Early Inflammatory Signatures Predict Subsequent Cognition in Long-Term Virally Suppressed Women With HIV

Rubin, Leah H.; Xu, Yanxun; Norris, Philip J.; Wang, Xuzhi; Dastgheyb, Raha; Fitzgerald, Kathryn C.; Keating, Sheila M.; Kaplan, Robert C.; Maki, Pauline M.; Anastos, Kathryn; Springer, Günter; Benning, Lorie; Kassaye, Seble; Gustafson, Deborah; Valcour, Victor; Williams, Dionna W.

doi:10.3389/fnint.2020.00020

Cited by 11 publications

(8 citation statements)

References 94 publications

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“…Emerging data from recent studies including CHARTER and the MACS/WIHS Combined Cohort Study (MWCCS) support that several indicators such as sex and inflammation are associated with deficits in specific NC domains, such as delayed recall or working memory (Dastgheyb et al 2019 ; Rubin et al 2020 ). We analyzed the associations of the three noncoding EIF2AK3 SNVs with deficits in NC domains in the CHARTER GWAS dataset.…”

Section: Resultsmentioning

confidence: 99%

Genetic Variations in EIF2AK3 are Associated with Neurocognitive Impairment in People Living with HIV

Akay-Espinoza,

Newton,

Dombroski

et al. 2024

J Neuroimmune Pharmacol

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Based on emerging evidence on the role for specific single-nucleotide variants (SNVs) in EIF2AK3 encoding the integrated stress response kinase PERK, in neurodegeneration, we assessed the association of EIF2AK3 SNVs with neurocognitive performance in people with HIV (PWH) using a candidate gene approach. This retrospective study included the CHARTER cohort participants, excluding those with severe neuropsychiatric comorbidities. Genome-wide data previously obtained for 1047 participants and targeted sequencing of 992 participants with available genomic DNA were utilized to interrogate the association of three noncoding and three coding EIF2AK3 SNVs with the continuous global deficit score (GDS) and global neurocognitive impairment (NCI; GDS ≥ 0.5) using univariable and multivariable methods, with demographic, disease-associated, and treatment characteristics as covariates. 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 levels ≤ 200 copies/mL. All three noncoding EIF2AK3 SNVs were associated with GDS and NCI (all p < 0.05). Additionally, 30.9%, 30.9%, and 41.2% of participants had at least one risk allele for the coding SNVs rs1805165 (G), rs867529 (G), and rs13045 (A), respectively. Homozygosity for all three coding SNVs was associated with significantly worse GDS (p < 0.001) and more NCI (p < 0.001). By multivariable analysis, the rs13045 A risk allele, current ART use, and Beck Depression Inventory-II value > 13 were independently associated with GDS and NCI (p < 0.001) whereas the other two coding SNVs did not significantly correlate with GDS or NCI after including rs13045 in the model. The coding EIF2AK3 SNVs were 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 present in multivariable analyses, raising the possibility of specific SNVs in EIF2AK3 as an important component of genetic vulnerability to neurocognitive complications in PWH. Graphical Abstract

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Section: Resultsmentioning

confidence: 99%

Genetic Variations in EIF2AK3 are Associated with Neurocognitive Impairment in People Living with HIV

Akay-Espinoza,

Newton,

Dombroski

et al. 2024

J Neuroimmune Pharmacol

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“…Chronic inflammation is another major contributor to CNS dysfunction that persists in people living with HIV, even with successful ART. − Inflammation in the periphery, perivascular space, and within the brain parenchyma contribute to CNS dysfunction during HIV. − Chronic inflammation promotes neuropathology, including accelerated brain aging, increased risk of developing psychiatric disorders, and cognitive decline . In the short term, the neuroimmune response is beneficial by promoting pathogen clearance, inducing angiogenesis, and increasing wound healing .…”

Section: Discussionmentioning

confidence: 99%

Spatial Heterogeneity of Brain Lipids in SIV-Infected Macaques Treated with Antiretroviral Therapy

White,

Gausepohl,

Wilkins

et al. 2024

J. Am. Soc. Mass Spectrom.

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Human immunodeficiency virus (HIV) infection continues to promote neurocognitive impairment, mood disorders, and brain atrophy, even in the modern era of viral suppression. Brain lipids are vulnerable to HIV-associated energetic strain and may contribute to HIV-associated neurologic dysfunction due to alterations in lipid breakdown and structural lipid composition. HIV neuropathology is region dependent, yet there has not been comprehensive characterization of the spatial heterogeneity of brain lipids during infection that possibly impacts neurologic function. To address this gap, we evaluated the spatial lipid distribution using matrix laser desorption/ionization imaging mass spectrometry (MALDI-IMS) across four brain regions (parietal cortex, midbrain, thalamus, and temporal cortex), as well as the kidney for a peripheral tissue control, in a simian immunodeficiency virus (SIV)infected rhesus macaque treated with a course of antiretroviral therapies (ARTs). We assessed lipids indicative of fat breakdown [acylcarnitines (CARs)] and critical structural lipids [phosphatidylcholines (PCs) and phosphatidylethanolamines (PEs)] across fatty acid chain lengths and degrees of unsaturation. CARs with very long-chain, polyunsaturated fatty acids (PUFAs) were more abundant across all brain regions than shorter chain, saturated, or monounsaturated species. We observed distinct brain lipid distribution patterns for the CARs and PCs. However, no clear expression patterns emerged for PEs. Surprisingly, the kidney was nearly devoid of ions corresponding to PUFAs common in brain. PEs and PCs with PUFAs had little intensity and less density than other species, and only one CAR species was observed in kidney at high intensity. Overall, our study demonstrates the stark variation in structural phospholipids and lipid-energetic intermediates present in the virally suppressed SIV-macaque brain. These findings may be useful for identifying regional vulnerabilities to damage due to brain lipid changes in people with HIV.

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“…Here plasma CRP, IL-6, sCD40L and sAPP were particularly strongly associated with decline in the domains of speed-of-information processing and executive function as compared to other domains. These domains are selectively affected by HIV brain disease ( Kanmogne et al., 2018 ; Naveed et al., 2021 ; Haase et al., 2014 ) and in the modern treatment era are strongly associated with markers of vascular disease ( Montoya et al., 2017 ; Becker et al., 2009 ) and inflammation ( Rubin et al., 2020 ; Monnig et al., 2017 ).…”

Section: Discussionmentioning

confidence: 99%

Peripheral inflammation and depressed mood independently predict neurocognitive worsening over 12 years

Tang

Collier

Morgello

et al. 2022

Brain, Behavior, & Immunity - Health

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Early Inflammatory Signatures Predict Subsequent Cognition in Long-Term Virally Suppressed Women With HIV

Cited by 11 publications

References 94 publications

Genetic Variations in EIF2AK3 are Associated with Neurocognitive Impairment in People Living with HIV

Genetic Variations in EIF2AK3 are Associated with Neurocognitive Impairment in People Living with HIV

Spatial Heterogeneity of Brain Lipids in SIV-Infected Macaques Treated with Antiretroviral Therapy

Peripheral inflammation and depressed mood independently predict neurocognitive worsening over 12 years

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