CCR5 promoter activity correlates with HIV disease progression by regulating CCR5 cell surface expression and CD4 T cell apoptosis

Anjali Joshi,Jayanta Gupta,Cassady Hossenlopp,Bethany Beauchamp,Rima Patel,Melina Sedano,Debabrata Mukherjee,Ogechika K Alozie,Himanshu Garg,Erin B Punke

doi:10.1038/s41598-017-00192-x

Abstract

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.

Highlights

CCR5 is a major co-receptor for HIV and has been known to play a significant role in HIV infection and pathogenesis
We find that Combined Relative Promoter Activity (CRPA) correlates with CD4 counts, AIDS phenotype and CD4 T cell apoptosis in HIV patients
This indicates that CCR5 promoter polymorphisms alter CCR5 expression levels that influence CD4 apoptosis and CD4 decline in HIV patients

Summary

Introduction

CCR5 is a major co-receptor for HIV and has been known to play a significant role in HIV infection and pathogenesis. Multiple single nucleotide polymorphisms have been identified in the CCR5 promoter region that have been shown to be associated with HIV disease progression[2, 4, 15] These SNPs make up 8 CCR5 promoter haplotypes (HHA-HHG)[6]. Suggest that the protective effect of CCR5 polymorphisms may largely be limited to progression to AIDS in HIV+ individuals, the precise mechanism underlying the role of CCR5 levels in HIV disease remains unclear. In normal individuals CRPA correlates with CCR5+ cells in peripheral blood confirming a direct relationship with CCR5 expression This indicates that CCR5 promoter polymorphisms alter CCR5 expression levels that influence CD4 apoptosis and CD4 decline in HIV patients. To the best of our knowledge, this is the first study demonstrating a new approach of assigning numerical scores (CRPA) based on CCR5 haplotype that correlates with HIV disease progression/pathogenesis

Methods

Results

Conclusion