T Cell Activation Markers and African Mitochondrial DNA Haplogroups among Non-Hispanic Black Participants in AIDS Clinical Trials Group Study

Introduction: Mitochondrial 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. Methods: ACTG 384 randomized ART-naı̈ve 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. Results: Data 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 (24% vs. 211%; 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 naı̈ve-to-memory CD4 cell ratio, haplogroup L2 was associated with lower baseline (p = 0.04) and 48week change in (p = 0.01) activated CD4 cells. Conclusions: Among ART-naı̈ve 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. Citation: Hulgan T, Robbins GK, Kalams SA, Samuels DC, Grady B, et al. (2012) T Cell Activation Markers and African Mitochondrial DNA Haplogroups among NonHispanic Black Participants in AIDS Clinical Trials Group Study 384. PLoS ONE 7(8): e43803. doi:10.1371/journal.pone. 0043803 Editor: Derya Unutmaz, New York University, United States of America Received March 30, 2012; Accepted July 26, 2012; Published August 27, 2012 Copyright: 2012 Hulgan et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: Funding for the genomic sequencing was provided by the National Institutes of Health (NIH)/National Institute of Neurological Diseases and Stroke grant NS059330. The project described was also supported by Award Number U01AI068636 from the National Institute of Allergy and Infectious Diseases and supported by National Institute of Mental Health (NIMH), and National Institute of Dental and Craniofacial Research (NIDCR). AIDS Clinical Trials Group (ACTG) Study 384 was also supported by grant AI38858, and by Agouron/Pfizer, Bristol Myers Squibb, and GlaxoSmithKline. The ACTG sites contributing DNA for these analyses were funded by NIH grants AI069513, AI34835, AI069432, AI069423, AI069477, AI069501, AI069474, AI069428, AI69467, AI069415, Al32782, AI27661, AI25859, AI069495, AI069471, AI069532, AI069452, AI069450, AI069556, AI069484, AI069472, AI34853, AI069465, AI069511, AI38844, AI069424, AI069434, AI46370, AI069502, and AI069419. The ACTG Human DNA Repository is also supported in part by the National Center for Advancing Translational Sciences of the National Institutes of Health under Award Number UL1 TR000445. Additional NIH grant support included: AI077505, AI54999, HL087726, AI69495, 5T32GM80178 and AI062435. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute of Allergy and Infectious Diseases or the National Institutes of Health. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have read the journal’s policy and have the following conflicts: TH has received research support from Merck. GKR has received research support from Gilead Sciences, Schering-Plough. DWH has received research grants from Boehringer-Ingelheim, Bristol-Myers Squibb, Gilead Sciences, and Merck, and has served as a consultant for Boehringer-Ingelheim. AIDS Clinical Trials Group (ACTG) Study 384 was also supported in part by Agouron/Pfizer, Bristol Myers Squibb, and GlaxoSmithKline. This does not alter the authors’ adherence to all the PLOS ONE policies on sharing data and materials. * E-mail: todd.hulgan@vanderbilt.edu " Membership of the AIDS Clinical Trials Group is provided in the Acknowledgments. PLOS ONE | www.plosone. org 1 August 2012 | Volume 7 | Issue 8 | e43803