, Stress Response, and Energy Metabolism Gene Expression Changes in Older HIV-Positive Patients on Antiretroviral Therapy

et al. 2019

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“…ART components may be neurotoxic, especially given the life‐long course of anti‐HIV treatment 100 . Nucleoside reverse transcriptase inhibitors (NRTI), the most common component of modern ART cocktails, affect mitochondrial polymerase γ and cause mitochondrial toxicity, which may impair functions of astrocytes and neurons 101,102 . However, no direct clinical association between NRTI use and HAND has been found.…”

Section: Pathogenesis Of Handmentioning

confidence: 99%

Neuro‐HIV—New insights into pathogenesis and emerging therapeutic targets

Sviridov,

Bukrinsky

2023

The FASEB Journal

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HIV‐associated neurocognitive disorders (HAND) is a term describing a complex set of cognitive impairments accompanying HIV infection. Successful antiretroviral therapy (ART) reduces the most severe forms of HAND, but milder forms affect over 50% of people living with HIV (PLWH). Pathogenesis of HAND in the ART era remains unknown. A variety of pathogenic factors, such as persistent HIV replication in the brain reservoir, HIV proteins released from infected brain cells, HIV‐induced neuroinflammation, and some components of ART, have been implicated in driving HAND pathogenesis in ART‐treated individuals. Here, we propose another factor—impairment of cholesterol homeostasis and lipid rafts by HIV‐1 protein Nef—as a possible contributor to HAND pathogenesis. These effects of Nef on cholesterol may also underlie the effects of other pathogenic factors that constitute the multifactorial nature of HAND pathogenesis. The proposed Nef‐ and cholesterol‐focused mechanism may provide a long‐sought unified explanation of HAND pathogenesis that takes into account all contributing factors. Evidence for the impairment by Nef of cellular cholesterol balance, potential effects of this impairment on brain cells, and opportunities to therapeutically target this element of HAND pathogenesis are discussed.

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“…NRTIs, however, cause off-target inhibition of mitochondrial DNA polymerase resulting in mitochondrial toxicity, energy depletion, and subsequent oxidative stress [48]. NRTIs are also known to induce ER stress and activate the UPR pathways in astrocytes in vitro [49]. This evidence suggests that NRTI-induced mitochondrial toxicity can indirectly cause neurotoxicity and contribute to HAND [50].…”

Section: The Role Of Art On Cns (Dys)functionmentioning

confidence: 99%

Crossroads of Drug Abuse and HIV Infection: Neurotoxicity and CNS Reservoir

et al. 2022

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Drug abuse is a common comorbidity in people infected with HIV. HIV-infected individuals who abuse drugs are a key population who frequently experience suboptimal outcomes along the HIV continuum of care. A modest proportion of HIV-infected individuals develop HIV-associated neurocognitive issues, the severity of which further increases with drug abuse. Moreover, the tendency of the virus to go into latency in certain cellular reservoirs again complicates the elimination of HIV and HIV-associated illnesses. Antiretroviral therapy (ART) successfully decreased the overall viral load in infected people, yet it does not effectively eliminate the virus from all latent reservoirs. Although ART increased the life expectancy of infected individuals, it showed inconsistent improvement in CNS functioning, thus decreasing the quality of life. Research efforts have been dedicated to identifying common mechanisms through which HIV and drug abuse lead to neurotoxicity and CNS dysfunction. Therefore, in order to develop an effective treatment regimen to treat neurocognitive and related symptoms in HIV-infected patients, it is crucial to understand the involved mechanisms of neurotoxicity. Eventually, those mechanisms could lead the way to design and develop novel therapeutic strategies addressing both CNS HIV reservoir and illicit drug use by HIV patients.

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Organellar stress intersects the astrocyte endoplasmic reticulum, mitochondria and nucleolus in HIV associated neurodegeneration

Cited by 14 publications

References 15 publications

White Matter Abnormalities Linked to Interferon, Stress Response, and Energy Metabolism Gene Expression Changes in Older HIV-Positive Patients on Antiretroviral Therapy

White Matter Abnormalities Linked to Interferon, Stress Response, and Energy Metabolism Gene Expression Changes in Older HIV-Positive Patients on Antiretroviral Therapy

Neuro‐HIV—New insights into pathogenesis and emerging therapeutic targets

Crossroads of Drug Abuse and HIV Infection: Neurotoxicity and CNS Reservoir

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