1. Sex-Biased Associations of Circulating Ferroptosis Inhibitors with Reduced Lipid Peroxidation and Better Neurocognitive Performance in People with HIV
- Author
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Kaur, Harpreet, Alluri, Ravi K, Wu, Kunling, Kalayjian, Robert C, Bush, William S, Palella, Frank J, Koletar, Susan L, Hileman, Corrilynn O, Erlandson, Kristine M, Ellis, Ronald J, Bedimo, Roger J, Taiwo, Babafemi O, Tassiopoulos, Katherine K, and Kallianpur, Asha R
- Subjects
Medical Biochemistry and Metabolomics ,Pharmacology and Pharmaceutical Sciences ,Biomedical and Clinical Sciences ,Neurosciences ,Sexually Transmitted Infections ,Behavioral and Social Science ,Basic Behavioral and Social Science ,HIV/AIDS ,Infectious Diseases ,Brain Disorders ,Clinical Research ,Mental Health ,2.1 Biological and endogenous factors ,HIV ,ferritin heavy chain ,ferritin light chain ,ferroptosis ,lipid peroxidation ,iron ,oxidative stress ,neurocognitive impairment ,neurocognitive domains ,ACTG A5322 Study Team ,Biochemistry and cell biology ,Medical biochemistry and metabolomics ,Pharmacology and pharmaceutical sciences - Abstract
Ferroptosis is implicated in viral neuropathogenesis and may underlie HIV-associated neurocognitive impairment (NCI). Emerging data also suggest differences in brain iron transport by sex. We hypothesized that circulating ferritins that inhibit ferroptosis associate with neurocognitive function and NCI in people with HIV (PWH) in a sex-biased manner. Serum ferritin heavy-chain-1 (FTH1), ferritin light-chain (FTL), and urinary F2-isoprostanes (uF2-isoPs, specific lipid peroxidation marker) were quantified in 324 PWH (including 61 women) with serial global (NPZ-4) and domain-specific neurocognitive testing. Biomarker associations with neurocognitive test scores and NCIs were evaluated by multivariable regression; correlations with uF2-isoPs were also assessed. Higher FTL and FTH1 levels were associated with less NCI in all PWH (adjusted odds ratios 0.53, 95% confidence interval (95% CI) 0.36-0.79 and 0.66, 95% CI 0.45-0.97, respectively). In women, higher FTL and FTH1 were also associated with better NPZ-4 (FTL adjusted beta (β) = 0.15, 95% CI 0.02-0.29; FTL-by-sex βinteraction = 0.32, p = 0.047) and domain-specific neurocognitive test scores. Effects on neurocognitive performance persisted for up to 5 years. Levels of both ferritins correlated inversely with uF2-isoPs in women (FTL: rho = -0.47, p < 0.001). Circulating FTL and FTH1 exert sustained, sex-biased neuroprotective effects in PWH, possibly by protecting against iron-mediated lipid peroxidation (ferroptosis). Larger studies are needed to confirm the observed sex differences and further delineate the underlying mechanisms.
- Published
- 2024