Sex-Biased Associations of Circulating Ferroptosis Inhibitors with Reduced Lipid Peroxidation and Better Neurocognitive Performance in People with HIV
Harpreet Kaur,
Ravi K. Alluri,
Kunling Wu,
Robert C. Kalayjian,
William S. Bush,
Frank J. Palella,
Susan L. Koletar,
Corrilynn O. Hileman,
Kristine M. Erlandson,
Ronald J. Ellis,
Roger J. Bedimo,
Babafemi O. Taiwo,
Katherine K. Tassiopoulos,
Asha R. Kallianpur
Affiliations
Harpreet Kaur
Department of Genomic Medicine, Cleveland Clinic/Lerner Research Institute, Cleveland, OH 44195, USA
Ravi K. Alluri
Department of Genomic Medicine, Cleveland Clinic/Lerner Research Institute, Cleveland, OH 44195, USA
Kunling Wu
Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA
Robert C. Kalayjian
Department of Medicine/Infectious Diseases, MetroHealth Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
William S. Bush
Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH 44106, USA
Frank J. Palella
Department of Medicine/Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Susan L. Koletar
Department of Medicine/Infectious Diseases, The Ohio State University, Columbus, OH 43210, USA
Corrilynn O. Hileman
Department of Medicine/Infectious Diseases, MetroHealth Medical Center and Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
Kristine M. Erlandson
Department of Medicine/Infectious Diseases, University of Colorado-Anschutz Medical Campus, Aurora, CO 80045, USA
Ronald J. Ellis
Department of Neurosciences, University of California-San Diego, San Diego, CA 92103, USA
Roger J. Bedimo
Medicine/Infectious Diseases Section, VA North Texas Health Care System, Dallas, TX 75216, USA
Babafemi O. Taiwo
Department of Medicine/Infectious Diseases, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA
Katherine K. Tassiopoulos
Harvard T. H. Chan School of Public Health, Harvard University, Boston, MA 02115, USA
Asha R. Kallianpur
Department of Genomic Medicine, Cleveland Clinic/Lerner Research Institute, Cleveland, OH 44195, USA
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.
