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

Todd Hulgan, Gregory K. Robbins, Spyros A. Kalams, David C. Samuels, Benjamin Grady, Robert Shafer, Deborah G. Murdock, Doug Selph, David W. Haas, Richard B Pollard, Victor de Gruttola, Sally Snyder, Thomas Nevin, Carla Pettinelli, Michael Dube, Margaret Fischl, Robert Delaphna, Linda Gideon, Richard D'Aquila, Stefano VellaThomas Merigan, Martin Hirsch

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Article numbere43803
JournalPLoS One
Volume7
Issue number8
DOIs
StatePublished - Aug 27 2012

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T-cells
Mitochondrial DNA
clinical trials
Acquired Immunodeficiency Syndrome
mitochondrial DNA
T-lymphocytes
Chemical activation
Clinical Trials
T-Lymphocytes
cells
efavirenz
RNA
therapeutics
HIV
Nelfinavir
Data storage equipment
Recovery
Nucleosides
Linear regression
nucleosides

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

T cell activation markers and African mitochondrial DNA Haplogroups among non-hispanic black participants in AIDS clinical trials group study 384. / Hulgan, Todd; Robbins, Gregory K.; Kalams, Spyros A.; Samuels, David C.; Grady, Benjamin; Shafer, Robert; Murdock, Deborah G.; Selph, Doug; Haas, David W.; Pollard, Richard B; de Gruttola, Victor; Snyder, Sally; Nevin, Thomas; Pettinelli, Carla; Dube, Michael; Fischl, Margaret; Delaphna, Robert; Gideon, Linda; D'Aquila, Richard; Vella, Stefano; Merigan, Thomas; Hirsch, Martin.

In: PLoS One, Vol. 7, No. 8, e43803, 27.08.2012.

Research output: Contribution to journalArticle

Hulgan, T, Robbins, GK, Kalams, SA, Samuels, DC, Grady, B, Shafer, R, Murdock, DG, Selph, D, Haas, DW, Pollard, RB, de Gruttola, V, Snyder, S, Nevin, T, Pettinelli, C, Dube, M, Fischl, M, Delaphna, R, Gideon, L, D'Aquila, R, Vella, S, Merigan, T & Hirsch, M 2012, 'T cell activation markers and African mitochondrial DNA Haplogroups among non-hispanic black participants in AIDS clinical trials group study 384', PLoS One, vol. 7, no. 8, e43803. https://doi.org/10.1371/journal.pone.0043803
Hulgan, Todd ; Robbins, Gregory K. ; Kalams, Spyros A. ; Samuels, David C. ; Grady, Benjamin ; Shafer, Robert ; Murdock, Deborah G. ; Selph, Doug ; Haas, David W. ; Pollard, Richard B ; de Gruttola, Victor ; Snyder, Sally ; Nevin, Thomas ; Pettinelli, Carla ; Dube, Michael ; Fischl, Margaret ; Delaphna, Robert ; Gideon, Linda ; D'Aquila, Richard ; Vella, Stefano ; Merigan, Thomas ; Hirsch, Martin. / T cell activation markers and African mitochondrial DNA Haplogroups among non-hispanic black participants in AIDS clinical trials group study 384. In: PLoS One. 2012 ; Vol. 7, No. 8.
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abstract = "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-na{\"i}ve 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 na{\"i}ve-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-na{\"i}ve 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.",
author = "Todd Hulgan and Robbins, {Gregory K.} and Kalams, {Spyros A.} and Samuels, {David C.} and Benjamin Grady and Robert Shafer and Murdock, {Deborah G.} and Doug Selph and Haas, {David W.} and Pollard, {Richard B} and {de Gruttola}, Victor and Sally Snyder and Thomas Nevin and Carla Pettinelli and Michael Dube and Margaret Fischl and Robert Delaphna and Linda Gideon and Richard D'Aquila and Stefano Vella and Thomas Merigan and Martin Hirsch",
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T1 - T cell activation markers and African mitochondrial DNA Haplogroups among non-hispanic black participants in AIDS clinical trials group study 384

AU - Hulgan, Todd

AU - Robbins, Gregory K.

AU - Kalams, Spyros A.

AU - Samuels, David C.

AU - Grady, Benjamin

AU - Shafer, Robert

AU - Murdock, Deborah G.

AU - Selph, Doug

AU - Haas, David W.

AU - Pollard, Richard B

AU - de Gruttola, Victor

AU - Snyder, Sally

AU - Nevin, Thomas

AU - Pettinelli, Carla

AU - Dube, Michael

AU - Fischl, Margaret

AU - Delaphna, Robert

AU - Gideon, Linda

AU - D'Aquila, Richard

AU - Vella, Stefano

AU - Merigan, Thomas

AU - Hirsch, Martin

PY - 2012/8/27

Y1 - 2012/8/27

N2 - 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.

AB - 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.

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