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

Patton, Stephanie M.; Wang, Quan; Hulgan, Todd; Connor, James R.; Jia, Peilin; Zhao, Zhongming; Letendre, Scott; Ellis, Ronald J.; Bush, William S.; Samuels, David C.; Franklin, Donald; Kaur, Harpreet; Iudicello, Jennifer E.; Grant, Igor; Kallianpur, Asha R.

doi:10.1186/s12987-017-0058-1

Cited by 23 publications

(30 citation statements)

References 95 publications

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“…We demonstrated in the cell culture model that Hft can limit Sema4A‐mediated cytotoxicity. Hft is not only present in the human CSF (Patton et al, ), but in support of the notion that it could impact cytotoxicity has been shown to be protective in HIV persons. Taken together, these findings indicate a role for Sema4A in the pathophysiology of demyelination and a clear relationship between Tim‐1, iron uptake in oligodendrocytes, and the immune system.…”

Section: Discussionmentioning

confidence: 72%

Semaphorin4A and H‐ferritin utilize Tim‐1 on human oligodendrocytes: A novel neuro‐immune axis

Chiou

Lucassen

Sather

et al. 2018

Glia

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Deficiency of trophic factors relating to the survival of oligodendrocytes, combined with direct interactions with the immune system, are favored paradigms that are increasingly implicated in demyelinating diseases of the central nervous system. We and others have previously shown that Sema4A and H-ferritin interact through the T-cell immunoglobulin and mucin domain (Tim-2) receptor in mice. H-ferritin has been identified as the iron delivery protein for oligodendrocytes, whereas Sema4A causes a direct cytotoxic effect. However, the expression of Tim-2 has not been detected in humans. Here, we demonstrate that, similar to rodents, human oligodendrocytes undergo apoptosis when exposed to Sema4A and take up H-ferritin for meeting iron requirements and that these functions are mediated via the Tim-1 receptor. Moreover, we also demonstrate the ability of H-ferritin to block Sema4A-mediated cytotoxicity. Furthermore, we show in a series of pilot studies that Sema4A is detectable in the CSF of multiple sclerosis patients and HIV-seropositive persons and can induce oligodendrocyte cell death. Together, these results identify a novel iron uptake mechanism for human oligodendrocytes and a connection between oligodendrocytes and the immune system.

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Section: Discussionmentioning

confidence: 72%

Semaphorin4A and H‐ferritin utilize Tim‐1 on human oligodendrocytes: A novel neuro‐immune axis

Chiou

Lucassen

Sather

et al. 2018

Glia

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“…Iron homeostasis is essential for maintenance of mitochondrial function and energy production in the brain, as neural tissues have extremely high metabolic demand, and iron is a key component of the molecular complexes that constitute the electron transport chain. Furthermore, by virtue of its ability to readily accept and donate electrons, iron is a required cofactor for a very large number of fundamental metabolic processes, including synthesis of DNA, heme, monoamine neurotransmitters, and myelin Patton et al 2017;Puig et al 2017). However, iron that is not tightly proteinbound is highly reactive and generates oxidative stress by catalyzing free radical reactions.…”

Section: Discussionmentioning

confidence: 99%

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

Fennema-Notestine

Thornton‐Wells

Hulgan

et al. 2019

Brain Imaging and Behavior

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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. Exploratory analyses stratified by NCI (Global Deficit Score ≥ 0.5 vs. <0.5), virus detectability in plasma, and comorbidity levels were also performed. Of 27 variants (in 12 iron-regulatory genes) associated with neuroimaging measures after correction for the 37 haplotype blocks represented, 3 variants survived additional correction for the 21 neuroimaging measures evaluated and demonstrated biologically plausible associations. SLC11A1 rs7576974_T was significantly associated with higher frontal gray matter N-acetylaspartate (p = 3.62e −5 ). Among individuals with detectable plasma virus, TFRC rs17091382_A was associated with smaller subcortical gray matter volume (p = 3.23e −5 ), and CP rs4974389_A (p = 3.52e −5 ) was associated with higher basal ganglia Choline in persons with mild comorbidities. Two other strong associations were observed for variants in SLC40A1 and ACO2 but were not robust due to low minor-allele frequencies in the study sample. Variants in iron metabolism and transport genes are associated with structural and metabolite neuroimaging measures in HIV-seropositive adults, regardless of virus suppression on antiretroviral therapy. These variants may confer susceptibility to HIV-related brain injury and NCI. Further studies are needed to determine the specificity of these findings to HIV infection and explore potential underlying mechanisms.

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“…The copyright holder for this preprint this version posted November 6, 2020. ; https://doi.org/10.1101/2020.11.04.20199760 doi: medRxiv preprint CSF iron-biomarker levels were determined using commercially available assay kits according to the manufacturer's protocol [17]. Concentrations of inflammatory cytokines and chemokines were measured in CSF by commercial, high-sensitivity multiplex assay Table S1).…”

Section: Quantification Of Csf Iron Biomarkers and Inflammationmentioning

confidence: 99%

“…The copyright holder for this preprint this version posted November 6, 2020. ; https://doi.org/10.1101/2020.11.04.20199760 doi: medRxiv preprint As iron homeostasis in HAND is a new area of investigation, and we previously associated CSF H-ferritin and transferrin with comorbidity and zidovudine use, we also stratified H-ferritin and transferrin models by comorbidity and zidovudine use, respectively, and tested for multiplicative interactions between these variables [17]. Adjustment for self-reported race/ethnicity did not significantly alter results, and the GDS includes corrections for demographic norms, so race/ethnicity was not included in the final models.…”

Section: Quantification Of Csf Iron Biomarkers and Inflammationmentioning

confidence: 99%

Cerebrospinal Fluid Iron Status Predicts Neurocognitive Performance Over Time in Adults with HIV

Kaur

Bush

Letendre

et al. 2020

Preprint

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Iron homeostasis is essential for brain health, and iron is also required for HIV replication, but the role of iron is largely unexplored in HIV-associated neurocognitive disorders. These disorders remain extremely common in people with HIV, despite antiretroviral therapy capable of suppressing viral replication, and they involve damage to white matter tracts and synaptodendritic architecture in the brain. We hypothesized that cerebrospinal fluid (CSF) levels of iron and two proteins involved in iron delivery, mitochondrial function, and protection against iron-mediated oxidative stress (H-ferritin and transferrin) are associated with neurocognitive performance over time in adults with HIV. These CSF iron-related biomarkers were measured at baseline (entry) in 403 adults with HIV from a large, prospective observational study who underwent comprehensive neurocognitive assessments at 6-month intervals. All participants were assigned a Global Deficit Score (GDS) and neurocognitive change status (improving/stable/declining), compared to baseline, at each visit. Biomarker associations with change status, and GDS differences over 30, 36, and 42 months of follow-up, were evaluated by multivariable regression. GDS-defined neurocognitive impairment was present in 120 study participants at entry (29.8%); 73% were on antiretroviral therapy. Of 267 participants with longitudinal follow-up, 16% were improving neurocognitively, and 20% were declining at their last follow-up visit (median 36 months). In multivariable-adjusted analyses, higher baseline CSF H-ferritin predicted improving neurocognitive performance at the last assessment (p=0.029), and a better GDS over at least 30 months. Higher H-ferritin levels were also associated with better GDS-defined neurocognitive performance over 30, 36, and 42 months in virally suppressed individuals (p-values <0.01 at all three time-points) and individuals aged<50 (all p-values <0.05). Higher CSF transferrin beneficially influenced GDS-defined neurocognitive performance at all three follow-up visits (all p<0.05), particularly in viremic individuals and people with HIV aged 50 and over, but the associations lost statistical significance in analyses restricted to virally suppressed persons. Significant multiplicative interactions with comorbidity were observed for both H-ferritin and transferrin in viremic adults. In summary, higher CSF H-ferritin is associated with better neurocognitive performance over time in adults with HIV, particularly in younger and virally suppressed individuals on antiretroviral therapy. Higher CSF transferrin may be particularly neuroprotective in pro-inflammatory settings such as in older and/or viremic people with HIV. Overall, our findings could reflect better iron delivery to neurons and myelinating oligodendrocytes, better mitochondrial function, and reduced oxidative stress under specific scenarios (e.g., viremia/aviremia) of HIV infection, and they may provide a rationale for the use of iron-modulating interventions to prevent or treat neurocognitive decline in people with HIV.

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

Cited by 23 publications

References 95 publications

Semaphorin4A and H‐ferritin utilize Tim‐1 on human oligodendrocytes: A novel neuro‐immune axis

Semaphorin4A and H‐ferritin utilize Tim‐1 on human oligodendrocytes: A novel neuro‐immune axis

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

Cerebrospinal Fluid Iron Status Predicts Neurocognitive Performance Over Time in Adults with HIV

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