Abstract
Neurocognitive (NC) impairment (NCI) is an important cause of morbidity in persons with HIV (PWH). In the high-energy environment of the central nervous system, mitochondria contribute to neuroinflammation and aging, which may ultimately drive the pathogenesis of neurodegenerative diseases. Mitochondrial DNA (mtDNA) haplogroups are associated with health outcomes in PWH. For example, we previously observed less global NCI in Hispanic ancestry PWH having mtDNA haplogroup B. Another study reported increased NCI among PWH having African subhaplogroup L2a. We therefore analyzed NC domains in relation to these haplogroups in CNS HIV Antiretroviral Therapy Effects Research (CHARTER), a multi-site observational neuro-HIV study. Haplogroups were assigned using mtDNA sequence in 1016 PWH. Outcomes were NCI, defined by domain deficit score and mean T-scores (TS) for seven NC domains. Ancestry-stratified analyses of NC performance included Wilcoxon rank sum, χ2, and Fisher’s exact tests. Multivariable regression adjusted for NC comorbidity, antiretroviral therapy use, and nadir CD4+ T cells. Among 98 Hispanic ancestry PWH, executive function, learning, and recall performance were better with haplogroup B (N = 17) than other haplogroups. With adjustment for covariates, haplogroup B remained associated with better executive function (p = 0.04) and recall TS (p = 0.03). PWH with haplogroup B had fewer impaired domains than other haplogroups (p < 0.01). Subhaplogroup L2a (N = 89) was associated with greater NCI in learning, recall, and working memory among 478 PWH of African ancestry, and had more impaired domains than other subhaplogroups (p < 0.01). These findings may inform risk stratification for NCI and studies to define mechanisms by which mtDNA variation may influence NCI in PWH.
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Acknowledgements
The authors are indebted to all study participants who made this study possible. The CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) group is affiliated with Johns Hopkins University; the Icahn School of Medicine at Mount Sinai; University of California, San Diego; University of Texas, Galveston; University of Washington, Seattle; and Washington University, St. Louis, and is headquartered at the University of California, San Diego and includes Director: Igor Grant, M.D.; Co-Directors: Ronald J. Ellis, M.D., Scott L. Letendre, M.D., Ph.D., Thomas D. Marcotte, Ph.D.; Center Manager: Donald Franklin, Jr.; Neuromedical Component: Ronald J. Ellis, M.D., Ph.D. (P.I.), J. Allen McCutchan, M.D.; Laboratory and Virology Component: Scott Letendre, M.D. (Co-P.I.), Davey M. Smith, M.D. (Co-P.I.).; Neurobehavioral Component: Robert K. Heaton, Ph.D. (P.I.), J. Hampton Atkinson, M.D., Matthew Dawson; Imaging Component: Christine Fennema-Notestine, Ph.D. (P.I.), Michael J Taylor, Ph.D., Rebecca Theilmann, Ph.D.; Data Management Component: Anthony C. Gamst, Ph.D. (P.I.), Clint Cushman; Statistics Component: Ian Abramson, Ph.D. (P.I.), Florin Vaida, Ph.D.; Johns Hopkins University Site: Ned Sacktor (P.I.), Vincent Rogalski; Icahn School of Medicine at Mount Sinai Site: Susan Morgello, M.D. (Co-P.I.) and David Simpson, M.D. (Co-P.I.), Letty Mintz, N.P.; University of California, San Diego Site: J. Allen McCutchan, M.D. (P.I.); University of Washington, Seattle Site: Ann Collier, M.D. (Co-P.I.) and Christina Marra, M.D. (Co-P.I.), Sher Storey, PA-C.; University of Texas, Galveston Site: Benjamin Gelman, M.D., Ph.D. (P.I.), Eleanor Head, R.N., B.S.N.; and Washington University, St. Louis Site: David Clifford, M.D. (P.I.); Muhammad Al-Lozi, M.D.; and Mengesha Teshome, M.D.
Funding
Funding for this study was provided by National Institutes of Health (NIH) R01 MH095621, R01 MH107345, and K24 MH097673. CHARTER was also supported by awards N01 MH22005, HHSN271201000036C, and HHSN271201000030C from the NIH.
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Volpe, K., Samuels, D., Kallianpur, A. et al. Mitochondrial DNA haplogroups and domain-specific neurocognitive performance in adults with HIV. J. Neurovirol. 27, 557–567 (2021). https://doi.org/10.1007/s13365-021-00989-7
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DOI: https://doi.org/10.1007/s13365-021-00989-7