TY - JOUR
T1 - Genetic and clinical predictors of CD4 lymphocyte recovery during suppressive antiretroviral therapy
T2 - Whole exome sequencing and antiretroviral therapy response phenotypes
AU - on behalf of the Women’s Interagency HIV Study¶
AU - Greenblatt, Ruth
AU - Bacchetti, Peter
AU - Boylan, Ross
AU - Kober, Kord
AU - Springer, Gayle
AU - Anastos, Kathryn
AU - Busch, Michael
AU - Cohen, Mardge
AU - Kassaye, Seble
AU - Gustafson, Deborah
AU - Aouizerat, Bradley
N1 - Publisher Copyright:
© 2019 Greenblatt 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.
PY - 2019/8/1
Y1 - 2019/8/1
N2 - Increase of peripheral blood CD4 lymphocyte counts is a key goal of combined antiretroviral therapy (cART); most, but not all, recipients respond adequately and promptly. A small number of studies have examined specific genetic factors associated with the extent of CD4 recovery. We report a genome-wide examination of factors that predict CD4 recovery in HIV-infected women. We identified women in in a cohort study who were on cART with viral load below 400 copies, and drew racially and ethnically matched samples of those with good CD4 response over 2 years or poor response. We analyzed the exomes of those women employing next generation sequencing for genes associated with CD4 recovery after controlling for non-genetic factors identified through forward stepwise selection as important. We studied 48 women with good CD4 recovery and 42 with poor CD4 recovery during virologically-suppressive cART. Stepwise logistic regression selected only age as a statistically significant (p<0.05) non-genetic predictor of response type (each additional year of age reduced the odds of good recovery by 11% (OR = 0.89, CI = 0.84–0.96, p = 0.0009). After adjustment for age and genomic estimates of race and ethnicity, 41 genes harbored variations associated with CD4 recovery group (p0.001); 5 of these have been previously reported to be associated with HIV infection, 4 genes would likely influence CD4 homeostasis, and 13 genes either had known functions or were members of product families that had functions for which interactions with HIV or effects on lymphocyte homeostasis were biologically plausible. Greater age was the strongest acquired factor that predicted poor CD4 cell recovery. Sequence variations spanning 41 genes were independently predictive of CD4 recovery. Many of these genes have functions that impact the cell cycle, apoptosis, lymphocyte migration, or have known interactions with HIV. These findings may help inform new hypotheses related to responses to HIV therapy and CD4 lymphocyte homeostasis.
AB - Increase of peripheral blood CD4 lymphocyte counts is a key goal of combined antiretroviral therapy (cART); most, but not all, recipients respond adequately and promptly. A small number of studies have examined specific genetic factors associated with the extent of CD4 recovery. We report a genome-wide examination of factors that predict CD4 recovery in HIV-infected women. We identified women in in a cohort study who were on cART with viral load below 400 copies, and drew racially and ethnically matched samples of those with good CD4 response over 2 years or poor response. We analyzed the exomes of those women employing next generation sequencing for genes associated with CD4 recovery after controlling for non-genetic factors identified through forward stepwise selection as important. We studied 48 women with good CD4 recovery and 42 with poor CD4 recovery during virologically-suppressive cART. Stepwise logistic regression selected only age as a statistically significant (p<0.05) non-genetic predictor of response type (each additional year of age reduced the odds of good recovery by 11% (OR = 0.89, CI = 0.84–0.96, p = 0.0009). After adjustment for age and genomic estimates of race and ethnicity, 41 genes harbored variations associated with CD4 recovery group (p0.001); 5 of these have been previously reported to be associated with HIV infection, 4 genes would likely influence CD4 homeostasis, and 13 genes either had known functions or were members of product families that had functions for which interactions with HIV or effects on lymphocyte homeostasis were biologically plausible. Greater age was the strongest acquired factor that predicted poor CD4 cell recovery. Sequence variations spanning 41 genes were independently predictive of CD4 recovery. Many of these genes have functions that impact the cell cycle, apoptosis, lymphocyte migration, or have known interactions with HIV. These findings may help inform new hypotheses related to responses to HIV therapy and CD4 lymphocyte homeostasis.
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U2 - 10.1371/journal.pone.0219201
DO - 10.1371/journal.pone.0219201
M3 - Article
C2 - 31415590
AN - SCOPUS:85070734887
SN - 1932-6203
VL - 14
JO - PloS one
JF - PloS one
IS - 8
M1 - e0219201
ER -