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. Methods and Findings 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). Conclusion 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.
References
[1]
Luzuriaga K (2007) Mother-to-child Transmission of HIV: A Global Perspective. Curr Infect Dis Rep 9: 511–517.
[2]
Pohlmann S, Soilleux EJ, Baribaud F, Leslie GJ, Morris LS, et al. (2001) DC-SIGNR, a DC-SIGN homologue expressed in endothelial cells, binds to human and simian immunodeficiency viruses and activates infection in trans. Proc Natl Acad Sci U S A 98: 2670–2675.
[3]
Mummidi S, Catano G, Lam L, Hoefle A, Telles V, et al. (2001) Extensive repertoire of membrane-bound and soluble dendritic cell-specific ICAM-3-grabbing nonintegrin 1 (DC-SIGN1) and DC-SIGN2 isoforms. Inter-individual variation in expression of DC-SIGN transcripts. J Biol Chem 276: 33196–33212.
[4]
Chan VS, Chan KY, Chen Y, Poon LL, Cheung AN, et al. (2006) Homozygous L-SIGN (CLEC4M) plays a protective role in SARS coronavirus infection. Nat Genet 38: 38–46.
[5]
Bryson YJ, Luzuriaga K, Sullivan JL, Wara DW (1992) Proposed definitions for in utero versus intrapartum transmission of HIV-1. N Engl J Med 327: 1246–1247.
[6]
Humphrey JH, Iliff PJ, Marinda ET, Mutasa K, Moulton LH, et al. (2006) Effects of a single large dose of vitamin A, given during the postpartum period to HIV-positive women and their infants, on child HIV infection, HIV-free survival, and mortality. Journal of Infectious Diseases 193: 960–971.
[7]
Boily-Larouche G, Zijenah LS, Mbizvo M, Ward BJ, Roger M (2007) DC-SIGN and DC-SIGNR genetic diversity among different ethnic populations: Potential implications for pathogen recognition and disease susceptibility. Human Immunology 68: 523–530.
[8]
Stephens M, Smith NJ, Donnelly P (2001) A new statistical method for haplotype reconstruction from population data. Am J Hum Genet 68: 978–989.
[9]
Zhang K, Jin L (2003) HaploBlockFinder: haplotype block analyses. Bioinformatics 19: 1300–1301.
[10]
Bashirova AA, Geijtenbeek TB, van Duijnhoven GC, van Vliet SJ, Eilering JB, et al. (2001) A dendritic cell-specific intercellular adhesion molecule 3-grabbing nonintegrin (DC-SIGN)-related protein is highly expressed on human liver sinusoidal endothelial cells and promotes HIV-1 infection. J Exp Med 193: 671–678.
[11]
Liu H, Hladik F, Andrus T, Sakchalathorn P, Lentz GM, et al. (2005) Most DC-SIGNR transcripts at mucosal HIV transmission sites are alternatively spliced isoforms. Eur J Hum Genet 13: 707–715.
[12]
Kourtis AP, Lee FK, Abrams EJ, Jamieson DJ, Bulterys M (2006) Mother-to-child transmission of HIV-1: timing and implications for prevention. Lancet Infect Dis 6: 726–732.
[13]
Wiley RD, Gummuluru S (2006) Immature dendritic cell-derived exosomes can mediate HIV-1 trans infection. Proc Natl Acad Sci U S A 103: 738–743.
[14]
Turville SG, Cameron PU, Handley A, Lin G, Pohlmann S, et al. (2002) Diversity of receptors binding HIV on dendritic cell subsets. Nat Immunol 3: 975–983.
[15]
Snyder GA, Ford J, Torabi-Parizi P, Arthos JA, Schuck P, et al. (2005) Characterization of DC-SIGN/R interaction with human immunodeficiency virus type 1 gp120 and ICAM molecules favors the receptor's role as an antigen-capturing rather than an adhesion receptor. J Virol 79: 4589–4598.
[16]
Limmer A, Ohl J, Kurts C, Ljunggren HG, Reiss Y, et al. (2000) Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nat Med 6: 1348–1354.
[17]
Pober JS, Sessa WC (2007) Evolving functions of endothelial cells in inflammation. Nat Rev Immunol 7: 803–815.
[18]
Soilleux EJ, Morris LS, Rushbrook S, Lee B, Coleman N (2002) Expression of human immunodeficiency virus (HIV)-binding lectin DC-SIGNR: Consequences for HIV infection and immunity. Hum Pathol 33: 652–659.
[19]
Mukhtar M, Harley S, Chen P, Bouhamdan M, Patel C, et al. (2002) Primary isolated human brain microvascular endothelial cells express diverse HIV/SIV-associated chemokine coreceptors and DC-SIGN and L-SIGN. Virology 297: 78–88.
[20]
Kanmogne GD, Schall K, Leibhart J, Knipe B, Gendelman HE, et al. (2007) HIV-1 gp120 compromises blood-brain barrier integrity and enhances monocyte migration across blood-brain barrier: implication for viral neuropathogenesis. J Cereb Blood Flow Metab 27: 123–134.
[21]
Yang B, Akhter S, Chaudhuri A, Kanmogne GD (2009) HIV-1 gp120 induces cytokine expression, leukocyte adhesion, and transmigration across the blood-brain barrier: modulatory effects of STAT1 signaling. Microvasc Res 77: 212–219.
[22]
Kwiek JJ, Arney LA, Harawa V, Pedersen B, Mwapasa V, et al. (2008) Maternal-fetal DNA admixture is associated with intrapartum mother-to-child transmission of HIV-1 in Blantyre, Malawi. J Infect Dis 197: 1378–1381.
[23]
Kwiek JJ, Mwapasa V, Milner DA Jr, Alker AP, Miller WC, et al. (2006) Maternal-fetal microtransfusions and HIV-1 mother-to-child transmission in Malawi. PLoS Med 3: e10.
[24]
Singh KK, Spector SA (2009) Host Genetic Determinants of HIV Infection and Disease Progression in Children. Pediatr Res.
[25]
Pedersen BR, Kamwendo D, Blood M, Mwapasa V, Molyneux M, et al. (2007) CCR5 haplotypes and mother-to-child HIV transmission in Malawi. PLoS One 2: e838.
[26]
Singh KK, Hughes MD, Chen J, Phiri K, Rousseau C, et al. (2008) Associations of chemokine receptor polymorphisms With HIV-1 mother-to-child transmission in sub-Saharan Africa: possible modulation of genetic effects by antiretrovirals. J Acquir Immune Defic Syndr 49: 259–265.
[27]
Singh KK, Barroga CF, Hughes MD, Chen J, Raskino C, et al. (2003) Genetic influence of CCR5, CCR2, and SDF1 variants on human immunodeficiency virus 1 (HIV-1)-related disease progression and neurological impairment, in children with symptomatic HIV-1 infection. J Infect Dis 188: 1461–1472.
[28]
Martinson JJ, Chapman NH, Rees DC, Liu YT, Clegg JB (1997) Global distribution of the CCR5 gene 32-basepair deletion. Nat Genet 16: 100–103.
[29]
Kuhn L, Schramm DB, Donninger S, Meddows-Taylor S, Coovadia AH, et al. (2007) African infants' CCL3 gene copies influence perinatal HIV transmission in the absence of maternal nevirapine. Aids 21: 1753–1761.
[30]
Meddows-Taylor S, Donninger SL, Paximadis M, Schramm DB, Anthony FS, et al. (2006) Reduced ability of newborns to produce CCL3 is associated with increased susceptibility to perinatal human immunodeficiency virus 1 transmission. J Gen Virol 87: 2055–2065.
[31]
Mangano A, Rocco C, Marino SM, Mecikovsky D, Genre F, et al. (2008) Detrimental effects of mannose-binding lectin (MBL2) promoter genotype XA/XA on HIV-1 vertical transmission and AIDS progression. J Infect Dis 198: 694–700.
[32]
Boniotto M, Crovella S, Pirulli D, Scarlatti G, Spano A, et al. (2000) Polymorphisms in the MBL2 promoter correlated with risk of HIV-1 vertical transmission and AIDS progression. Genes Immun 1: 346–348.
