Immunogenetics of CD4 lymphocyte count recovery during antiretroviral therapy: An AIDS Clinical Trials Group study.
During antiretroviral therapy, CD4 lymphocyte count increases are modest in some patients despite virologic control. We explored whether polymorphisms in genes important for T cell expansion, survival, and apoptosis are associated with the magnitude of CD4 lymphocyte count recovery during antiretroviral therapy. We studied treatment-naive individuals who achieved sustained control of plasma viremia (<400 HIV-1 RNA copies/mL) for at least 48 weeks after initiation of antiretroviral therapy and compared genotypes among individuals who had an increase of either <200 or > or =200 CD4 cells/mm3 from baseline. A total of 137 single-nucleotide polymorphisms across 17 genes were characterized in 873 study participants. In multivariate analyses that controlled for clinical variables, polymorphisms in genes encoding tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), TNF- alpha , Bcl-2-interacting molecule (Bim), interleukin (IL)-15, and IL-15 receptor alpha chain (IL-15R alpha ) were associated with the magnitude of the increase in CD4 lymphocyte count, as were haplotypes in genes encoding interferon- alpha , IL-2, and IL-15R alpha (P < .05, for each). Multifactor dimensionality reduction identified a gene-gene interaction between IL-2/IL-15 receptor common beta chain and IL-2/IL-7/IL-15 receptor common gamma chain. Immune recovery during antiretroviral therapy is a complex phenotype that is influenced by multiple genetic variants. Future studies should validate these tentative associations and define underlying mechanisms.
Haas
David W
DW
Center for Human Genetics Research, Vanderbilt University, Nashville, TN, 37203, USA. david.w.haas@vanderbilt.edu
Geraghty
Daniel E
DE
Andersen
Janet
J
Mar
Jessica
J
Motsinger
Alison A
AA
D'Aquila
Richard T
RT
Unutmaz
Derya
D
Benson
Constance A
CA
Ritchie
Marylyn D
MD
Landay
Alan
A
D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology*; D005260:Female; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000235:genetics; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D011110:Polymorphism, Genetic; D011647:Puerto Rico / Q000453:epidemiology; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2 / Q000235:genetics; D012189:Retrospective Studies; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D014481:United States / Q000453:epidemiology
D051017:Apoptosis Regulatory Proteins; C508024:IL15RA protein, human; D007376:Interleukin-2; D008562:Membrane Glycoproteins; D053647:Receptors, Interleukin-15; D015375:Receptors, Interleukin-2; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha