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

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.

Host and Viral Factors in HIV-Mediated Bystander Apoptosis

“…The therapeutic potential of CCR5 antagonist Maraviroc in suppressing virus replication and virus-related pathologies in patients harboring CCR5 tropic viruses has been well documented [ 107 ]. Furthermore, the natural variations in CCR5 expression in humans, as a result of gene and promoter polymorphisms, have been linked to HIV disease progression [ 108 , 109 ].…”

“…Other factors affecting cell surface CCR5 levels in the host are several single nucleotide polymorphisms (SNPs) in the CCR5 promoter region [ 108 , 115 ]. Seven major SNPs in the CCR5 promoter make up eight different promoter haplotypes (HHA–HHG) and haplotypes such as HHC have been associated with slower disease progression [ 109 , 116 ]. Recent evidence suggests that CCR5 expression is further influenced by epigenetic factors along with activation status of T cell cells playing a role in this process [ 117 ].…”

“…Multiple genotypic and phenotypic variations in Env have been associated with disease including coreceptor usage, virus subtype, fusogenic activity of Env, N-glycosylation sites and coreceptor binding [ 60 , 66 ]. The binding of Env to CCR5 is also fundamental to HIV pathogenesis and bystander apoptosis and variations in CCR5 levels as a result of CCR5 gene and promoter polymorphisms can influence this phenomenon [ 65 , 109 ]. Immune activation is a key immunopathological feature of HIV infections that correlates with CD4 decline.…”

HIV-1 subtype CRF01_AE and B differ in utilization of low levels of CCR5, Maraviroc susceptibility and potential N-glycosylation sites

“…The rapid spread of the AE subtype throughout Southeast Asia makes these viral variants both interesting and important to study (Hemelaar et al, 2011). This is likely a result of complex multifactorial processes with both the replicative capacity of the transmitted virus (Claiborne et al, 2015) and host genetics (Joshi et al, 2017) playing important roles in the outcome of this phenomenon. With regards to co-receptor usage we saw interesting results.…”

“…CCR5 levels vary considerably in the human population due to CCR5 gene and promoter polymorphisms (Chalmet et al, 2008; Gornalusse et al, 2015; Ometto et al, 2001; Samson et al, 1996) and this variability in CCR5 levels translates to differences HIV disease progression (Joshi et al, 2017). This is best documented by slower disease progression in CCR5Δ32 heterozygous individuals who show reduced CCR5 expression on the cell surface (Liu et al, 1996).…”