CCR5 promoter activity correlates with HIV disease progression by regulating CCR5 cell surface expression and CD4 T cell apoptosis.
CCR5 is the major co-receptor for HIV and polymorphisms in the CCR5 gene as well as promoter region that alter cell surface expression have been associated with disease progression. We determined the relationship between CCR5 promoter polymorphisms and CD4 decline and other immunopathological features like immune activation and CD4+ T cell apoptosis in HIV patients. CCR5 promoter haplotype HHC was significantly associated with higher CD4 counts in patients. The relative promoter activity (RPA) of each haplotype was determined in vitro and combined promoter activity based on both alleles (CRPA) was assigned to each patients. Interestingly, CCR5 CRPA correlated inversely with CD4 counts and CD4:CD8 ratio specifically in viremic patients. In normal individuals, the CRPA correlated with the number of CCR5+ CD4+ T cells in the peripheral blood suggesting an effect on CCR5 expression. In a subset of high viremic patients harboring R5 tropic HIV, there was a strong correlation between CCR5 CRPA and both CD4 counts and CD4 T cell apoptosis. Our study demonstrates that, CCR5 promoter polymorphisms correlate with CD4 T cell loss possibly by regulating CD4 T cell apoptosis in HIV patients. Furthermore, assigning CRPAs to each patient is a new method of translating genotype to phenotype.
Center of Emphasis in Infectious Diseases, Texas Tech University Health Sciences Center, El Paso, TX, USA.
Anjali
A
Joshi
Center of Emphasis in Infectious Diseases, Texas Tech University Health Sciences Center, El Paso, TX, USA.
Erin B
EB
Punke
Center of Emphasis in Infectious Diseases, Texas Tech University Health Sciences Center, El Paso, TX, USA.
Melina
M
Sedano
Paul L Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA.
Bethany
B
Beauchamp
Paul L Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA.
Rima
R
Patel
Paul L Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA.
Cassady
C
Hossenlopp
Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA.
Ogechika K
OK
Alozie
Department of Biomedical Sciences, Texas Tech University Health Sciences Center, El Paso, TX, USA.|Department of Health Sciences, College of Health Professions and Social Work, Florida Gulf Coast University, Fort Myers, FL, USA.
Jayanta
J
Gupta
Department of Internal Medicine, Texas Tech University Health Sciences Center, El Paso, TX, USA.
Debabrata
D
Mukherjee
Center of Emphasis in Infectious Diseases, Texas Tech University Health Sciences Center, El Paso, TX, USA. himanshu.garg@ttuhsc.edu.
Himanshu
H
Garg
D000328:Adult; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology*; D005260:Female; D015870:Gene Expression; D015658:HIV Infections / Q000473:pathology*; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D019713:Receptors, CCR5 / Q000096:biosynthesis* / Q000235:genetics; D013781:Texas; D055815:Young Adult
C584933:CCR5 protein, human; D019713:Receptors, CCR5