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.

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 (Aβ) 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).

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.

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: and . 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 allele decreased the odds of NCI (defined by a global deficit score, GDS, ; Odds Ratio, = 0.

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.

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).

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.

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.

Iron-regulatory genes are associated with Neuroimaging measures in HIV infection.

The pathogenesis of HIV-associated neurocognitive impairment (NCI) may involve iron dysregulation. In 243 HIV-seropositive adults without severe comorbidities, we therefore genotyped 250 variants in 20 iron-related genes and evaluated their associations with magnetic resonance imaging measures of brain structure and metabolites, including measures previously linked to NCI. Multivariable regression analyses examined associations between genetic variants and neuroimaging measures, adjusting for relevant covariates and multiple testing.

Peripheral Blood Mitochondrial DNA Copy Number Obtained From Genome-Wide Genotype Data Is Associated With Neurocognitive Impairment in Persons With Chronic HIV Infection.

Background: Mitochondrial DNA (mtDNA) copy number varies by cell type and energy demands. Blood mtDNA copy number has been associated with neurocognitive function in persons without HIV. Low mtDNA copy number may indicate disordered mtDNA replication; high copy number may reflect a response to mitochondrial dysfunction.

Hemochromatosis (HFE) Gene Variants Are Associated with Increased Mitochondrial DNA Levels During HIV-1 Infection and Antiretroviral Therapy.

Some HIV-associated complications involve mitochondrial dysfunction and may be less common in individuals with iron-loading HFE (hemochromatosis gene) variants. We evaluated HFE 845A and 187G alleles in relation to mitochondrial DNA (mtDNA) levels in peripheral blood mononuclear cells from 85 individuals with HIV infection on uninterrupted antiretroviral therapy (ART) for 15 or more consecutive weeks. Carriers of HFE gene variants (N = 24) had significantly higher mtDNA levels than noncarriers (N = 61), after adjusting for age, race, sex, and type of ART [adjusted β-coefficient 297, p-value < .

Genome-wide association study of HIV-associated neurocognitive disorder (HAND): A CHARTER group study.

HIV-associated neurocognitive disorder (HAND) often complicates HIV infection despite combination antiretroviral therapy (ART) and may be influenced by host genomics. We performed a genome-wide association study (GWAS) of HAND in 1,050 CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) Study participants. All participants underwent standardized, comprehensive neurocognitive, and neuromedical assessments to determine if they had cognitive impairment as assessed by the Global Deficit Score (GDS), and individuals with comorbidities that could confound diagnosis of HAND were excluded.

Cerebrospinal fluid (CSF) biomarkers of iron status are associated with CSF viral load, antiretroviral therapy, and demographic factors in HIV-infected adults.

Background: HIV-associated neurocognitive disorder (HAND) remains common, despite antiretroviral therapy (ART). HIV dysregulates iron metabolism, but cerebrospinal fluid (CSF) levels of iron and iron-transport proteins in HIV-infected (HIV+) persons are largely unknown. The objectives of this study were to characterize CSF iron-related biomarkers in HIV+ adults and explore their relationships to known predictors of HAND.

European Mitochondrial DNA Haplogroups are Associated with Cerebrospinal Fluid Biomarkers of Inflammation in HIV Infection.

Background: Mitochondrial DNA (mtDNA) haplogroups are ancestry-related patterns of single-nucleotide polymorphisms that are associated with differential mitochondrial function in model systems, neurodegenerative diseases in HIV-negative populations, and chronic complications of HIV infection, including neurocognitive impairment. We hypothesized that mtDNA haplogroups are associated with neuroinflammation in HIV-infected adults.

Methods: CNS HIV Antiretroviral Therapy Effects Research (CHARTER) is a US-based observational study of HIV-infected adults who underwent standardized neurocognitive assessments.

Anemia and Red Blood Cell Indices Predict HIV-Associated Neurocognitive Impairment in the Highly Active Antiretroviral Therapy Era.

Background: Anemia has been linked to adverse human immunodeficiency virus (HIV) outcomes, including dementia, in the era before highly active antiretroviral therapy (HAART). Milder forms of HIV-associated neurocognitive disorder (HAND) remain common in HIV-infected persons, despite HAART, but whether anemia predicts HAND in the HAART era is unknown.

Methods: We evaluated time-dependent associations of anemia and cross-sectional associations of red blood cell indices with neurocognitive impairment in a multicenter, HAART-era HIV cohort study (N = 1261), adjusting for potential confounders, including age, nadir CD4(+) T-cell count, zidovudine use, and comorbid conditions.

Mitochondrial DNA Haplogroups and Neurocognitive Impairment During HIV Infection.

Background: Neurocognitive impairment (NCI) remains an important complication in persons infected with human immunodeficiency virus (HIV). Ancestry-related mitochondrial DNA (mtDNA) haplogroups have been associated with outcomes of HIV infection and combination antiretroviral therapy (CART), and with neurodegenerative diseases. We hypothesize that mtDNA haplogroups are associated with NCI in HIV-infected adults and performed a genetic association study in the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort.

Genetic variation in iron metabolism is associated with neuropathic pain and pain severity in HIV-infected patients on antiretroviral therapy.

HIV sensory neuropathy and distal neuropathic pain (DNP) are common, disabling complications associated with combination antiretroviral therapy (cART). We previously associated iron-regulatory genetic polymorphisms with a reduced risk of HIV sensory neuropathy during more neurotoxic types of cART. We here evaluated the impact of polymorphisms in 19 iron-regulatory genes on DNP in 560 HIV-infected subjects from a prospective, observational study, who underwent neurological examinations to ascertain peripheral neuropathy and structured interviews to ascertain DNP.

Host genetic factors predisposing to HIV-associated neurocognitive disorder.

The success of combination antiretroviral therapy (cART) in transforming the lives of HIV-infected individuals with access to these drugs is tempered by the increasing threat of HIV-associated neurocognitive disorders (HAND) to their overall health and quality of life. Intensive investigations over the past two decades have underscored the role of host immune responses, inflammation, and monocyte-derived macrophages in HAND, but the precise pathogenic mechanisms underlying HAND remain only partially delineated. Complicating research efforts and therapeutic drug development are the sheer complexity of HAND phenotypes, diagnostic imprecision, and the growing intersection of chronic immune activation with aging-related comorbidities.

Higher serum iron is associated with increased oxidant stress in HIV-infected men.

Background: F₂-isoprostanes (F₂-IsoP) are oxidant stress biomarkers that are higher in HIV-infected women than men. We explored whether the effect of hemoglobin (Hgb), serum iron, or anemia on F₂-IsoP is different between HIV-infected women and men.

Methods: Plasma F₂-IsoP were quantified by gas chromatography/mass spectrometry; clinical and laboratory data were collected at enrollment or from the medical record.

Mitochondrial DNA variation and HIV-associated sensory neuropathy in CHARTER.

HIV-associated sensory neuropathy remains an important complication of combination antiretroviral therapy and HIV infection. Mitochondrial DNA haplogroups and single nucleotide polymorphisms (SNPs) have previously been associated with symptomatic neuropathy in clinical trial participants. We examined associations between mitochondrial DNA variation and HIV-associated sensory neuropathy in CNS HIV Antiretroviral Therapy Effects Research (CHARTER).

African mitochondrial DNA subhaplogroups and peripheral neuropathy during antiretroviral therapy.

Susceptibility to peripheral neuropathy during antiretroviral therapy with nucleoside reverse-transcriptase inhibitors was previously associated with a European mitochondrial DNA (mtDNA) haplogroup among non-Hispanic white persons. To determine whether nucleoside reverse-transcriptase inhibitor-associated peripheral neuropathy was related to mtDNA variation in non-Hispanic black persons, we sequenced mtDNA of participants from AIDS Clinical Trials Group study 384. Of 156 non-Hispanic black persons with genomic data, 51 (33%) developed peripheral neuropathy.

Dietary iron intake and risk of endometrial cancer: a population-based case-control study in Shanghai, China.

Dietary red meat and animal fat have been linked to endometrial cancer (EC) risk, but the impact of bioavailable iron in animal-derived foods has been less well studied. Our objective was to investigate the effects of iron and fats on the risk of EC in a large, population-based, case-control study. The Shanghai Endometrial Cancer Study enrolled 1,204 EC cases and 1,212 controls who completed in-person interviews, including a food frequency questionnaire.