CCR5 Haplotypes and Mother-to-Child HIV Transmission in Malawi

Abstract

BackgroundCCR5 and CCR2 gene polymorphisms (SNPs) have been associated with protection against HIV transmission in adults and with delayed progression to AIDS. The CCR5 Δ32 deletion and SNP -2459G are associated with reduced expression of the CCR5 protein.Methodology/Principal FindingsWe 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 Δ32 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/SignificanceResults 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.

Associations of Chemokine Receptor Polymorphisms With HIV-1 Mother-to-Child Transmission in Sub-Saharan Africa: Possible Modulation of Genetic Effects by Antiretrovirals

“…Because the basic biology and thus the genetic determinants of these 2 routes of transmission may differ, it would be interesting to assess the timing of transmission in larger cohorts. A recent study reported the potential protective effects of CCR 5-59029-G and CCR 5-593563-T alleles against MTCT in Malawian children with lower maternal viral load25; however, this effect was lost in children with higher maternal viral load.…”

Congenital toxoplasmosis: candidate host immune genes relevant for vertical transmission and pathogenesis

“…11,13,14,[25][26][27] The 64I allele of CCR2 and the D32 deletion of CCR5 negatively influence expression of the products, which have shown implications in noninfectious diseases and, of special interest, human immunodeficiency virus congenital transmission. [65][66][67] Similarly, CCL5 (RANTES) production in response to Brucella abortus correlated with IFN-g induction and contributed to abortion in mice. 68 Two polymorphisms of CCL5 in either the mother or the product would have opposite effects on congenital toxoplasmosis occurrence or pathology: the À28 C/G or G/G would be protective against infection, but without proper control it could relate to sterile abortion.…”

Regulation of CCR5 Expression in Human Placenta: Insights from a Study of Mother-to-Child Transmission of HIV in Malawi

“…Referring to the association between infant CCR2 / CCR5 SNPs and HIV MTCT previously described [44] and based on our replicate analyses, we found that this was not always the case. Notably, CCR5 -2733G was associated with higher CCR5 expression compared to a lower risk of HIV MTCT, although the association with expression was not statistically significant (Table S3).…”

“…One exception was the association between CCR5 -1835T and the risk of HIV MTCT, which varied slightly in direction compared to previous findings (OR = 1.06 vs. RR = 0.84) [44]. Some findings also had variable statistical significance which may be a reflection of sample size (Table S3).…”