Preprint Article Version 1 This version is not peer-reviewed

Sex-Biased Associations of Circulating Ferroptosis Inhibitors with Reduced Lipid Peroxidation and Better Neurocognitive Performance in People with HIV

Version 1 : Received: 23 August 2024 / Approved: 23 August 2024 / Online: 24 August 2024 (00:22:41 CEST)

How to cite: Kaur, H.; Alluri, R. K.; Wu, K.; Kalayjian, R. C.; Bush, W. S.; Palella, F. J.; Koletar, S. L.; Hileman, C. O.; Erlandson, K. M.; Ellis, R. J.; Bedimo, R. J.; Taiwo, B. O.; Tassiopoulos, K. K.; Kallianpur, A. R. Sex-Biased Associations of Circulating Ferroptosis Inhibitors with Reduced Lipid Peroxidation and Better Neurocognitive Performance in People with HIV. Preprints 2024, 2024081759. https://doi.org/10.20944/preprints202408.1759.v1 Kaur, H.; Alluri, R. K.; Wu, K.; Kalayjian, R. C.; Bush, W. S.; Palella, F. J.; Koletar, S. L.; Hileman, C. O.; Erlandson, K. M.; Ellis, R. J.; Bedimo, R. J.; Taiwo, B. O.; Tassiopoulos, K. K.; Kallianpur, A. R. Sex-Biased Associations of Circulating Ferroptosis Inhibitors with Reduced Lipid Peroxidation and Better Neurocognitive Performance in People with HIV. Preprints 2024, 2024081759. https://doi.org/10.20944/preprints202408.1759.v1

Abstract

Ferroptosis is implicated in viral neuropathogenesis and may underlie HIV-associated neu-rocognitive impairment (NCI). Emerging data also suggest differences in brain iron transport by sex. We hypothesized that circulating ferritins that inhibit ferroptosis associate with neurocogni-tive function and NCI in people with HIV (PWH) in a sex-biased manner. Serum ferritin heavy-chain-1 (Fth-1), ferritin light-chain (Ftl), and urinary F2-isoprostanes (uF2-isoPs, specific li-pid 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 NCI were evaluated by multivariable regression; correlations with uF2-isoPs were also assessed. Higher Ftl and Fth-1 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 Fth-1 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 in-versely with uF2-isoPs in women (Ftl: rho=-0.47, p

Keywords

HIV; ferritin heavy-chain; ferritin light-chain; ferroptosis; lipid peroxidation; iron; oxidative stress; neurocognitive impairment; neurocognitive domains

Subject

Biology and Life Sciences, Neuroscience and Neurology

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