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Abstract
Background:Mitochondrial DNA (mtDNA) haplogroups are ancestry-related patterns of single-nucleotide polymorphisms that are associated with differential mitochondrial function in model systems, neurodegenerative diseases in HIV-negative populations, and chronic complications of HIV infection, including neurocognitive impairment. We hypothesized that mtDNA haplogroups are associated with neuroinflammation in HIV-infected adults.Methods:CNS HIV Antiretroviral Therapy Effects Research (CHARTER) is a US-based observational study of HIV-infected adults who underwent standardized neurocognitive assessments. Participants who consented to DNA collection underwent whole blood mtDNA sequencing, and a subset also underwent lumbar puncture. IL-6, IL-8, TNF-α (high-sensitivity), and IP-10 were measured in cerebrospinal fluid (CSF) by immunoassay. Multivariable regression of mtDNA haplogroups and log-transformed CSF biomarkers were stratified by genetic ancestry using whole-genome nuclear DNA genotyping (European [EA], African [AA], or Hispanic ancestry [HA]), and adjusted for age, sex, antiretroviral therapy (ART), detectable CSF HIV RNA, and CD4 nadir. A total of 384 participants had both CSF cytokine measures and genetic data (45% EA, 44% AA, 11% HA, 22% female, median age 43 years, 74% on ART).Results:In analyses stratified by the 3 continental ancestry groups, no haplogroups were significantly associated with the 4 biomarkers. In the subgroup of participants with undetectable plasma HIV RNA on ART, European haplogroup H participants had significantly lower CSF TNF-α (P = 0.001).Conclusions:Lower CSF TNF-α may indicate lower neuroinflammation in the haplogroup H participants with well-controlled HIV on ART.
Highlights
Central nervous system (CNS) immune surveillance is dysregulated in many neurodegenerative disorders, including HIV-associated neurocognitive disorder (HAND) [1,2,3]
We explore the contribution of Mitochondrial DNA (mtDNA) haplogroups to inter-individual variability in Cerebrospinal fluid (CSF) cytokine and chemokine levels as biomarkers of inflammation in the CNS
A total of 384 participants had genetic data and CSF samples (Table 1); 45% were of European ancestry, 43% African ancestry, and 11% Hispanic ancestry
Summary
Central nervous system (CNS) immune surveillance is dysregulated in many neurodegenerative disorders, including HIV-associated neurocognitive disorder (HAND) [1,2,3]. HIV infection of the CNS occurs soon after transmission, resulting in activation of monocytes and glial cells, and their ongoing recruitment to the CNS [4,5,6]. Ongoing neuronal injury due to persistent CNS inflammation and oxidative stress may promote HAND in the setting of HIV infection, despite effective viral suppression with ART [8, 9]. Cerebrospinal fluid (CSF) biomarkers are acceptable, albeit imperfect, surrogates for inflammation in brain tissue, and studies have reported pro-inflammatory cytokine and chemokine abnormalities in the CSF of HIV-infected adults even after ART initiation [10, 11]. Mitochondrial DNA (mtDNA) haplogroups are ancestry-related patterns of single-nucleotide polymorphisms that are associated with differential mitochondrial function in model systems, neurodegenerative diseases in HIV-negative populations, and chronic complications of HIV infection, including neurocognitive impairment. We hypothesized that mtDNA haplogroups are associated with neuroinflammation in HIV-infected adults
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