Genetic Variability in Markers of HLA-C Expression in Two Diverse South African Populations

<div><p>An insertion-deletion (indel) polymorphism within the 3′ untranslated region (UTR) of <i>HLA-C</i> has been shown to be involved in the regulation of HLA-C expression. Individuals who carry a deletion at this position exhibit increased HLA-C expression, which associates with lower viral set point in HIV-1 infected individuals. This <i>263</i> indel (rs67384697) is reported to be in strong linkage disequilibrium (LD) with a single nucleotide polymorphism (SNP) 35 kilobases upstream of <i>HLA-C</i> (<i>-35T/C</i>; rs9264942) in Caucasian individuals, making this SNP a potential marker for both HLA-C expression and HIV-1 disease progression. We therefore examined genetic variation within the <i>HLA-C</i> 3′ UTR of 265 Black and Caucasian South Africans by direct sequencing and identified haplotypes encompassing the <i>263</i> indel and another indel at position 230 in both populations. Concomitant evaluation of variability at the <i>−35</i> SNP revealed this polymorphism to be an inappropriate marker for the <i>263</i> indel in these populations. These findings provide important insights into genetic variability within the regulatory regions of <i>HLA-C</i> that have potential implications for our understanding of the regulation of HLA-C expression and its impact on HIV-1 disease progression.</p></div

Linkage disequilibrium between the <i>-35</i> SNP and the <i>HLA-C</i> alleles present in the Black and Caucasian South African population groups.

1<p>the total number of individuals genotyped in each population group.</p>2<p>the observed frequency of each two-locus haplotype.</p>3<p>Lewontin's D' measure of linkage disequilibrium <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067780#pone.0067780-Lewontin1" target="_blank">[19]</a>.</p>4<p>p-values are calculated using an exact test for linkage disequilibrium <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0067780#pone.0067780-Slatkin1" target="_blank">[20]</a>, and are significant at p<0.05.</p>5<p>the number of chromosomes on which the two-locus haplotype was found to occur.</p

The haplotypes identified within the <i>HLA-C</i> 3′ UTR.

<p>The positions involved in the two haplotypes identified are indicated in colour. The haplotype encompassing the <i>263</i> indel is shown in pink, while the haplotype encompassing the <i>230</i> indel is shown in blue. The major and minor alleles at each position are also indicated. Positions were only included in the haplotypes if both D' and r² measures of pairwise LD were equal to 1. Polymorphic positions are indicated by their position relative to the start of the <i>HLA-C</i> 3′ UTR.</p

Genetic variation within <i>HLA-C</i> 3′ UTR sequences of the <i>HLA-C</i> alleles observed in the Caucasian South African population group.

1<p>positions are given relative to the start of the HLA-C 3′ UTR.</p>2<p><i>HLA-C</i> alleles <i>C*02∶02</i> and <i>C*03∶04</i> were found to have more than one 3′ UTR sequence.</p>3<p>where more than one allele has been observed alleles are reported using standard IUB ambiguity codes.</p>4<p>I refers to an insertion and D to a deletion.</p

Genetic variation within <i>HLA-C</i> 3′ UTR sequences of the <i>HLA-C</i> alleles observed in the Black South African population group.

1<p>positions are given relative to the start of the HLA-C 3′ UTR.</p>2<p><i>HLA-C</i> alleles <i>C*02∶02, C*02∶10, C*03∶04, C*07∶01, C*16∶01</i> and <i>C*18∶01</i> were found to have more than one 3′ UTR sequence.</p>3<p>where more than one allele has been observed alleles are reported using standard IUB ambiguity codes.</p>4<p>I refers to an insertion and D to a deletion.</p

Infection-Free Probability As a Function of Time and of Randomization

<p>This figure represents the infection-free probability using a piecewise exponential distribution with boundaries at M3, M12, and M21 obtained with a Poisson log-linear model (see text). Each segment of exponential has been fitted to the data in each period for each randomization group. The 95% confidence intervals have been represented in the middle of each period. x/y is the number of HIV infections observed in each period (x) and the number of persons at the beginning of the period (y).</p

Trial Profile

<div><p>This figure describes the state of the trial corresponding to planned visits up to 30 April 2005. HIV-positive and HIV-negative participants were randomized. All were followed, but only participants HIV-negative at randomization were analyzed and are represented in the three follow-up visits of the figure. After randomization, the participants could attend the 3-mo visit, miss it, or be excluded from follow-up (death or loss to follow-up). The non-excluded participants who attended the 3-mo visit could then attend the 12-mo visit, miss it, or be excluded (death or loss to follow-up). The non-excluded participants of the 12-mo visit could then attend the 21-mo visit, be excluded (death or loss to follow-up) or were planning to attend the 21-mo visit but had not yet done so, because of the interruption of the trial.</p> <p>*, did not come for the scheduled visit (refused, withdrew, moved away or died); **, no blood sample</p></div

Women’s knowledge and perception of male circumcision before and after its roll-out in the South African township of Orange Farm from community-based cross-sectional surveys

<div><p>The roll-out of medical male circumcision (MC) is progressing in Southern and Eastern Africa. Little is known about the effect of this roll-out on women. The objective of this study was to assess the knowledge and perceptions of women regarding MC in a setting before and after the roll-out. This study was conducted in the South African township of Orange Farm where MC prevalence among men increased from 17% to 53% in the period 2008–2010. Data from three community-based cross sectional surveys conducted in 2007, 2010 and 2012 among 1258, 1197 and 2583 adult women, respectively were studied. In 2012, among 2583 women, 73.7% reported a preference for circumcised partners, and 87.9% knew that circumcised men could become infected with HIV. A total of 95.8% preferred to have their male children circumcised. These three proportions increased significantly during the roll-out. In 2007, the corresponding values were 64.4%, 82.9% and 80.4%, respectively. Among 2581 women having had sexual intercourse with circumcised and uncircumcised men, a majority (55.8%, 1440/2581) agreed that it was easier for a circumcised man to use a condom, 20.5% (530/2581) disagreed; and 23.07 (611/2581) did not know. However, some women incorrectly stated that they were fully (32/2579; 1.2%; 95%CI: 0.9% to 1.7%) or partially (233/2579; 9.0%; 95%CI: 8.0% to 10.2%) protected when having unprotected sex with a circumcised HIV-positive partner. This study shows that the favorable perception of women and relatively correct knowledge regarding VMMC had increased during the roll-out of VMMC. When possible, women should participate in the promotion of VMMC although further effort should be made to improve their knowledge.</p></div

HIV incidence estimates.

<p>CI = confidence interval, FPR = false-positive ratio.</p