HIV‐induced neuroinflammation inhibits oligodendrocyte maturation via glutamate‐dependent activation of the PERK arm of the integrated stress response

Roth, Lindsay M; Akay, Cagla; Grinspan, Judith B.; Jordan‐Sciutto, Kelly L.

doi:10.1002/glia.24033

Cited by 13 publications

(11 citation statements)

References 108 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The observed association between an EIF2AK3 SNV and higher IL-6 concentrations in CSF is particularly interesting since several studies have linked systemic and CNS inflammation to neuropsychiatric conditions, including worse NC performance and depressive symptoms 89; 113 . This finding provides additional evidence for a potential role of PERK in neuroinflammation in several disorders including NCI in PWH 94; 114; 115 .…”

Section: Discussionmentioning

confidence: 54%

Genetic variations inEIF2AK3are associated with neurocognitive impairment in people living with HIV

Akay

Bond

Dombroski

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

Coding and noncoding single-nucleotide variants (SNVs) of EIF2AK3, which encodes an integrated stress response (ISR) kinase, may play a role in neurodegenerative disorders. We used a candidate gene approach to determine the correlation of EIF2AK3 SNVs with neurocognitive (NC) impairment (NCI), which can persist with viral suppression from antiretroviral therapy (ART) in people with HIV (PWH). This retrospective study of prospectively collected data included participants of the CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) cohort, after excluding participants with severe neuropsychiatric comorbidities. Genome-wide data previously obtained in the CHARTER cohort participants (n=1,047) were analyzed to interrogate the association of three noncoding EIF2AK3 SNVs with the continuous global deficit score (GDS) and global NCI (GDS≥0.5). Targeted sequencing (TS) was performed in 992 participants with available genomic DNA to determine the association of three coding EIF2AK3 SNVs with GDS and NCI. Analyses included univariable and multivariable methods such as analysis of variance and regression. Multivariable models covaried demographic, disease-associated, and treatment characteristics. The cohort characteristics were as follows: median age, 43.1 years; females, 22.8%; European ancestry, 41%; median CD4+ T cell counts, 175/µL (nadir) and 428/µL (current). At first assessment, 70.5% used ART and 68.3% of these had plasma HIV RNA ≤ 200 copies/mL. A minority of participants had at least one risk allele for rs6739095 (T,41.7%), rs1913671 (C,41.4%), and rs11684404 (C,39.4%). All three noncoding EIF2AK3 SNVs were associated with significantly worse GDS and more NCI (all p<0.05). By TS, fewer participants had at least one risk allele for rs1805165 (G,30.9%), rs867529 (G,30.9%), and rs13045 (A,41.2%). Homozygosity for all three coding SNVs was associated with significantly worse GDS and more NCI (all p<0.001). By multivariable analysis, the rs13045 A risk allele, current ART use, and Beck Depression Inventory-II (BDI) > 13 were independently associated with GDS and NCI (p<0.001). The other two coding SNVs did not significantly correlate with GDS or NCI after including rs13045 in the model. The coding EIF2AK3 SNVs were specifically associated with worse performance in executive functioning, motor functioning, learning, and verbal fluency. Coding and non-coding SNVs of EIF2AK3 were associated with global NC and domain-specific performance. The effects were small-to-medium in size but were present in multivariable analyses. Specific SNVs in EIF2AK3 may be an important component of genetic vulnerability to NC complications in PWH. Identification of host factors that predict NCI could allow for earlier interventions, including those directly modulating the ISR, to improve NC outcomes.

show abstract

Section: Discussionmentioning

confidence: 54%

Genetic variations inEIF2AK3are associated with neurocognitive impairment in people living with HIV

Akay

Bond

Dombroski

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…The implicated roles of PERK in the context of HIV infection are multipronged. HIV-induced neuroinflammation inhibits oligodendrocyte maturation via glutamate-dependent activation of PERK, and blocking PERK protects oligodendrocyte precursor cells from HIV/monocyte-derived macrophage-mediated inhibition of oligodendrocyte maturation [ 50 ]. HIV Tat-mediated induction of human brain microvascular endothelial cell apoptosis involves endoplasmic reticulum stress and mitochondrial dysfunction [ 51 ].…”

Section: Discussionmentioning

confidence: 99%

PKR-like ER kinase (PERK) Haplotypes Are Associated with Depressive Symptoms in People with HIV

Ellis¹

2023

J Neurol Psychol

View full text Add to dashboard Cite

Background: Depression is a debilitating and difficult-to-treat condition in people with HIV (PWH) despite viral suppression on antiretroviral therapy (ART). Depression is associated with activation of the PKR-like ER kinase (PERK) pathway, which regulates protein synthesis in response to metabolic stress. We evaluated common PERK haplotypes that influence PERK expression in relation to depressed mood in PWH.Methods: PWH from 6 research centers were enrolled in the study. Genotyping was conducted using targeted sequencing with TaqMan. The major PERK haplotypes A, B, and D were identified. Depressive symptom severity was assessed using the Beck Depression Inventory-II (BDI-II). Covariates including genetically-defined ancestry, demographics, HIV disease/treatment parameters and antidepressant treatments were assessed. Data were analyzed using multivariable regression models.Results: A total of 287 PWH with a mean (SD) age of 57.1±7.8 years were enrolled. Although the largest ethnic group was non-Hispanic white (n=129, 45.3%), African-American (n=124, 43.5%) and Hispanic (n=30, 10.5%) made up over half the sample. 20.3% were female and 96.5% were virally suppressed. Mean BDI-II was 9.6±9.5, and 28.9% scored above the cutoff for mild depression (BDI-II>13). PERK haplotype frequencies were AA57.8%, AB25.8%, AD 10.1%, and BB4.88%. PERK haplotypes were differentially represented according to genetic ancestry (p=6.84e-6). BDI-II scores were significantly higher in participants with the AB haplotype (F=4.45, p=0.0007).This finding was robust to consideration of potential confounds. Conclusion:PERK haplotypes were associated with depressed mood in PWH.Consequently, pharmacological targeting of PERKrelated pathways might amelioratedepression in PWH.

show abstract

“…The implicated roles of PERK in the context of HIV infection are multipronged. HIV-induced neuroin ammation inhibits oligodendrocyte maturation via glutamate-dependent activation of PERK, and blocking PERK protects oligodendrocyte precursor cells from HIV/monocyte-derived macrophage-mediated inhibition of oligodendrocyte maturation (50). HIV Tatmediated induction of human brain microvascular endothelial cell apoptosis involves endoplasmic reticulum stress and mitochondrial dysfunction (51).…”

Section: Discussionmentioning

confidence: 99%

PKR-like ER kinase (PERK) Haplotypes Are Associated with Depressive Symptoms in People with HIV

Haddadi

Jordan‐Sciutto

Akay

et al. 2022

Preprint

View full text Add to dashboard Cite

Background. Depression is a debilitating and difficult-to-treat condition in people with HIV (PWH) despite viral suppression on antiretroviral therapy (ART). Depression is associated with activation of the PKR-like ER kinase (PERK) pathway, which regulates protein synthesis in response to metabolic stress. We evaluated common PERK haplotypes that influence PERK expression in relation to depressed mood in PWH. Methods. PWH from 6 research centers were enrolled in the study. Genotyping was conducted using targeted sequencing with TaqMan. The major PERK haplotypes A, B, and D were identified. Depressive symptom severity was assessed using the Beck Depression Inventory-II (BDI-II). Covariates including genetically-defined ancestry, demographics, HIV disease/treatment parameters and antidepressant treatments were assessed. Data were analyzed using multivariable regression models. Results. A total of 287 PWH with a mean (SD) age of 57.1±7.8 years were enrolled. Although the largest ethnic group was non-Hispanic white (n=129, 45.3%), African-American (n=124, 43.5%) and Hispanic (n=30, 10.5%) made up over half the sample. 20.3% were female and 96.5% were virally suppressed. Mean BDI-II was 9.6±9.5, and 28.9% scored above the cutoff for mild depression (BDI-II>13). PERK haplotype frequencies were AA 57.8%, AB 25.8%, AD 10.1%, and BB 4.88%. PERK haplotypes were differentially represented according to genetic ancestry (p= 6.84e-6). BDI-II scores were significantly higher in participants with the AB haplotype (F=4.45, p=0.0007). This finding was robust to consideration of potential confounds. Conclusions. PERK haplotypes were associated with depressed mood in PWH. Consequently, pharmacological targeting of PERK-related pathways might ameliorate depression in PWH.

show abstract

HIV‐induced neuroinflammation inhibits oligodendrocyte maturation via glutamate‐dependent activation of the PERK arm of the integrated stress response

Cited by 13 publications

References 108 publications

Genetic variations inEIF2AK3are associated with neurocognitive impairment in people living with HIV

Genetic variations inEIF2AK3are associated with neurocognitive impairment in people living with HIV

PKR-like ER kinase (PERK) Haplotypes Are Associated with Depressive Symptoms in People with HIV

PKR-like ER kinase (PERK) Haplotypes Are Associated with Depressive Symptoms in People with HIV

Contact Info

Product

Resources

About