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

PAR07-231，艾滋病毒母婴传播的遗传易感性

• 批准号: 7613090
• 负责人: Bonnie Pedersen
• 金额: $ 3.39万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-30 至 2009-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7613090
• 关键词: PAR07; 231; Genetic; Susceptibility; Mother

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.

描述（由研究者提供）：艾滋病毒母婴传播（MTCT）是一个全球性的公共卫生问题，但在撒哈拉以南非洲尤为重要，那里每年有超过1330万妇女感染艾滋病毒，超过60万婴儿感染艾滋病毒。尽管使用单剂量奈韦拉平等抗逆转录病毒药物可以减少传播，但传播率仍高达30%，而且传播机制尚未完全了解。确定与病毒传播有关的遗传变异将更充分地描述艾滋病毒母婴传播的机制，并有助于开发药物干预措施，包括保护婴儿免受感染的疫苗。本申请的目的是评估两个关键基因的表达与HIV母婴传播风险之间的关联。具体来说，我们希望描述的胎盘表达的基因HS 3ST 3A 1和CCR 5在人口的母婴对马拉维。初步工作包括对婴儿基因组的变异进行全基因组关联扫描，以确定对母体艾滋病毒感染的易感性。分析显示，HS 3ST 3A 1基因的变异与MTCT的风险相关。该基因在人胎盘中高度表达，并产生硫酸乙酰肝素（HS）的3-O-硫酸化亚型生物合成的限速酶。这种HS亚型被单纯疱疹病毒1用于病毒进入，但其在HIV的MTCT中的应用尚不清楚。另一个基因CCR 5在艾滋病毒感染和发展为艾滋病的风险中发挥着已知的作用。HS 3ST 3A 1和CCR 5均未在胎盘表达和MTCT风险的背景下进行评价。我们的目标是进行这项工作，以及评估基因-基因相互作用。这项研究的意义是更清楚地了解母婴传播的机制，特别是遗传基础的机制。最终，这项工作可能有助于艾滋病毒/艾滋病的药物进步。