CCR5 haplotypes influence HCV serostatus in Caucasian intravenous drug users.

Up to 90% HIV-1 positive intravenous drug users (IDUs) are co-infected with HCV. Although best recognized for its function as a major co-receptor for cell entry of HIV, CC chemokine receptor 5 (CCR5) has also been implicated in the pathogenesis of HCV infection. Here, we investigated whether CCR5 haplotypes influence HIV-1 and HCV seropositivity among 373 Caucasian IDUs from Estonia.Of these IDUs, 56% and 44% were HIV and HCV seropositive, respectively, and 47% were coinfected. 500 blood donors seronegative for HIV and HCV were also evaluated. CCR5 haplotypes (HHA to HHG*2) were derived after genotyping nine CCR2-CCR5 polymorphisms. The association between CCR5 haplotypes with HIV and/or HCV seropositivity was determined using logistic regression analysis. Co-variates included in the models were length of intravenous drug use, HBV serostatus and copy number of CCL3L1, the gene encoding the most potent HIV-suppressive chemokine and ligand for CCR5.Compared to IDUs seronegative for both HCV and HIV (HCV-/HIV-), IDUs who were HCV+/HIV- and HCV+/HIV+were 92% and 82%, respectively, less likely to possess the CCR5-HHG*1 haplotype, after controlling for co-variates (P(adjusted) = 1.89 × 10(-4) and 0.003, respectively). This association was mostly due to subjects bearing the CCR5 HHE and HHG*1 haplotype pairs. Approximately 25% and<10% of HCV-/HIV- IDUs and HCV-/HIV- blood donors, respectively, possessed the HHE/HHG*1 genotype.Our findings suggest that HHG*1-bearing CCR5 genotypes influence HCV seropositivity in a group of Caucasian IDUs

<i>CCR5</i> polymorphisms and haplotypes.

<p>On the basis of the linkage disequilibrium patterns between the polymorphisms in the coding (Δ32) and noncoding (promoter) region of <i>CCR5</i> and the coding polymorphism (V64I) in <i>CCR2</i>, we previously used an evolutionary-based strategy to generate the <i>CCR5</i> human haplogroups (HH) shown below the CCR5 gene structure. These <i>CCR5</i> HH are designated as HHA to HHG*2, with HHF*2 and HHG*2 denoting the haplotypes that bear the CCR2–64I and CCR5-Δ32 polymorphisms, respectively. Because of its similarity to the chimpanzee <i>CCR5</i> sequence, the human <i>CCR5</i> HHA haplotype is classified as the ancestral CCR5 haplotype <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0070561#pone.0070561-Mummidi1" target="_blank">[28]</a>. Nucleotide variations relative to the ancestral sequence are shown. The <i>CCR5</i> numbering systems used in the literature are shown. Top numbering is based on GenBank accession numbers AF031236 and AF031237; middle numbering is based on GenBank accession number U95626; bottom numbering is the numbering system in which the first nucleotide of the <i>CCR5</i> translational start site is designated as+1 and the nucleotide immediately upstream as -1 <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0070561#pone.0070561-Mummidi1" target="_blank">[28]</a>. ORF, open-reading frame; Wt, wild-type; Δ32, 32-basepair deletion.</p

Factors influencing HCV and HIV serostatus by univariate analyses.

#<p>The OR was estimated by every increased year of age;</p>*<p>The OR was estimated by every increased year of IVDU use;</p>&<p>The median of <i>CCL3L1</i> copy number is 2 copies in our studied IDUs.</p

Prevalence of HIV, HBV and HCV infection in Estonia.

<p>Incidence per 100,000 population of HIV (dashed line), HBV (dotted line) and HCV (solid line) infection in Estonia between 1985–2010, as reported by the Estonian Health Board.</p

HIV, HCV and HBV serostatus among 373 IDUs from Estonia in 2006–2007^*.

*<p>HBV serostatus was unknown for 7 individuals.</p

Association of <i>CCR5</i> HHG*1 with HCV or HIV serostatus.

#<p>Co-variates: HBV serostatus, <i>CCL3L1</i> copy number, IVDU duration and HBV serostatus.</p

Association of <i>CCR5</i> HHG^*1 with HCV serostatus in univariate and stepwise multivariate logistic regression model.

*<p>Dichotomized by the median of 2 <i>CCL3L1</i> copies;</p>#<p>Syringe exchange program or Prisoners;</p>&<p>Each additional year of IVDU use.</p

The distribution of <i>CCR5</i> haplotypes among IDUs and blood donors.

<p><i>CCR5</i> haplotype frequency among (<b>A</b>) IDUs vs. blood donors, (<b>B</b>) HCV+vs. HCV- IDUs, and (<b>C</b>) HIV- vs. HIV+IDUs. HHB and HHD are absent in the study populations. Frequency of (<b>D</b>) <i>CCR5</i> HHG*1 haplotype and (<b>E</b>) <i>CCR5</i> HHG*1-containing genotypes in IDUs by HCV and HIV serostatus.</p