Abstract
BackgroundHIV-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.MethodsWe quantified total iron, transferrin and heavy-chain (H)-ferritin by immunoassay in CSF sampled by lumbar puncture in 403 HIV+ participants in a multi-center, observational study and evaluated biomarker associations with demographic and HIV-related correlates of HAND [e.g., age, sex, self-reported race/ethnicity, ART, and detectable plasma virus and CSF viral load (VL)] by multivariable regression. In a subset (N = 110) with existing CSF: serum albumin (QAlb) measurements, QAlb and comorbidity severity were also included as covariates to account for variability in the blood–CSF-barrier.ResultsAmong 403 individuals (median age 43 years, 19% women, 56% non-Whites, median nadir CD4+ T cell count 180 cells/µL, 46% with undetectable plasma virus), men had 25% higher CSF transferrin (median 18.1 vs. 14.5 µg/mL), and 71% higher H-ferritin (median 2.9 vs. 1.7 ng/mL) than women (both p-values ≤0.01). CSF iron was 41% higher in self-reported Hispanics and 27% higher in (non-Hispanic) Whites than in (non-Hispanic) Blacks (median 5.2 and 4.7 µg/dL in Hispanics and Whites, respectively, vs. 3.7 µg/dL in Blacks, both p ≤ 0.01); these findings persisted after adjustment for age, sex, and HIV-specific factors. Median H-ferritin was 25% higher (p < 0.05), and transferrin 14% higher (p = 0.06), in Whites than Blacks. Transferrin and H-ferritin were 33 and 50% higher, respectively, in older (age > 50 years) than in younger persons (age ≤ 35 years; both p < 0.01), but these findings lost statistical significance in subset analyses that adjusted for QAlb and comorbidity. After these additional adjustments, associations were observed for CSF iron and transferrin with race/ethnicity as well as CSF VL, for transferrin with sex and ART, and for H-ferritin with plasma virus detectability and significant comorbidity (all p < 0.05).ConclusionsCSF iron biomarkers are associated with demographic factors, ART, and CSF VL in HIV+ adults. Future studies should investigate a role for CNS iron dysregulation, to which an altered blood-CSF barrier may contribute, in HAND.
Highlights
HIV-associated neurocognitive disorder (HAND) remains common, despite antiretroviral therapy (ART)
IQR interquartile range, LLQ lower limit of quantitation, CSF cerebrospinal fluid, VL viral load (HIV RNA), ZDV zidovudine, SD standard deviation, μg/ng//dL/mL micrograms or nanograms per deciliter or milliliter a Three individuals did not have CSF viral load measurements b Values of zero for iron biomarkers were at or below the lower limit of detection of the assay biomarkers in HIV+ persons, we measured CSF iron, transferrin, and H-ferritin in 403 cryopreserved CSF samples from CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study participants collected at baseline and in 100 of the same persons at 6 months of follow-up
CSF iron, transferrin and ferritin levels measured at the baseline visit were correlated with levels of the same biomarkers measured at the 6-month visit
Summary
HIV-associated neurocognitive disorder (HAND) remains common, despite antiretroviral therapy (ART). Risk factors for HAND include the nadir CD4+ T-cell count, indicating the depth of immunosuppression achieved during the course of HIV disease, older age at seroconversion, anemia, delay in initiating ART, and the presence of HIV RNA in the CSF and plasma, as well as comorbidity [11,12,13,14]. The possibility that CNS toxicity due to ART contributes to HAND remains a matter of debate; certain antiretroviral drugs such as zidovudine (ZDV) have well-described effects on iron transport and frequently cause anemia, and others may exhibit neurotoxicity [14, 16, 17]. HIV+ persons of Hispanic ethnicity experience an increased risk of neurocognitive decline, possibly due in part to reduced or delayed access to health care [13, 18, 21,22,23]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
