CCR5 haplotypes and mother-to-child HIV transmission in Malawi

Abstract

Background: CCR5 and CCR2 gene polymorphisms (SNPs) have been associated with protection against HIV transmission in adults and with delayed progression to AIDS. The CCR5 Delta32 deletion and SNP -2459G are associated with reduced expression of the CCR5 protein.

Methodology/principal findings: We investigated the association between infant CCR2/CCR5 diplotype and HIV mother to child transmission (MTCT) in Malawi. Blood samples from infants (n = 552) of HIV positive women who received nevirapine were genotyped using a post-PCR multiplex ligase detection reaction and haplotypes were identified based on 8 CCR2/CCR5 SNPs and the open reading frame 32 base pair deletion. Following verification of Hardy-Weinberg equilibrium, log linear regression was performed to examine the association between mutations and MTCT. Overall, protection against MTCT was weakly associated with two CCR5 SNPs, -2459G (Risk ratio [RR], 0.78; confidence interval [CI], 0.54-1.12), and the linked CCR5 -2135T (RR, 0.78; CI, 0.54-1.13). No child carried the CCR5 Delta32 SNP. Maternal Viral Load (MVL) was found to be an effect measure modifier. Among mothers with low MVL, statistically significant protection against MTCT was observed for -2459G (RR, 0.50; CI, 0.27-0.91), and -2135T (RR, 0.51; CI, 0.28-0.92). Statistically significant protection was not found at high MVL.

Conclusions/significance: Results from this study suggest that CCR5 SNPs -2459G and -2135T associated with reduced receptor expression protect against MTCT of HIV at low MVLs, whereas high MVLs may over-ride differences in coreceptor availability.

Figure 1. CCR2/CCR5 Haplotypes and abridged phylogenetic tree.

Haplotypes were constructed based on the evolution of linked CCR2 and CCR5 mutations, including a valine to isoleucine substitution at codon 64 in the CCR2b gene (CCR2-64I), CCR5 mutations -2733A→G, -2554 G→T, -2459A→G, -2135C→T, -2132C→T, -2086A→G, -1835C→T, and the delta-32 deletion in the open reading frame of CCR5 (CCR5-ORF).

Figure 2. Genotype Frequencies.

Infant genotype frequencies were calculated for all eligible births. Wild type and variant alleles correspond to the evolutionary history outlined in Figure 1.

Figure 3. Haplotype Frequencies.

Infant haplotype frequencies were calculated for all eligible births.

Figure 4. Effect Measure Modification by MVL.

Carriers of CCR5 -2459G and -2135T with low MVL were protected from MTCT, whereas carriers of -2459G and -2135T with high MVL demonstrated no change in susceptibility to MTCT.