I am indebted to the Canadian Institutes of Health Research (grant # MOP82921) for funding our proteomics research. I also wish to thank Kerstin Radtke for excellent suggestions and Daniel Henaff for critical reading of the manuscript. 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. METHODS AND FINDINGS: 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. CONCLUSION: This study provides compelling evidence to support an important role of DC-SIGN in IU HIV-1 infection. In 2010, UNAIDS estimates that 390,000 children acquired HIV-1-infection worldwide mostly through mother-to-child transmission (MTCT) [1] . Overall transmission rates in the absence of any intervention vary from 12 to 42%. Although antiretroviral therapy (ART) can reduce MTCT to as low as 2% [2] , limited access to timely diagnostics and drugs in resource-poor settings blunts the potential impact of this strategy. A better understanding of the mechanisms acting in MTCT of HIV-1 is crucial for the design of interventions other than ART for transmission prevention.