Routes of Transmission of HIV in Malawian Mothers

描述（由申请人提供）：本提案的目的是研究艾滋病毒母婴传播（MTCT）的生物学机制，使用已经从860名艾滋病毒（阳性）孕妇及其后代中收集的样本。我们假设：1)母胎微量输血增加了MTCT的风险；2)母体HIV多样性是MTCT的一个危险因素；3)异质双工追踪试验可用于区分经肠外感染HIV的婴儿与经粘膜感染的婴儿；4)HIV通过细胞相关病毒传播给婴儿。在一项初步研究中，我们测量了胎盘碱性磷酸酶（PLAP），一种胎盘不渗透的高分子量酶，在脐带血清中作为母胎微量输血的标志物。在一项对204对母婴的巢式病例队列研究中，发现脐带PLAP升高是分娩时的危险因素，但不是宫内MTCT的危险因素。我们的第一个具体目标是通过a)测量全队列脐带血清中的PLAP，以及b)开发和使用基于遗传多态性的母胎微输血的第二种方法来扩展这些观察结果。在第二个目标中，我们将使用异双工跟踪测定法记录母婴病毒多样性，并评估母体多样性与MTCT之间的相关性；此外，我们将使用婴儿HIV人群多样性数据，以及来自Specific Aim 1的数据，来确定婴儿感染是由于粘膜暴露还是通过母体污染胎儿循环直接接种的结果。在第三个目标中，我们将比较母体、脐带和新生儿血浆和细胞相关病毒的概况，以确定这两个区室对传播的相对重要性。因此，该项目的结果将提出一个与艾滋病毒垂直传播有关的媒介、途径和母体因素的综合模型。

DESCRIPTION (provided by applicant): The aim of this proposal is to study the biological mechanism of mother-to-child transmission (MTCT) of HIV using samples already collected from a well-characterized cohort of 860 HIV(+) pregnant Malawian women and their offspring. We hypothesize that: 1) the risk of MTCT is increased as a result of increased maternal-fetal microtransfusion, 2) maternal HIV diversity is a risk factor for MTCT, 3) heteroduplex tracking assays can be used to distinguish infants infected with HIV parenterally versus infants infected through mucosal membranes and 4) HIV is transmitted to infants through cell-associated virus. In a preliminary study, we measured placental alkaline phosphatase (PLAP), a placenta-impermeable high-molecular weight enzyme, in umbilical serum as a marker for maternal-fetal microtransfusion. In a nested case-cohort study of 204 mother-child pairs, elevated umbilical PLAP was found to be is a risk factor for intrapartum, but not intrauterine MTCT. Our first specific aim is to extend these observations by a) measuring PLAP in the umbilical cord sera from the full cohort, and b) developing and using a second method for maternal fetal microtransfusion based on genetic polymorphisms. In the second aim we will document maternal and infant viral diversity using heteroduplex tracking assays and assess the correlation between maternal diversity and MTCT; furthermore, we will use the infant HIV population diversity data, along with the data from Specific Aim 1, to determine if infant infections are a result of a mucosal exposure or direct inoculation via maternal contamination of fetal circulation. In the third Aim we will compare the profiles of maternal, umbilical and neonatal plasma^ and cell-associated virus to determine the relative importance of the two compartments to transmission. Thus, the results of this project will suggest a comprehensive model of the vector, the route, and the maternal factors associated with HIV vertical transmission.