Dataset Information

Genetic variation within the gene encoding the HIV-1 CCR5 coreceptor in two South African populations.

ABSTRACT: Polymorphisms within the open reading frame as well as the promoter and regulatory regions can influence the amount of CCR5 expressed on the cell surface and hence an individual's susceptibility to HIV-1. In this study we characterize CCR5 genes within the South African African (SAA) and Caucasian (SAC) populations by sequencing a 9.2kb continuous region encompassing the CCR5 open reading frame (ORF), its two promoters and the 3' untranslated region. Full length CCR5 sequences were obtained for 70 individuals (35 SAA and 35 SAC) and sequences were analyzed for the presence of single-nucleotide polymorphisms (SNPs), indels and intragenic haplotypes. A novel SNP (+258G/C) within the ORF leading to a non-synonomous amino acid (Trp-->Cys) change was detected in one Caucasian individual. Results demonstrate a high degree of genetic variation: 68 SNP positions, four indels, as well as the Delta32 deletion mutant, were detected. Seven complex putative haplotypes spanning the length of the sequenced region have been identified. These haplotypes appear to be extensions of haplotypes previously described within CCR5. Two haplotypes, SAA-HHE and SAC-HHE were found in high frequency in the SAA and SAC population groups studied (20.0% and 18.6%, respectively) and share four SNP positions suggesting an evolutionary link between the two haplotypes. Only one of the identified haplotypes, SAA/C-HHC, is common to both study populations but the haplotype frequency differs markedly between the two groups (8.6% in SAA and 52.9% in SAC). The two population groups show differences in both haplotype arrangement as well as SNP profile.

SUBMITTER: Picton AC

PROVIDER: S-EPMC2877777 | biostudies-literature | 2010 May

REPOSITORIES: biostudies-literature

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Genetic variation within the gene encoding the HIV-1 CCR5 coreceptor in two South African populations.

Picton Anabela C P AC Paximadis Maria M Tiemessen Caroline T CT

Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 20100304 4

Polymorphisms within the open reading frame as well as the promoter and regulatory regions can influence the amount of CCR5 expressed on the cell surface and hence an individual's susceptibility to HIV-1. In this study we characterize CCR5 genes within the South African African (SAA) and Caucasian (SAC) populations by sequencing a 9.2kb continuous region encompassing the CCR5 open reading frame (ORF), its two promoters and the 3' untranslated region. Full length CCR5 sequences were obtained for ...[more]

PMID: 20206716

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Project description:The chemokine receptor CCR5 is a cofactor for the entry of R5 tropic strains of human immunodeficiency viruses (HIV)-1 and -2 and simian immunodeficiency virus. Cells susceptible to infection by these viruses can be protected by treatment with the CCR5 ligands regulated on activation, normal T cell expressed and secreted (RANTES), MIP-1alpha, and MIP-1beta. A major component of the mechanism through which chemokines protect cells from HIV infection is by inducing endocytosis of the chemokine receptor. Aminooxypentane (AOP)-RANTES, an NH(2)-terminal modified form of RANTES, is a potent inhibitor of infection by R5 HIV strains. AOP-RANTES efficiently downmodulates the cell surface expression of CCR5 and, in contrast with RANTES, appears to prevent recycling of CCR5 to the cell surface. Here, we investigate the cellular basis of this effect. Using CHO cells expressing human CCR5, we show that both RANTES and AOP-RANTES induce rapid internalization of CCR5. In the absence of ligand, CCR5 shows constitutive turnover with a half-time of 6-9 h. Addition of RANTES or AOP-RANTES has little effect on the rate of CCR5 turnover. Immunofluorescence and immunoelectron microscopy show that most of the CCR5 internalized after RANTES or AOP-RANTES treatment accumulates in small membrane-bound vesicles and tubules clustered in the perinuclear region of the cell. Colocalization with transferrin receptors in the same clusters of vesicles indicates that CCR5 accumulates in recycling endosomes. After the removal of RANTES, internalized CCR5 recycles to the cell surface and is sensitive to further rounds of RANTES-induced endocytosis. In contrast, after the removal of AOP-RANTES, most CCR5 remains intracellular. We show that these CCR5 molecules do recycle to the cell surface, with kinetics equivalent to those of receptors in RANTES-treated cells. However, these recycled CCR5 molecules are rapidly reinternalized. Our results indicate that AOP-RANTES-induced changes in CCR5 alter the steady-state distribution of the receptor and provide the first evidence for G protein-coupled receptor trafficking through the recycling endosome compartment.

Project description:Unique Individuals who exhibit either suppressive HIV-1 control, or the ability to maintain low viral load set-points and preserve their CD4+ T cell counts for extended time periods in the absence of antiretroviral therapy, are broadly termed HIV-1 controllers. We assessed the extent to which black South African controllers (n=9), differ from uninfected healthy controls (HCs, n=22) in terms of lymphocyte and monocyte CCR5 expression (density and frequency of CCR5-expressing cells), immune activation as well as peripheral blood mononuclear cell (PBMC) mitogen-induced chemokine/cytokine production. In addition, relative CD4+ T cell CCR5 mRNA expression was assessed in a larger group of controllers (n=20) compared to HCs (n=10) and HIV-1 progressors (n=12). Despite controllers having significantly higher frequencies of activated CD4+ and CD8+ T cells (HLA-DR+) compared to HCs, CCR5 density was significantly lower in these T cell populations (P=0.039 and P=0.064, respectively). This lower CCR5 density was largely attributable to controllers with higher VLs (>400 RNA copies/ml). Significantly lower CD4+ T cell CCR5 density in controllers was maintained (P=0.036) when HCs (n=12) and controllers (n=9) were matched for age. CD4+ T cell CCR5 mRNA expression was significantly less in controllers compared to HCs (P=0.007) and progressors (P=0.002), whereas HCs and progressors were similar (P=0.223). The levels of soluble CD14 in plasma did not differ between controllers and HCs, suggesting no demonstrable monocyte activation. While controllers had lower monocyte CCR5 density compared to the HCs (P=0.02), significance was lost when groups were age-matched (P=0.804). However, when groups were matched for both CCR5 promoter haplotype and age (n=6 for both) reduced CCR5 density on monocytes in controllers relative to HCs was highly significant (P=0.009). Phytohemagglutinin-stimulated PBMCs from the controllers produced significantly less CCL3 (P=0.029), CCL4 (P=0.008) and IL-10 (P=0.028) compared to the HCs, which was largely attributable to the controllers with lower VLs (<400 RNA copies/ml). Our findings support a hypothesis of an inherent (genetic) predisposition to lower CCR5 expression in individuals who naturally control HIV-1, as has been suggested for Caucasian controllers, and thus, likely involves a mechanism shared between ethnically divergent population groups.

Dataset Information

Genetic variation within the gene encoding the HIV-1 CCR5 coreceptor in two South African populations.

Publications

Genetic variation within the gene encoding the HIV-1 CCR5 coreceptor in two South African populations.

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