Background:  The role of CC chemokines CCL3, CCL4, and CCL5 in protection against mother-to-child transmission of HIV-1 is not well understood. We questioned whether fetal CC chemokine production was associated with protection against HIV-1 transmission due to viral exposure at delivery.

Methods:  Using a nested case-control design, we measured, by ELISA, spontaneous and mitogen-induced production of CCL3, CCL4, and CCL5 by mononuclear cells for 60 HIV-1 infected and 20 uninfected mother/infant pairs. We found that 13 infants were infected intrapartum and 4 in utero. Immune activation markers were quantitated by ELISA in cord blood plasma samples. The promoter and first intron of the 2 functional CCL3 genes (CCL3 and CCL3-L1) were sequenced. Copy numbers of CCL3 (occurs as 2 per diploid genome) and CCL3-L1 (variable in most populations) was determined by real-time polymerase chain reaction (PCR) quantitation (cohort extended to give a total of 46 transmitting and 74 non-transmitting mother/child pairs).

Results:  PHA-induced production of CCL3 (p = 0.002) and CCL4 (p = 0.001) by cord blood mononuclear cells was increased in infants born to HIV-1-infected mothers but that remained uninfected. However, infants who became infected intrapartum showed a deficiency in the production of CCL3 at birth. The production of CCL5 showed no relationship with HIV-1 infection outcome in the infant. Differences in production of CCL3 between exposed-uninfected and intrapartum-infected infants could not be explained by differences in immune activation events prior to birth as measured by plasma levels of neopterin, b2-microglobulin and sL-selectin. However, a similar deficiency in mitogen-induced CCL3 production was evident in intrapartum-transmitting mothers relative to non-transmitting mothers, suggesting that the underlying nature of this deficient response was genetically encoded. CCL3-L1 gene copy number was associated with CCL3 production (exposed uninfected infants, p = 0.035) and with vertical transmission (p = 0.019). However, at equivalent CCL3-L1 gene copy numbers, intrapartum-infected infants relative to their exposed uninfected counterparts had lower production of CCL3 suggesting that they may harbor some non-functional copies of this gene. Nucleotide changes that may influence CCL3 production were evident in CCL3 and CCL3-L1 genes upstream of exon 2.

Conclusions:  Overall findings suggest that infants who display a deficient production phenotype of CCL3 are more likely to acquire HIV-1 infection during delivery, and that this reduced production is partly explained by reduced CCL3-L1 gene copy number.