Naturally-occurring genetic variants in human DC-SIGN increase HIV-1 capture, cell-transfer and risk of mother-to-child transmission.
BACKGROUND
Mother-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.


RESULTS
We 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.


CONCLUSIONS
This study provides compelling evidence to support an important role of DC-SIGN in IU HIV-1 infection.
Laboratoire d'Immunogénétique, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada.
Geneviève
G
Boily-Larouche
Miroslav P
MP
Milev
Lynn S
LS
Zijenah
Annie-Claude
AC
Labbé
Djimon M
DM
Zannou
Jean H
JH
Humphrey
Brian J
BJ
Ward
Johanne
J
Poudrier
Andrew J
AJ
Mouland
Eric A
EA
Cohen
Michel
M
Roger
D001483:Base Sequence; D015815:Cell Adhesion Molecules / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D015658:HIV Infections / Q000235:genetics / Q000635:transmission; D015497:HIV-1 / Q000502:physiology*; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D037181:Lectins, C-Type / Q000235:genetics*; D008264:Macrophages / Q000378:metabolism; D008969:Molecular Sequence Data; D010920:Placenta / Q000473:pathology; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D049590:Postpartum Period; D011247:Pregnancy; D011401:Promoter Regions, Genetic / Q000235:genetics; D011956:Receptors, Cell Surface / Q000235:genetics*; D013601:T-Lymphocytes / Q000821:virology; D014158:Transcription, Genetic; D015030:Zimbabwe; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin
D015815:Cell Adhesion Molecules; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface; D000099215:DC-Specific ICAM-3 Grabbing Nonintegrin