Implication de DC-SIGN et DC-SIGNR dans la transmission mère-enfant du VIH-1

Mother-to-child transmission (MTCT) is the main cause of HIV-1 infection in children worldwide. MTCT of HIV-1 can occur during pregnancy (in utero, IU), delivery (intrapartum, IP) or breastfeeding (postpartum, PP). Dendritic cell-specific ICAM-grabbing non-integrin (DC-SIGN) and its homolog DC-SIGN related (DC-SIGNR) are attachment receptors for HIV-1 and are expressed in the placenta. They have been implicated in viral capture and transmission to T cells. To investigate the potential role of DC-SIGN and DC-SIGNR in MTCT of HIV-1, we carried out a genetic association study in a well-characterized cohort of 197 HIV-infected mothers and their infants recruited in Harare, Zimbabwe.  Infants harbouring two copies of DC-SIGNR H1 and/or H3 haplotypes (H1-H1, H1-H3, H3-H3) had a 4-fold increased risk of IU and 6-fold increased risk of IP HIV-1 infection after adjusting for a number of maternal factors. The implicated H1 and H3 haplotypes share two single nucleotide polymorphisms (SNPs) in promoter region (p-198A) and intron 2 (int2-180A) that were associated with increased risk of both IU and IP HIV-1 infection. The promoter variant reduced transcriptional activity in vitro. In homozygous H1 infants bearing both the p-198A and int2-180A mutations, we observed a 4-fold decrease in the level of placental DC-SIGNR transcripts, disproportionately affecting the expression of membrane-bound isoforms compared to infant noncarriers. Infants carrying H4 and H6 haplotypes in DC-SIGN gene were more likely to be HIV-1-infected during pregnancy. These haplotypes contain promoter variants (p-336T/C and p-201C/A) and exon 4 variants (R198Q, E214D, R221Q and L242V) that were all significantly associated with increased risk of MTCT of HIV-1. Compared with wild-type sequence, the promoter variants reduced both the DC-SIGN transcription in vitro and expression (2-fold) in placental macrophages of HIV-1-unexposed infants. However, in HIV-1-exposed infants, the level of DC-SIGN expression in placental macrophages was similar in infants carrying either the promoter wild-type or variant sequences. Exon 4 variants increased HIV-1 capture and transmission to T cells in vitro. Association between DC-SIGN SNPs and HIV-1 IP and PP infection also suggests that DC-SIGN plays an important role in intestinal mucosa. This is the first study reporting on functional impact of DC-SIGN and DC-SIGNR natural polymorphisms on HIV-1 transmission from mother-to-child. Decreased levels of expression of membrane DC-SIGNR isoforms at the placental endothelial cell surface increased child susceptibility to HIV-1. Presence of DC-SIGN variants increasing its affinity for the virus augmented child susceptibility to HIV-1 and may favour viral dissemination across the placental barrier. This study provides compelling evidence to support an important role of DC-SIGN and DC-SIGNR in various modes of MTCT of HIV-1 and shed light on the possible mechanisms involved in HIV-1 passage from mother-to-infant. These findings raise the possibility that similar mechanisms may operate with other human pathogens known to interact with DC-SIGN and DC-SIGNR.

Keyphrases: DC-SIGN, DC-SIGNR, genetic variant, mother-to-child transmission, HIV-1, cell-to-cell transfer