Functional genetic variants in DC-SIGNR are associated with mother-to-child transmission of HIV-1.
BACKGROUND
Mother-to-child transmission (MTCT) is the main cause of HIV-1 infection in children worldwide. Given that the C-type lectin receptor, dendritic cell-specific ICAM-grabbing non-integrin-related (DC-SIGNR, also known as CD209L or liver/lymph node-specific ICAM-grabbing non-integrin (L-SIGN)), can interact with pathogens including HIV-1 and is expressed at the maternal-fetal interface, we hypothesized that it could influence MTCT of HIV-1.


RESULTS
To investigate the potential role of DC-SIGNR in MTCT of HIV-1, we carried out a genetic association study of DC-SIGNR 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 3.6-fold increased risk of in utero (IU) (P = 0.013) HIV-1 infection and a 5.7-fold increased risk of intrapartum (IP) (P = 0.025) 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 (P = 0.045 and P = 0.003, respectively) and IP (P = 0.025, for int2-180A) 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 (P = 0.011).


CONCLUSIONS
These results suggest that DC-SIGNR plays a crucial role in MTCT of HIV-1 and that impaired placental DC-SIGNR expression increases risk of transmission.
Boily-Larouche
Geneviève
G
Laboratoire d'Immunogénétique, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Canada.
Iscache
Anne-Laure
AL
Zijenah
Lynn S
LS
Humphrey
Jean H
JH
Mouland
Andrew J
AJ
Ward
Brian J
BJ
Roger
Michel
M
D015815:Cell Adhesion Molecules / Q000235:genetics*; D015331:Cohort Studies; D005260:Female; D014644:Genetic Variation; D015658:HIV Infections / Q000235:genetics* / Q000635:transmission* / Q000821:virology; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D037102:Lectins; D037181:Lectins, C-Type / Q000235:genetics*; D009035:Mothers; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*; D012306:Risk
C433029:CLEC4M protein, human; D015815:Cell Adhesion Molecules; D037102:Lectins; D037181:Lectins, C-Type; D011956:Receptors, Cell Surface