PAR07-231, Genetic Susceptibility to Mother-To-Child Transmission of HIV

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DESCRIPTION (provided by the investigator): Mother-To-Child transmission (MTCT) of HIV is a worldwide public health problem but is of particular importance in Sub-Saharan Africa, where over 13.3 million women are living with HIV and over 600,000 infants are infected with HIV each year. Despite the reduction in transmission by the use of antiretrovirals such as single-dose nevirapine, transmission rates remain up to 30%, and the mechanisms of transmission are not completely understood. Identification of genetic variants associated with viral transmission will more adequately describe the mechanisms of MTCT of HIV and aid the development of pharmaceutical interventions, including a vaccine to protect infants from infection. The objective of this application is to evaluate the association between expression of two key genes and the risk of MTCT of HIV. Specifically, we wish to describe the placental expression of the gene HS3ST3A1 and CCR5 in a population of mother-infant pairs from Malawi. Preliminary work involved a genome wide association scan for variants of infant genomes to determine susceptibility to maternal HIV infection. Analyses revealed a variant in the gene, HS3ST3A1, associated with the risk of MTCT. This gene is highly expressed in human placenta and produces a rate-limiting enzyme for the biosynthesis of the 3-O-sulfated subtype of heparan sulfate (HS). This HS subtype is used by herpes simplex virus 1 for viral entry, but its application to MTCT of HIV is unclear. Another gene, CCR5, plays a known role in the risk of HIV infection and progression to AIDS. Neither HS3ST3A1 nor CCR5 have been evaluated in the context of placental expression and risk of MTCT. We aim to perform this work as well as to evaluate gene-gene interactions. The implications of this study are a clearer understanding of the mechanisms of MTCT, most notably the mechanisms with genetic underpinnings. Ultimately, this work may contribute to pharmaceutical advancements for HIV/AIDS.