Mitochondrial DNA Variation and Changes in Adiponectin and Endothelial Function in HIV-Infected Adults After Antiretroviral Therapy Initiation

Abstract

Studies in persons of European descent have suggested that mitochondrial DNA (mtDNA) haplogroups influence antiretroviral therapy (ART) toxicity. We explored associations between mtDNA variants and changes in endothelial function and biomarkers among non-Hispanic white, ART-naive subjects starting ART. A5152s was a substudy of A5142, a randomized trial of initial class-sparing ART regimens that included efavirenz or lopinavir/ritonavir with nucleoside reverse transcriptase inhibitors (NRTIs), or both without NRTIs. Brachial artery flow-mediated dilation (FMD) and cardiovascular biomarker assessments were performed at baseline and at weeks 4 and 24. Ten haplogroup-defining mtDNA polymorphisms were determined. FMD and biomarker changes from baseline to week 24 by mtDNA variant were assessed using Wilcoxon rank-sum tests. Thirty-nine non-Hispanic white participants had DNA and 24-week data. The nonsynonymous m.10398A > G mtDNA polymorphism (N = 8) was associated with higher median baseline adiponectin (5.0 vs. 4.2 lg/ml; p = 0.003), greater absolute ( -1.9 vs. -0.2 lg/ml) and relative ( -33% vs. -3%) adiponectin decreases ( p < 0.001 for both), and lower week 24 brachial artery FMD (3.6% vs. 5.4%; p = 0.04). Individual mtDNA haplogroups, including haplogroups H (N = 13) and U (N = 6), were not associated with adiponectin or FMD changes. In this small pilot study, adiponectin and brachial artery FMD on ART differed in non-Hispanic whites with a nonsynonymous mtDNA variant associated with several human diseases. These preliminary findings support the hypothesis that mtDNA variation influences metabolic ART effects. Validation studies in larger populations and in different racial/ethnic groups that include m.10398G carriers are needed.

Psychological Stress and Mitochondria: A Conceptual Framework

“…Possibly as a result of the influence of mitochondrial function on innate immunity, mtDNA variants – which vary according to ethic origin (107) – influence not only mitochondrial function, but also correlate with metabolic and immune parameters during anti-retroviral therapy (133, 134), as well as HIV/AIDS progression and mortality (135). This modulatory effect of mtDNA on infectious disease progression is believed to result from biochemical differences in mitochondrial respiratory capacity (136), and is reminiscent of the modulatory effect of both positive and negative psychosocial factors, such as social support and depressive symptoms, on HIV/AIDS disease (137).…”

Investigating the importance of individual mitochondrial genotype in susceptibility to drug-induced toxicity

“…Conversely, in a retrospective study of 346 white HIV positive participants, it was concluded that there were no significant associations between ART-induced lipodystrophy and haplogroups [ 39 ]. Following on from this, a pilot study explored associations between mitochondrial haplogroup and changes in endothelial function [ 37 ]. White, non-Hispanic participants (30 participants) were recruited and temporal changes in brachial artery flow-mediated dilation (FMD) and cardiovascular biomarkers, including adiponectin were measured.…”

Factors Associated With Insulin Resistance in Adults With HIV Receiving Contemporary Antiretroviral Therapy: a Brief Update

“…Our group has also examined mtDNA variants and metabolic biomarkers, including HOMA-IR, in analyses using data from small subgroups of ART-naïve participants in AIDS Clinical Trials Group (ACTG) studies A5142 and A5202 [84, 85]. Among 39 persons starting ART with one of three randomized class-sparing regimens in A5142 (described in detail elsewhere [86]), serum adiponectin (an adipose-derived adipokine associated with glucose homeostasis and IR) was higher at baseline but decreased to a greater extent after 24 weeks of ART among persons with a non-synonymous mtDNA mutation in mitochondrial complex I (m.10398A>G).…”