Concordance of CCR5 Genotypes that Influence Cell-Mediated Immunity and HIV-1 Disease Progression Rates

Abstract

We used cutaneous delayed-type hypersensitivity responses, a powerful in vivo measure of cell-mediated immunity, to evaluate the relationships among cell-mediated immunity, AIDS, and polymorphisms in CCR5, the HIV-1 coreceptor. There was high concordance between CCR5 polymorphisms and haplotype pairs that influenced delayed-type hypersensitivity responses in healthy persons and HIV disease progression. In the cohorts examined, CCR5 genotypes containing -2459G/G (HHA/HHA, HHA/HHC, HHC/HHC) or -2459A/A (HHE/HHE) associated with salutary or detrimental delayed-type hypersensitivity and AIDS phenotypes, respectively. Accordingly, the CCR5-Δ32 allele, when paired with non-Δ32-bearing haplotypes that correlate with low (HHA, HHC) versus high (HHE) CCR5 transcriptional activity, associates with disease retardation or acceleration, respectively. Thus, the associations of CCR5-Δ32 heterozygosity partly reflect the effect of the non-▵32 haplotype in a background of CCR5 haploinsufficiency. The correlations of increased delayed-type hypersensitivity with -2459G/G-containing CCR5 genotypes, reduced CCR5 expression, decreased viral replication, and disease retardation suggest that CCR5 may influence HIV infection and AIDS, at least in part, through effects on cell-mediated immunity.

Epigenetic mechanisms, T-cell activation, andCCR5genetics interact to regulate T-cell expression of CCR5, the major HIV-1 coreceptor

“…Thus, the effects associated with a CCR5 genotype (e.g., surface levels and HIV/AIDS risk) depend on both epigenetic and genetic mechanisms. However, epigenetic mechanisms could have dominant effects, as illustrated by the associations of HHE: (i) HHE/HHE is consistently associated with increased CCR5 expression and HIV/AIDS susceptibility, and (ii) pairing of HHE with HHA, HHC, or HHG*2 is also associated with adverse clinical outcomes (5,12).…”

“…When placed in a single model, lower methylation in intron 2 but not in CCR5-Pr2 was associated with higher CCR5 surface levels (P < 0.001 and P = 0.31, respectively; SI Appendix, Table S2, models 1-3). The associations between methylation status of intron 2 and CCR5 levels persisted after controlling for the accompanying levels of T-cell activation and proportion of naïve T cells (P = 0.001), CCR5 haplotypes including the Δ32-bearing allele (P = 0.003), and variables such as CD4+ counts before ART (P = 0.006; SI Appendix, Table S2, models [4][5][6]. The associations between CCR5-Pr2 with CCR5 levels were less robust (P = 0.05, P = 0.05, and P = 0.08; SI Appendix, Table S2, models 4-6).…”

“…7A) (6). Also, genotypes containing HHA and HHE haplotypes are associated with reduced vs. enhanced HIV/AIDS susceptibility, respectively (4,5,7,(10)(11)(12).…”

“…CCR5 levels on T cells influence HIV acquisition, disease progression rates, viral load, and immune recovery during antiretroviral therapy (ART), among other traits (1-4) (discussed in ref. 5). In these instances, lower CCR5 levels correlate with beneficial outcomes.…”

“…In these instances, lower CCR5 levels correlate with beneficial outcomes. Polymorphisms in the ORF and cis-regulatory regions (cis-regions) of CCR5 that correlate with higher vs. lower surface and/or gene expression levels are associated with increased vs. decreased HIV/AIDS risk and immune recovery (4)(5)(6)(7)(8)(9)(10)(11)(12). Classic examples are homozygosity Significance Levels of CC chemokine receptor 5 (CCR5) on T cells are a critical factor influencing HIV/AIDS susceptibility.…”