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

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.

Mitochondrial DNA mutation pathogenicity score and neurocognitive performance in persons with HIV.

BACKGROUND: Mitochondrial DNA (mtDNA) genetic variation is associated with neurocognitive (NC) impairment (NCI) in people with HIV (PWH). Other approaches use sequence conservation and protein structure to predict the impact of mtDNA variants on protein function. We examined predicted mtDNA variant pathogenicity in the CHARTER study using MutPred scores, hypothesizing that persons with higher scores (greater predicted pathogenicity) have more NCI. METHODS: CHARTER included NC testing in PWH from 2003 to 2007. MutPred scores were assigned to CHARTER participants with mtDNA sequence; any score > 0.5 was considered potentially deleterious. Outcomes at cohort entry were NCI, defined by global and seven NC domain deficit scores, and by mean global and domain NC performance T-scores. Univariate and multivariable regression analyses assessed associations between having a deleterious variant and NCI. Additional models included estimated peripheral blood cell mtDNA copy number. RESULTS: Data were available for 744 PWH (357 African ancestry; 317 European; 70 Hispanic). In the overall cohort, PWH having any potentially deleterious variant were less likely to have motor impairment (16 vs. 25 %, p = 0.001). In multivariable analysis, having a deleterious variant remained associated with lower likelihood of motor impairment (adjusted odds ratio 0.59 [95 % CI 0.41-0.88]; p = 0.009), and better motor performance by T-score (ß 1.71 [0.31-3.10], p = 0.02). Associations persisted after adjustment for estimated mtDNA quantity. CONCLUSIONS: In these PWH, having a potentially deleterious mtDNA variant was associated with less motor impairment. These unexpected findings suggest that potentially deleterious mtDNA variations may confer protection against impaired motor function by as yet unknown mechanisms.

Contemporary Antiretroviral Therapy Dysregulates Iron Transport and Augments Mitochondrial Dysfunction in HIV-Infected Human Microglia and Neural-Lineage Cells.

HIV-associated cognitive dysfunction during combination antiretroviral therapy (cART) involves mitochondrial dysfunction, but the impact of contemporary cART on chronic metabolic changes in the brain and in latent HIV infection is unclear. We interrogated mitochondrial function in a human microglia (hµglia) cell line harboring inducible HIV provirus and in SH-SY5Y cells after exposure to individual antiretroviral drugs or cART, using the MitoStress assay. cART-induced changes in protein expression, reactive oxygen species (ROS) production, mitochondrial DNA copy number, and cellular iron were also explored. Finally, we evaluated the ability of ROS scavengers or plasmid-mediated overexpression of the antioxidant iron-binding protein, Fth1, to reverse mitochondrial defects. Contemporary antiretroviral drugs, particularly bictegravir, depressed multiple facets of mitochondrial function by 20-30%, with the most pronounced effects in latently infected HIV+ hµglia and SH-SY5Y cells. Latently HIV-infected hµglia exhibited upregulated glycolysis. Increases in total and/or mitochondrial ROS, mitochondrial DNA copy number, and cellular iron accompanied mitochondrial defects in hµglia and SH-SY5Y cells. In SH-SY5Y cells, cART reduced mitochondrial iron-sulfur-cluster-containing supercomplex and subunit expression and increased Nox2 expression. Fth1 overexpression or pre-treatment with N-acetylcysteine prevented cART-induced mitochondrial dysfunction. Contemporary cART impairs mitochondrial bioenergetics in hµglia and SH-SY5Y cells, partly through cellular iron accumulation; some effects differ by HIV latency.

A haptoglobin (HP) structural variant alters the effect of APOE alleles on Alzheimer's disease.

BACKGROUND: Haptoglobin (HP) is an antioxidant of apolipoprotein E (APOE), and previous reports have shown HP binds with APOE and amyloid beta (Aß) to aid its clearance. A common structural variant of the HP gene distinguishes it into two alleles: HP1 and HP2. METHODS: HP genotypes were imputed in 29 cohorts from the Alzheimer's Disease Genetics Consortium (N = 20,512). Associations between the HP polymorphism and Alzheimer's disease (AD) risk and age of onset through APOE interactions were investigated using regression models. RESULTS: The HP polymorphism significantly impacts AD risk in European-descent individuals (and in meta-analysis with African-descent individuals) by modifying both the protective effect of APOE ε2 and the detrimental effect of APOE ε4. The effect is particularly significant among APOE ε4 carriers. DISCUSSION: The effect modification of APOE by HP suggests adjustment and/or stratification by HP genotype is warranted when APOE risk is considered. Our findings also provided directions for further investigations on potential mechanisms behind this association.

Anemia and Erythrocyte Indices Are Associated With Neurocognitive Performance Across Multiple Ability Domains in Adults With HIV.

BACKGROUND: Anemia is linked to neurocognitive impairment (NCI) in people with HIV (PWH), but its impact within specific ability domains, and in diverse populations with HIV, is uncertain. METHODS: Participants included 1339 PWH enrolled in observational HIV cohort studies with a mean of 3 comprehensive neurocognitive assessments over 30 months. Global and domain-specific neurocognitive function were assessed by the global deficit score and domain deficit score (GDS and DDS, respectively) or as GDS-defined or DDS-defined NCI (GDS ≥ 0.5, DDS > 0.5). Time-dependent associations of anemia or red-cell indices with neurocognitive function were evaluated by multivariable regression. RESULTS: The mean age at entry was 43.6 years (85% male, 23.9% Hispanic, 16.7% African ancestry by self-report, and 69.8% virally suppressed). Anemia occurred at entry in 297 (22.2%) and developed subsequently in another 129 (9.6%). Anemia (present in 26.8% of cognitively impaired PWH at entry) and lower hemoglobin were associated with higher (worse) GDS values; the association for anemia persisted after multivariable adjustment and in virally suppressed persons ( P < 0.0001). Anemia was also associated with reduced processing speed, motor function, learning, delayed recall, working memory (all P < 0.01), executive function ( P = 0.021), and verbal fluency ( P = 0.035), and these findings persisted in longitudinal analyses (adjusted P < 0.01 for all domains, except verbal fluency). Higher mean corpuscular volume and mean corpuscular hemoglobin were associated with less impairment in learning and recall (all P < 0.05). CONCLUSIONS: Anemia in diverse and virally suppressed PWH associates with reduced neurocognitive performance in multiple domains, cross-sectionally and over time. The impact of identifying and treating anemia to prevent or slow neurocognitive decline in PWH should be prospectively evaluated.

Isofurans and Isoprostanes as Potential Markers of Delayed Cerebral Ischemia Following Aneurysmal Subarachnoid Hemorrhage: A Prospective Observational Study.

BACKGROUND: F2-Isoprostanes (F2-IsoPs) and Isofurans (IsoF), specific markers of lipid peroxidation in vivo, have been reported to be elevated and have prognostic implications following subarachnoid hemorrhage (SAH). Platelet activation and vasoconstriction are attributed to these compounds. Elevated IsoF to F2-IsoPs ratios have been proposed as in vivo biomarkers of mitochondrial dysfunction. In this pilot study, we examined their performance as specific biomarkers for delayed cerebral ischemia (DCI) development following SAH. METHODS: Eighteen patients with SAH and six controls with normal neuroimaging and cerebrospinal fluid (CSF) analysis results underwent CSF sampling and abstraction of clinical, demographic, and laboratory data. Samples (two) of CSF were collected on day 1 and once on days 5-8 post bleed. F2-IsoP and IsoF assays were performed by gas chromatography/mass spectroscopy methods. Levels are expressed in median (interquartile range) for nonnormally distributed data. Repeated sample measurements were compared using the Wilcoxon signed-rank test, whereas the Mann-Whitney U-test was used for other nonnormally distributed data. RESULTS: Mean age was 61 ± 15.7 (SAH cases) versus 48 ± 10 (controls) years, and 80% of patients with SAH were women. Median Hunt and Hess score was 3 (2-4), and modified Fisher scale was 3 (3-4). Thirty nine percent of patients developed DCI. F2-IsoP were significantly higher in SAH cases than in controls [47.5 (30.2-53.5) vs. 26.0 (21.2-34.5) pg/mL]. No significant differences were observed in patients with or without DCI [41 (33.5-52) vs. 44 (28.5-55.5) pg/mL]. IsoF were elevated in the second CSF sample in nine patients but were undetectable in the remainder cases and all controls. Patients who developed DCI had significantly higher IsoF than those who did not [57 (34-72) vs. 0 (0-34) pg/mL]. Patients who met criteria for DCI had a significantly higher IsoF to F2IsoPs ratio on the late CSF sample [1.03 (1-1.38) vs. 0 (0-0.52)]. CONCLUSIONS: Preliminary findings from this study suggest that IsoF may represent a specific biomarker predicting DCI following SAH. Future studies to further explore the value of IsoF as biomarkers of secondary brain injury following SAH seem warranted.

Replication of European hypertension associations in a case-control study of 9,534 African Americans.

OBJECTIVE: Hypertension is more prevalent in African Americans (AA) than other ethnic groups. Genome-wide association studies (GWAS) have identified loci associated with hypertension and other cardio-metabolic traits like type 2 diabetes, coronary artery disease, and body mass index (BMI), however the AA population is underrepresented in these studies. In this study, we examined a large AA cohort for the generalizability of 14 Metabochip array SNPs with previously reported European hypertension associations. METHODS: To evaluate associations, we analyzed genotype data of 14 SNPs for their associations with a diagnosis of hypertension, systolic blood pressure (SBP), and diastolic blood pressure (DBP) in a case-control study of an AA population (N = 9,534). We also performed an age-stratified analysis (>30, 30≥59 and ≥60 years) following the hypertension definition described by the 8th Joint National Committee (JNC). Associations were adjusted for BMI, age, age2, sex, clinical confounders, and genetic ancestry using multivariable regression models to estimate odds ratios (ORs) and beta-coefficients. Analyses stratified by sex were also conducted. Meta-analyses (including both BioVU and COGENT-BP cohorts) were performed using a random-effects model. RESULTS: We found rs880315 to be associated with systolic hypertension (SBP≥140 mmHg) in the entire cohort (OR = 1.14, p = 0.003) and within women only (OR = 1.16, p = 0.012). Variant rs17080093 associated with lower SBP and DBP (ß = -2.99, p = 0.0352 and - ß = 1.69, p = 0.0184) among younger individuals, particularly in younger women (ß = -3.92, p = 0.0025 and ß = -1.87, p = 0.0241 for SBP and DBP respectively). SNP rs1530440 associated with higher SBP and DBP measurements (younger individuals ß = 4.1, p = 0.039 and ß = 2.5, p = 0.043 for SBP and DBP; (younger women ß = 4.5, p = 0.025 and ß = 2.9, p = 0.028 for SBP and DBP), and hypertension risk in older women (OR = 1.4, p = 0.050). rs16948048 increases hypertension risk in younger individuals (OR = 1.31, p = 0.011). Among mid-age women rs880315 associated with higher risk of hypertension (OR = 1.20, p = 0.027). rs1361831 associated with DBP (ß = -1.96, p = 0.02) among individuals older than 60 years. rs3096277 increases hypertension risk among older individuals (OR = 1.26 p = 0.0015), however, this variant also reduces SBP among younger women (ß = -2.63, p = 0.0102). CONCLUSION: These findings suggest that European-descent and AA populations share genetic loci that contribute to blood pressure traits and hypertension. However, the OR and beta-coefficient estimates differ, and some are age-dependent. Additional genetic studies of hypertension in AA are warranted to identify new loci associated with hypertension and blood pressure traits in this population.

Higher CSF Ferritin Heavy-Chain (Fth1) and Transferrin Predict Better Neurocognitive Performance in People with HIV.

HIV-associated neurocognitive disorder (HAND) remains prevalent despite antiretroviral therapy and involves white matter damage in the brain. Although iron is essential for myelination and myelin maintenance/repair, its role in HAND is largely unexplored. We tested the hypotheses that cerebrospinal fluid (CSF) heavy-chain ferritin (Fth1) and transferrin, proteins integral to iron delivery and myelination, are associated with neurocognitive performance in people with HIV (PWH). Fth1, transferrin, and the pro-inflammatory cytokines TNF-α and IL-6 were quantified in CSF at baseline (entry) in 403 PWH from a prospective observational study who underwent serial, comprehensive neurocognitive assessments. Associations of Fth1 and transferrin with Global Deficit Score (GDS)-defined neurocognitive performance at baseline and 30-42 months of follow-up were evaluated by multivariable regression. While not associated with neurocognitive performance at baseline, higher baseline CSF Fth1 predicted significantly better neurocognitive performance over 30 months in all PWH (p < 0.05), in PWH aged < 50 at 30, 36, and 42 months (all p < 0.05), and in virally suppressed PWH at all three visit time-points (all p < 0.01). Higher CSF transferrin was associated with superior neurocognitive performance at all visits, primarily in viremic individuals (all p < 0.05). All associations persisted after adjustment for neuro-inflammation. In summary, higher CSF Fth1 is neuroprotective over prolonged follow-up in all and virally suppressed PWH, while higher CSF transferrin may be most neuroprotective during viremia. We speculate that higher CSF levels of these critical iron-delivery proteins support improved myelination and consequently, neurocognitive performance in PWH, providing a rationale for investigating their role in interventions to prevent and/or treat HAND.

Multimodal single-cell omics analysis identifies epithelium-immune cell interactions and immune vulnerability associated with sex differences in COVID-19.

Sex differences in the susceptibility of SARS-CoV-2 infection and severity have been controversial, and the underlying mechanisms of COVID-19 in a sex-specific manner remain understudied. Here we inspected sex differences in SARS-CoV-2 infection, hospitalization, admission to the intensive care unit (ICU), sera inflammatory biomarker profiling, and single-cell RNA-sequencing (scRNA-seq) profiles across nasal, bronchoalveolar lavage fluid (BALF), and peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with varying degrees of disease severities. Our propensity score-matching observations revealed that male individuals have a 29% elevated likelihood of SARS-CoV-2 positivity, with a hazard ratio (HR) 1.32 (95% confidence interval [CI] 1.18-1.48) for hospitalization and HR 1.51 (95% CI 1.24-1.84) for admission to ICU. Sera from male patients at hospital admission had elevated neutrophil-lymphocyte ratio and elevated expression of inflammatory markers (C-reactive protein and procalcitonin). We found that SARS-CoV-2 entry factors, including ACE2, TMPRSS2, FURIN, and NRP1, have elevated expression in nasal squamous cells from male individuals with moderate and severe COVID-19. We observed male-biased transcriptional activation in SARS-CoV-2-infected macrophages from BALF and sputum samples, which offers potential molecular mechanism for sex-biased susceptibility to viral infection. Cell-cell interaction network analysis reveals potential epithelium-immune cell interactions and immune vulnerability underlying male-elevated disease severity and mortality in COVID-19. Mechanistically, monocyte-elevated expression of Toll-like receptor 7 (TLR7) and Bruton tyrosine kinase (BTK) is associated with severe outcomes in males with COVID-19. In summary, these findings provide basis to decipher immune responses underlying sex differences and designing sex-specific targeted interventions and patient care for COVID-19.

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment.

BACKGROUND: Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive and therapeutic interventions. METHODS: In this study, we conducted a network-based, multimodal omics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9-based genetic assay results and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer's disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2. RESULTS: We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors (BSG and FURIN) and antiviral defense genes (LY6E, IFITM2, IFITM3, and IFNAR1) was elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Overall, individuals with the AD risk allele APOE E4/E4 displayed reduced expression of antiviral defense genes compared to APOE E3/E3 individuals. CONCLUSION: Our results suggest significant mechanistic overlap between AD and COVID-19, centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions, although causal relationship and mechanistic pathways between COVID-19 and AD need future investigations.

Mitochondrial DNA haplogroups and domain-specific neurocognitive performance in adults with HIV.

Neurocognitive (NC) impairment (NCI) is an important cause of morbidity in persons with HIV (PWH). In the high-energy environment of the central nervous system, mitochondria contribute to neuroinflammation and aging, which may ultimately drive the pathogenesis of neurodegenerative diseases. Mitochondrial DNA (mtDNA) haplogroups are associated with health outcomes in PWH. For example, we previously observed less global NCI in Hispanic ancestry PWH having mtDNA haplogroup B. Another study reported increased NCI among PWH having African subhaplogroup L2a. We therefore analyzed NC domains in relation to these haplogroups in CNS HIV Antiretroviral Therapy Effects Research (CHARTER), a multi-site observational neuro-HIV study. Haplogroups were assigned using mtDNA sequence in 1016 PWH. Outcomes were NCI, defined by domain deficit score and mean T-scores (TS) for seven NC domains. Ancestry-stratified analyses of NC performance included Wilcoxon rank sum, χ2, and Fisher's exact tests. Multivariable regression adjusted for NC comorbidity, antiretroviral therapy use, and nadir CD4+ T cells. Among 98 Hispanic ancestry PWH, executive function, learning, and recall performance were better with haplogroup B (N = 17) than other haplogroups. With adjustment for covariates, haplogroup B remained associated with better executive function (p = 0.04) and recall TS (p = 0.03). PWH with haplogroup B had fewer impaired domains than other haplogroups (p < 0.01). Subhaplogroup L2a (N = 89) was associated with greater NCI in learning, recall, and working memory among 478 PWH of African ancestry, and had more impaired domains than other subhaplogroups (p < 0.01). These findings may inform risk stratification for NCI and studies to define mechanisms by which mtDNA variation may influence NCI in PWH.

Large Mitochondrial DNA Deletions in HIV Sensory Neuropathy.

OBJECTIVE: The primary objective of this study was to evaluate the correlation of large mitochondrial DNA (mtDNA) deletions in skin samples of people with HIV (PWH) with measures of neuropathy and prior exposure to therapy. We hypothesized that deletions would be associated with neuropathy. As secondary objectives, we determined the correlation of deletion burden with demographic data and neuropathy measures. METHODS: In this retrospective cohort study, we measured the accumulation of large mtDNA deletions in skin biopsies from PWH recruited as part of the AIDS Clinical Trials Group (ACTG). Our cohort includes individuals with and without sensory neuropathy, as well as individuals with normal or abnormal skin biopsies. Skin biopsies, sural and peroneal nerve conduction studies, total neuropathy score, and deletion burden scores were measured, along with baseline demographic data such as age, CD4+ cell count, viral counts, and prior nucleoside reverse transcriptase inhibitor exposures. RESULTS: Sixty-seven PWH were enrolled in the study. The mean age of the cohort (n = 67) was 44 years (SD 6.8, range 32-65 years), and 9 participants were female. The mean CD4+ T-cell count was 168 cells/mm3 (SD 97 cells/mm3, range 1-416 cells/mm3) and mean viral load was 51,129 copies/mL (SD 114,586 copies/mL, range 147-657,775 copies/mL). We determined that there was a correlation between the total mtDNA deletion and intraepidermal nerve fiber density (IENFD) (r = -0.344, p = 0.04) and sural nerve amplitude (r = -0.359, p = 0.004). CONCLUSIONS: Both IENFD and sural nerve amplitude statistically correlate with mitochondrial mutation burden in PWH, specifically in those with HIV-associated sensory neuropathy as assessed by skin biopsy.

Network medicine links SARS-CoV-2/COVID-19 infection to brain microvascular injury and neuroinflammation in dementia-like cognitive impairment.

BACKGROUND: Dementia-like cognitive impairment is an increasingly reported complication of SARS-CoV-2 infection. However, the underlying mechanisms responsible for this complication remain unclear. A better understanding of causative processes by which COVID-19 may lead to cognitive impairment is essential for developing preventive interventions. METHODS: In this study, we conducted a network-based, multimodal genomics comparison of COVID-19 and neurologic complications. We constructed the SARS-CoV-2 virus-host interactome from protein-protein interaction assay and CRISPR-Cas9 based genetic assay results, and compared network-based relationships therein with those of known neurological manifestations using network proximity measures. We also investigated the transcriptomic profiles (including single-cell/nuclei RNA-sequencing) of Alzheimer's disease (AD) marker genes from patients infected with COVID-19, as well as the prevalence of SARS-CoV-2 entry factors in the brains of AD patients not infected with SARS-CoV-2. RESULTS: We found significant network-based relationships between COVID-19 and neuroinflammation and brain microvascular injury pathways and processes which are implicated in AD. We also detected aberrant expression of AD biomarkers in the cerebrospinal fluid and blood of patients with COVID-19. While transcriptomic analyses showed relatively low expression of SARS-CoV-2 entry factors in human brain, neuroinflammatory changes were pronounced. In addition, single-nucleus transcriptomic analyses showed that expression of SARS-CoV-2 host factors ( BSG and FURIN ) and antiviral defense genes ( LY6E , IFITM2 , IFITM3 , and IFNAR1 ) was significantly elevated in brain endothelial cells of AD patients and healthy controls relative to neurons and other cell types, suggesting a possible role for brain microvascular injury in COVID-19-mediated cognitive impairment. Notably, individuals with the AD risk allele APOE E4/E4 displayed reduced levels of antiviral defense genes compared to APOE E3/E3 individuals. CONCLUSION: Our results suggest significant mechanistic overlap between AD and COVID-19, strongly centered on neuroinflammation and microvascular injury. These results help improve our understanding of COVID-19-associated neurological manifestations and provide guidance for future development of preventive or treatment interventions.

Plasma Citrate and Succinate Are Associated With Neurocognitive Impairment in Older People With HIV.

BACKGROUND: Neurocognitive impairment (NCI) is associated with monocyte activation in people with HIV (PWH). Activated monocytes increase glycolysis, reduce oxidative phosphorylation, and accumulate citrate and succinate, tricarboxylic acid (TCA) cycle metabolites that promote inflammation-this metabolic shift may contribute to NCI and slowed gait speed in PWH. METHODS: Plasma citrate and succinate were assayed by liquid chromatography-mass spectrometry from 957 participants upon entry to a multicenter, prospective cohort of older PWH. Logistic, linear, and mixed-effects linear regression models were used to examine associations between entry/baseline TCA cycle metabolites and cross-sectional and longitudinal NCI, neuropsychological test scores (NPZ-4), and gait speed. RESULTS: Median age was 51 (range 40-78) years. Each 1 standard deviation (SD) citrate increment was associated with 1.18 higher odds of prevalent NCI at baseline (P = .03), 0.07 SD lower time-updated NPZ-4 score (P = .01), and 0.02 m/s slower time-updated gait speed (P < .0001). Age accentuated these effects. In the oldest age-quartile, higher citrate was associated with 1.64 higher odds of prevalent NCI, 0.17 SD lower NPZ-4, and 0.04 m/s slower gait speed (P ≤ .01 for each). Similar associations were apparent with succinate in the oldest age-quintile, but not with gait speed. In participants without NCI at entry, higher citrate predicted a faster rate of neurocognitive decline. CONCLUSIONS: Higher plasma citrate and succinate are associated with worse cross-sectional and longitudinal measures of neurocognitive function and gait speed that are age-dependent, supporting the importance of altered bioenergetic metabolism in the pathogenesis of NCI in older PWH.

A Haptoglobin Exon Copy Number Variant Associates With HIV-Associated Neurocognitive Impairment in European and African-Descent Populations.

A common two-exon deletion distinguishes the gene encoding the free hemoglobin capturing protein-haptoglobin (HP)-into two alleles: HP1 and HP2. To evaluate the impact of this copy number variant (CNV) on neurocognitive impairment (NCI) in people living with HIV, we imputed this variant in 432 European-descent (EUR) and 491 African-descent (AFR) participants from the CNS HIV Antiretroviral Therapy Effects Research Study using an optimized imputation pipeline and evaluated its associations with NCI. At baseline, in AFR, the HP2 allele decreased the odds of NCI (defined by a global deficit score, GDS, ⩾ 0.5 ; Odds Ratio, OR = 0.584, p = 0.022). However, in EUR, HP2 increased the odds (OR = 2.081, p = 0.040) of NCI suggesting a detrimental effect. These effects were extended to longitudinal analyses using repeated measurements where the protective effect of the HP2 allele in AFR became marginally significant (p = 0.054) and in EUR the detrimental effect increased in significance (p = 0.037). In EUR, the HP2 allele slightly reduced the risk of NCI over time (OR = 0.028 per allele per year, p = 0.024). Further analyses of cognitive domain-specific impairment revealed that the HP-NCI effect was based on changes in learning, speed of information processing, and verbal domains over time differing by ancestry groups. Overall, these findings suggest that these functional HP CNV alleles influence the likelihood of NCI and contribute to changes in neurocognitive function over time in people living with HIV.

A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19.

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of coexisting medical conditions, while the underlying mechanisms remain unclear. Furthermore, there are no approved therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, disease manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus-host protein-protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measurement revealed underlying pathogenesis for broad COVID-19-associated disease manifestations. Analyses of single-cell RNA sequencing data show that co-expression of ACE2 and TMPRSS2 is elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn disease patients compared to uninflamed tissues, revealing shared pathobiology between COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicate that COVID-19 shares an intermediate inflammatory molecular profile with asthma (including IRAK3 and ADRB2). To prioritize potential treatments, we combined network-based prediction and a propensity score (PS) matching observational study of 26,779 individuals from a COVID-19 registry. We identified that melatonin usage (odds ratio [OR] = 0.72, 95% CI 0.56-0.91) is significantly associated with a 28% reduced likelihood of a positive laboratory test result for SARS-CoV-2 confirmed by reverse transcription-polymerase chain reaction assay. Using a PS matching user active comparator design, we determined that melatonin usage was associated with a reduced likelihood of SARS-CoV-2 positive test result compared to use of angiotensin II receptor blockers (OR = 0.70, 95% CI 0.54-0.92) or angiotensin-converting enzyme inhibitors (OR = 0.69, 95% CI 0.52-0.90). Importantly, melatonin usage (OR = 0.48, 95% CI 0.31-0.75) is associated with a 52% reduced likelihood of a positive laboratory test result for SARS-CoV-2 in African Americans after adjusting for age, sex, race, smoking history, and various disease comorbidities using PS matching. In summary, this study presents an integrative network medicine platform for predicting disease manifestations associated with COVID-19 and identifying melatonin for potential prevention and treatment of COVID-19.

Higher iron stores and the HFE 187C>G variant delay onset of peripheral neuropathy during combination antiretroviral therapy.

OBJECTIVE: People with HIV (PWH) continue to experience sensory neuropathy and neuropathic pain in the combination antiretroviral therapy (cART) era for unclear reasons. This study evaluated the role of iron in a previously reported association of iron-loading hemochromatosis (HFE) gene variants with reduced risk of neuropathy in PWH who received more neurotoxic cART, since an iron-related mechanism also might be relevant to neuropathic symptoms in PWH living in low-resource settings today. DESIGN: This time-to-event analysis addressed the impact of systemic iron levels on the rapidity of neuropathy onset in PWH who initiated cART. METHODS: Soluble transferrin receptor (sTFR), the sTFR-ferritin index of iron stores, and high-sensitivity C-reactive protein (hsCRP) levels were determined in stored baseline sera from participants of known HFE genotype from AIDS Clinical Trials Group (ACTG) Study 384, a multicenter randomized clinical trial that evaluated cART strategies. Associations with incident neuropathy were evaluated in proportional-hazards, time-to-event regression models, adjusting for potential confounders. RESULTS: Of 151 eligible participants with stored serum who were included in the original genetic study, 43 had cART-associated neuropathy; 108 had sufficient serum for analysis, including 30 neuropathy cases. Carriers of HFE variants had higher systemic iron (lower sTFR and sTFR-ferritin index) and lower hsCRP levels than non-carriers (all p<0.05). Higher sTFR or iron stores, the HFE 187C>G variant, and lower baseline hsCRP were associated with significantly delayed neuropathy in self-reported whites (n = 28; all p-values<0.05), independent of age, CD4+ T-cell count, plasma HIV RNA, and cART regimen. CONCLUSIONS: Higher iron stores, the HFE 187C>G variant, and lower hsCRP predicted delayed onset of neuropathy among self-reported white individuals initating cART. These findings require confirmation but may have implications for cART in HIV+ populations in areas with high endemic iron deficiency, especially those PWH in whom older, more neurotoxic antiretroviral drugs are occasionally still used.

Correction to: HIV Infection and Neurocognitive Disorders in the Context of Chronic Drug Abuse: Evidence for Divergent Findings Dependent upon Prior Drug History.

Corrected sentence in Interactions between the Effects of Drug Use and HIV-1 Infection Leads to Accelerated Disease Progression: "White matter damage (Tang et al. 2015; Alakkas et al. 2019), mitochondrial dysfunction (Buch et al. 2011), and iron dysregulation (Drakesmith et al. 2005; Ersche et al. 2017) occur with cocaine use and have also been associated with HIV infection and HAND; these processes may therefore be promising targets for treatment development."

New insights into genetic susceptibility of COVID-19: an ACE2 and TMPRSS2 polymorphism analysis.

BACKGROUND: Coronavirus Disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has now been confirmed worldwide. Yet, COVID-19 is strangely and tragically selective. Morbidity and mortality due to COVID19 rise dramatically with age and co-existing health conditions, including cancer and cardiovascular diseases. Human genetic factors may contribute to the extremely high transmissibility of SARS-CoV-2 and to the relentlessly progressive disease observed in a small but significant proportion of infected individuals, but these factors are largely unknown. MAIN BODY: In this study, we investigated genetic susceptibility to COVID-19 by examining DNA polymorphisms in ACE2 and TMPRSS2 (two key host factors of SARS-CoV-2) from ~ 81,000 human genomes. We found unique genetic susceptibility across different populations in ACE2 and TMPRSS2. Specifically, ACE2 polymorphisms were found to be associated with cardiovascular and pulmonary conditions by altering the angiotensinogen-ACE2 interactions, such as p.Arg514Gly in the African/African-American population. Unique but prevalent polymorphisms (including p.Val160Met (rs12329760), an expression quantitative trait locus (eQTL)) in TMPRSS2, offer potential explanations for differential genetic susceptibility to COVID-19 as well as for risk factors, including those with cancer and the high-risk group of male patients. We further discussed that polymorphisms in ACE2 or TMPRSS2 could guide effective treatments (i.e., hydroxychloroquine and camostat) for COVID-19. CONCLUSION: This study suggested that ACE2 or TMPRSS2 DNA polymorphisms were likely associated with genetic susceptibility of COVID-19, which calls for a human genetics initiative for fighting the COVID-19 pandemic.

A Network Medicine Approach to Investigation and Population-based Validation of Disease Manifestations and Drug Repurposing for COVID-19.

The global Coronavirus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of co-existing medical conditions while the underlying mechanisms remain unclear. Furthermore, there are no proven effective therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, diseases manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus-host protein-protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measure revealed underlying pathogenesis for broad COVID-19-associated manifestations. Multi-modal analyses of single-cell RNA-sequencing data showed that co-expression of ACE2 and TMPRSS2 was elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn's disease patients compared to uninflamed tissues, revealing shared pathobiology by COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicated that COVID-19 shared intermediate inflammatory endophenotypes with asthma (including IRAK3 and ADRB2). To prioritize potential treatment, we combined network-based prediction and propensity score (PS) matching observational study of 18,118 patients from a COVID-19 registry. We identified that melatonin (odds ratio (OR) = 0.36, 95% confidence interval (CI) 0.22-0.59) was associated with 64% reduced likelihood of a positive laboratory test result for SARS-CoV-2. Using PS-matching user active comparator design, melatonin was associated with 54% reduced likelihood of SARS-CoV-2 positive test result compared to angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (OR = 0.46, 95% CI 0.24-0.86).