T Cell Activation Markers and African Mitochondrial DNA Haplogroups among Non-Hispanic Black Participants in AIDS Clinical Trials Group Study 384

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-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

T cell activation markers and African mitochondrial DNA haplogroups among non-Hispanic black participants in AIDS clinical trials group study 384.

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.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.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.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

Mitochondrial DNA haplogroup frequencies among black, non-Hispanic ACTG 384 participants.

a<p>Totals may not  = 100% due to rounding;</p>b<p>Total includes haplogroup L3, not sub-haplogrouped;</p>c<p>Includes haplogroups H, I, J1, T1, T2b, U6, U9 (N≤2 each).</p

Multivariate models of associations between baseline covariates, haplogroup L2, and percentage CD4 cell activation.

<p>Multivariate models of associations between baseline covariates, haplogroup L2, and percentage CD4 cell activation.</p

T cell parameters at 48 weeks and 48 week changes among the black, non-Hispanic ACTG 384 population with baseline CD4 activation markers and 48 week HIV RNA <400 copies/mL, total and by African L2 and non-L2 mtDNA haplogroups.

<p>Data are median (IQR) except where noted.</p>a<p>Wilcoxon ranksum, Fisher’s exact, or Pearson Chi² tests, L2 vs. non-L2;</p>b<p>N with available data shown.</p

Scatter plots of 48 week changes in CD4 cells (Panel A), and percentage activated (CD38+/HLA-DR+) CD4 cells (Panel B).

<p>Haplogroup L2 individuals had a significantly lower median increase in CD4 cells and a lower decrease in percentage activated CD4 cells. Unadjusted p-values by Wilcoxon ranksum test shown. x-lines  =  median; dashed lines = 25^th and 75^th percentiles.</p

Baseline demographic data, T cell parameters, HIV RNA, and ART randomization arms among the black, non-Hispanic ACTG 384 population with baseline CD4 activation markers and 48 week HIV RNA <400 copies/mL, total and by African L2 and non-L2 mtDNA haplogroups.

<p>Data are median (IQR) except where noted.</p>a<p>Wilcoxon ranksum, Fisher’s exact, or Pearson Chi² tests, L2 vs. non-L2;</p>b<p>N with available baseline data shown;</p>c<p>p-values for NRTI backbone comparison shown.</p