title: T cell activation markers and African mitochondrial DNA haplogroups among non-Hispanic black participants in AIDS clinical trials group study 384.
abstract: BACKGROUND
  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-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.
  
  
  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 (-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.
  
  
  CONCLUSIONS
  Among 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.
authors.affiliation: Vanderbilt University School of Medicine, Nashville, Tennessee, USA. todd.hulgan@vanderbilt.edu
authors.forename: Todd
authors.initials: T
authors.lastname: Hulgan
authors.forename: Gregory K
authors.initials: GK
authors.lastname: Robbins
authors.forename: Spyros A
authors.initials: SA
authors.lastname: Kalams
authors.forename: David C
authors.initials: DC
authors.lastname: Samuels
authors.forename: Benjamin
authors.initials: B
authors.lastname: Grady
authors.forename: Robert
authors.initials: R
authors.lastname: Shafer
authors.forename: Deborah G
authors.initials: DG
authors.lastname: Murdock
authors.forename: Doug
authors.initials: D
authors.lastname: Selph
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
authors.forename: Richard B
authors.initials: RB
authors.lastname: Pollard
mesh_terms: D000163:Acquired Immunodeficiency Syndrome / Q000097:blood / Q000188:drug therapy / Q000821:virology; D000328:Adult; D001741:Black or African American; D019380:Anti-HIV Agents / Q000627:therapeutic use; D016516:CD4-CD8 Ratio; D004272:DNA, Mitochondrial / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D015497:HIV-1 / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D016014:Linear Models; D008213:Lymphocyte Activation; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012367:RNA, Viral / Q000097:blood; D016032:Randomized Controlled Trials as Topic; D017422:Sequence Analysis, DNA; D018709:Statistics, Nonparametric; D013601:T-Lymphocytes / Q000378:metabolism*; D019562:Viral Load
chemical_list: D019380:Anti-HIV Agents; D004272:DNA, Mitochondrial; D012367:RNA, Viral