Naturally-occurring genetic variants in human DC-SIGN increase HIV-1 capture, cell-transfer and risk of mother-to-child transmission |
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Authors: | Geneviève Boily-Larouche Miroslav P Milev Lynn S Zijenah Annie-Claude Labbé Djimon M Zannou Jean H Humphrey Brian J Ward Johanne Poudrier Andrew J Mouland Eric A Cohen Michel Roger |
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Institution: | Laboratoire d'Immunogénétique, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada. |
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Abstract: | BackgroundMother-to-child transmission (MTCT) is the main cause of HIV-1 infection in children worldwide. Dendritic cell–specific ICAM-3 grabbing-nonintegrin (DC-SIGN, also known as CD209) is an HIV-1 receptor that enhances its transmission to T cells and is expressed on placental macrophages.Methods and FindingsWe have investigated the association between DC-SIGN genetic variants and risk of MTCT of HIV-1 among Zimbabwean infants and characterized the impact of the associated mutations on DC-SIGN expression and interaction with HIV-1. DC-SIGN promoter (p-336C and p-201A) and exon 4 (198Q and 242V) variants were all significantly associated with increased risk of intrauterine (IU) HIV-1 infection. Promoter variants decreased DC-SIGN expression both in vitro and in placental CD163+ macrophages (Hofbauer cells) of HIV-1 unexposed infants but not of HIV-1 exposed infants. The exon 4 protein-modifying mutations increased HIV-1 capture and transmission to T cells in vitro.ConclusionThis study provides compelling evidence to support an important role of DC-SIGN in IU HIV-1 infection. |
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