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

BACKGROUND: Human 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 FINDINGS: We 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/SIGNIFICANCE: These 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.