Abstract
BackgroundHuman promoter polymorphisms in the chemokine co-receptor 5 gene (CCR5) have been noted for association with mother-to-child transmission of HIV (HIV MTCT) as well as reduced receptor expression in vitro, but have not been clearly associated with CCR5 expression in vivo. Placental expression of CCR5 may be influenced by such polymorphisms as well as other in vivo regulatory factors.Methodology/Principal FindingsWe evaluated the associations between infant CCR5 polymorphisms, measures of maternal infection, and placental expression of CCR5 among mother-infant pairs in Blantyre, Malawi. RNA was extracted from placental tissue and used in multiplex real-time PCR to quantify gene expression. Through linear regression, we observed that CCR5-2554T (β = −0.67, 95% CI = −1.23, −0.11) and -2132T (β = −0.75, 95% CI = −0.131, −0.18) were significantly associated with reduced placental expression of CCR5. An incremental increase in CCR5 expression was observed for incremental increases in expression of two heparan sulfate genes involved in viral infection, HS3ST3A1 (β = 0.27, 95% CI = 0.18, 0.35) and HS3ST3B1 (β = 0.11, 95% CI = 0.06, 0.18). Among HIV infected mothers, an incremental increase in maternal HIV viral load was also associated with higher CCR5 expression (β = 0.76, 95% CI = 0.12, 1.39). Maternal HIV status had no overall effect (β = 0.072, 95% CI = −0.57, −0.72). Higher CCR5 expression was observed for mothers with malaria but was not statistically significant (β = 0.37, 95% CI = −0.43, 1.18).Conclusions/SignificanceThese results provide in vivo evidence for genetic and environmental factors involved in the regulation of CCR5 expression in the placenta. Our findings also suggest that the measurement of placental expression of CCR5 alone is not an adequate indicator of the risk of mother-to-child transmission of HIV.
Highlights
In sub-Saharan Africa, over 1,300,000 pregnant women were living with HIV in 2007, and more than 300,000 children are newly infected with HIV each year, primarily through mother-tochild transmission (HIV MTCT) [1]
This study evaluated the regulation of co-receptor 5 gene (CCR5) expression in the placenta by genetic and environmental factors involved in the risk of HIV MTCT
Infant CCR5 promoter polymorphisms -2132T and -2554T were associated with lower expression of CCR5 in the placenta, as was the infant haplotype D, which is tagged by these alleles
Summary
In sub-Saharan Africa, over 1,300,000 pregnant women were living with HIV in 2007, and more than 300,000 children are newly infected with HIV each year, primarily through mother-tochild transmission (HIV MTCT) [1]. Genetic variants of the CCR5 gene such as the 32-basepair deletion in the open reading frame (CCR5 D32) and promoter polymorphisms are associated with human susceptibility to infection and/or progression of HIV-1 [2,6,7,8,9,10,11,12,13]. This is likely explained by variable receptor expression resulting from mutation [14,15,16]. Placental expression of CCR5 may be influenced by such polymorphisms as well as other in vivo regulatory factors
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