Abstract
IntroductionMitochondrial function influences T cell dynamics and is affected by mitochondrial DNA (mtDNA) variation. We previously reported an association between African mtDNA haplogroup L2 and less robust CD4 cell recovery on antiretroviral therapy (ART) in non-Hispanic black ACTG 384 subjects. We explored whether additional T cell parameters in this cohort differed by mtDNA haplogroup.MethodsACTG 384 randomized ART-naïve subjects to two different nucleoside regimens with efavirenz, nelfinavir, or both. CD4 and CD8 memory and activation markers were available at baseline and week 48 on most subjects. mtDNA sequencing was performed on whole blood DNA, and haplogroups were determined. We studied non-Hispanic black subjects with HIV RNA <400 copies/mL at week 48. Analyses included Wilcoxon ranksum test and linear regression.ResultsData from 104 subjects were included. Major African mtDNA haplogroups included L1 (N = 25), L2 (N = 31), and L3 (N = 32). Baseline age, HIV RNA, and CD4 cells did not differ between L2 and non-L2 haplogroups. Compared to non-L2 haplogroups, L2 subjects had lower baseline activated CD4 cells (median 12% vs. 17%; p = 0.03) and tended toward lower activated CD8 cells (41% vs. 47%; p = 0.06). At 48 weeks of ART, L2 subjects had smaller decreases in activated CD4 cells (−4% vs. −11%; p = 0.01), and smaller CD4 cell increases (+95 vs. +178; p = 0.002). In models adjusting for baseline age, CD4 cells, HIV RNA, and naïve-to-memory CD4 cell ratio, haplogroup L2 was associated with lower baseline (p = 0.04) and 48-week change in (p = 0.01) activated CD4 cells.ConclusionsAmong ART-naïve non-Hispanic blacks, mtDNA haplogroup L2 was associated with baseline and 48-week change in T cell activation, and poorer CD4 cell recovery. These data suggest mtDNA variation may influence CD4 T cell dynamics by modulating T cell activation. Further study is needed to replicate these associations and identify mechanisms.
Highlights
Mitochondrial function influences T cell dynamics and is affected by mitochondrial DNA variation
We previously reported associations between several mitochondrial DNA (mtDNA) single nucleotide polymorphisms (SNPs)- and with the major African mtDNA haplogroup L2 defined by several of these SNPs- and magnitude of CD4 T cell recovery after antiretroviral therapy (ART) initiation in non-Hispanic black participants in AIDS Clinical Trials Group (ACTG) study 384 [39]
Study Population ACTG 384 (NCT00000919) was a multicenter, double-blind, prospective randomized clinical trial comparing the efficacy of ART regimens consisting of three or four drugs in antiretroviralnaıve adults [40,41]
Summary
Mitochondrial function influences T cell dynamics and is affected by mitochondrial DNA (mtDNA) variation. Studies have suggested possible associations between CD4 count recovery on ART and single nucleotide polymorphisms (SNPs) in chemokine receptor [5,6], human leukocyte antigen [7,8], cytokine [9], and apoptosis-related [10] genes. These results highlight the possibility that an important host factor that influences HIV-infected CD4 cell turnover is regulation of apoptosis [11,12]
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