DC-SIGN promoter p-336C and exon 4 242V variants are observed on the H4 haplotype while p-336C, p-201A and 198Q variants are found on the H6 haplotype. Thus exon 4 variants are always transmitted with one or both promoter variants. These variants were all associated with IU HIV-1 infection and yet the promoter variants reduced DC-SIGN expression in Hofbauer cells whereas the exon 4 mutations enhanced capture and transmission of HIV-1 to CD4 + T lymphocytes. Compensatory mutations frequently evolve to dampen the effect of other mutations. Since the DC-SIGN gene has been under strong evolutionary pressure to conserve its function [42] it is not surprising that mutations increasing the affinity of DC-SIGN for pathogens have appeared that can compensate for mutations that reduce its expression. Interestingly, HIV-1 itself can also affect DC-SIGN expression. Indeed, HIV-or antibody-stimulated DC-SIGN signalling in monocytes-derived dendritic cells (MDDC) reduced DC-SIGN expression and prevented cell maturation [19, 43] . In infants harbouring the WT sequence, levels of DC-SIGN expression were significantly lower in infants born from HIV-1-positive mothers than those born from HIV-1-negative mothers ( Figure 2D ). However, the impact of HIV-1 was negligible or not noticeable in infants carrying the promoter variants since baseline DC-SIGN expression levels were already low in these subjects. Although we cannot exclude that ART may also modulate DC-SIGN expression, it is reasonable to believe that HIV affects DC-SIGN expression in the tissue since in vitro experiments support this hypothesis [19, 43] . In the present study, Zimbabwean infants were born from ART-naive HIV-1-positive mothers. Given the fact that they were all exposed to HIV during their intra-uterine life, they may have harboured similar levels of DC-SIGN expression ( Figure 2D) . Hence, the positive association observed between IU HIV-1 infection and DC-SIGN H4 and H6 haplotypes may thus result from exon 4 protein-modifying mutations found within these haplotypes that enhanced capture of HIV-1 by Hofbauer cells within the chorionic villi in close proximity to maternal infected cells and facilitate short-term transfer of the virus to the infant's T lymphocytes [16] . On the other hand, we cannot rule out the possibility that DC-SIGN variants might promote HIV-1 infection of Hofbauer cells and subsequently IU transmission of HIV-1. Hofbauer cells express both the HIV-1 CD4 receptor and the CCR5 co-receptor [16, 44] and HIV-1 genomic materials have been detected in placental macrophages [45] . Kumar et al observed compartmentalized HIV-1 replication within the placenta during IU transmission [46] and proposed that viral selection during IU transmission could be the manifestation of HIV-1 placental adaptation to the unique repertoire of cellular targets and increased adherence to C-type lectins which further support the implication of DC-SIGN in IU transmission of HIV-1. However, the net impact of this phenomenon on MTCT of HIV-1 remains to be determined since it has also been shown that placental macrophages can restrict HIV-1 replication [47] .