MECHANISMS AND COFACTORS OF HIV TRANSMISSION TO WOMEN

描述(申请人提供)：女性感染HIV-1是一种相对罕见的性接触HIV-1的结果。每个女性的风险可能不同，同一个女性在不同的暴露期间风险也可能不同。易感性是由一系列复杂的因素决定的，包括妇女接触的病毒的数量和性质、个体宿主遗传因素以及接触时存在的多种可改变的生物辅助因素。在这项计划项目拨款中，我们建议研究生物辅助因素增加妇女感染HIV-1的易感性的机制。拟议的研究将包括多个高危群体的妇女：性工作者、孕妇/产后妇女和处于HIV-1不和谐关系中的妇女。具体地说，我们将研究以下因素的作用：1)怀孕和产后的影响(项目1)；2)阴道菌群和特定的细菌感染(项目2)；3)先天免疫因素，包括它们与激素和生殖道感染有关的因素(项目3)；以及4)反复接触艾滋病毒-1后诱导的粘膜艾滋病毒-1抗体(项目4)对妇女感染艾滋病毒-1的易感性。对于这些研究，我们将利用我们的研究团队西雅图/肯尼亚合作研究小组在过去约15年中开发的队列研究、合作伙伴关系和基础设施。我们的研究小组包括病毒学家、免疫学家、细菌学家、流行病学家、统计学家和临床科学家，有着长期而富有成效的合作历史，并以专注于女性的翻译研究而闻名。在这里，我们将在此基础上，在该计划拨款内开展多个协作项目。我们预计，这些项目中的每一个都将借鉴团队中其他人的专业知识，在某些情况下，还将包括解决同一人群中的协同生物学问题的平行研究。 相关性：总的来说，这些研究旨在全面了解导致妇女感染艾滋病毒-1风险增加的生物因素。这类研究对于了解艾滋病毒-1在妇女中传播的独特方面以及寻找减少传播的方法至关重要，这些方法考虑了与妇女有关的问题。 项目1：围产期和产后妇女感染HIV-1高危因素的发生率、时间和辅助因素 (项目负责人：John-Stewart，G) 项目1说明(由申请人提供)：怀孕和产后与艾滋病毒-1风险增加有关。在艾滋病毒-1血清阳性率和生育率都很高的非洲，孕期/产后期可能是艾滋病毒-1感染对妇女的艾滋病毒-1有很大贡献的时期。怀孕、分娩和产后期与荷尔蒙、生殖器粘膜和生殖器菌群的变化有关，这些变化可能容易感染HIV-1。项目1将招募2,000名在怀孕期间和产后9个月内发现的未感染艾滋病毒-1的妇女，以确定艾滋病毒-1感染的风险和相关因素。将感染HIV-1的妇女与未感染HIV-1的妇女进行比较，以确定生殖器联合感染、溃疡、分娩方式、哺乳、伴侣特征、阴道菌群变化、HSV-2、生殖器先天免疫因素和全身免疫激活对HIV-1传播的作用。此外，孕期和产后辅助因素的变化可能会影响对HIV-1的易感性。因此，在100名女性的子组中，我们将纵向比较怀孕期间、产后早期和产后后期生殖器先天免疫因子和系统细胞免疫激活情况。这些比较将提供机会，以确定在妇女这一动态变化时期生殖道的变化模式。在量化混合感染、粘膜天然免疫反应和系统细胞免疫激活时，我们将能够确定这些重要决定因素在三个不同但相互关联的领域(联合感染、粘膜天然环境、全身细胞)之间的相互作用，这些因素影响对HIV-1的易感性。项目1将与项目2(阴道菌群变化对艾滋病毒-1传播的影响)、项目3(将涉及项目1队列中妇女体内的细胞因子谱分析)和项目4(艾滋病毒-1未感染妇女与感染艾滋病毒-1的伴侣的适应性体液粘膜反应)建立科学联系。由于女性生殖器生态系统的复杂性以及可能改变对艾滋病毒-1易感性的各种因素，每个项目都将侧重于可能改变艾滋病毒-1传播的补充因素。总而言之，这些将导致对感染艾滋病毒-1的不同重要妇女群体(怀孕/产后、女性工作者和不和谐的夫妇)中妇女的传播情况进行多方面的评估，可以想象，这些妇女具有艾滋病毒-1易感性的一些共同因素，但在其他方面是不同的。 相关性：女性在怀孕期间和怀孕后感染艾滋病毒-1的风险可能会增加。这项研究将确定肯尼亚一群妇女在怀孕期间和怀孕后感染艾滋病毒-1的风险和辅助因素。将评估包括生殖器感染和免疫力在内的因素。这些数据将直接关系到制定适当的战略，以保护妇女在怀孕期间和怀孕后免受艾滋病毒-1感染。

DESCRIPTION (provided by applicant): HIV-1 infection of women is a relatively rare outcome of sexual exposure to HIV-1. The risk may vary for each woman, and it may also vary for the same woman during different exposures. Susceptibility is determined by a complex set of factors, including the amount and properties of the virus to which a woman is exposed, individual host genetic factors, as well as multiple modifiable biological cofactors present at the time of exposure. In this program project grant, we proposed to examine the mechanisms by which biological cofactors increase susceptibility of women to HIV-1. The proposed studies will include women in multiple high-risk groups: sex workers, pregnant/postpartum women and women in HIV-1 discordant relationships. Specifically, we will examine the role of: 1) pregnancy and the postpartum effects (Project 1); 2) vaginal flora and specific bacterial infections (Project 2); 3) innate immune factors, including as they relate to hormones and genital tract infections (Project 3); and 4) mucosal HIV-1 antibodies induced in response to repeated HIV-1 exposure (Project 4) on susceptibility to HIV-1 infection in women. For these studies, we will take advantage of cohort studies, collaborative partnerships and infrastructure developed by our research team, the Seattle/Kenya collaborative research group, over the past ~ 15 years. Our research group, which includes virologists, immunologists, bacteriologists, epidemiologist, statisticians and clinical scientists, has a long and productive history of collaboration, and is known for its focus on translational research in women. Here we will build on that foundation to conduct multiple collaborative projects within this program grant. We expect that each of these projects will draw on the expertise of others in the team, and in some cases, will include parallel studies that address synergistic biological questions in the same populations. RELEVANCE: Collectively, these studies are designed to provide a comprehensive picture of the biological factors that contribute to increased risk of HIV-1 infection in women. Such studies will be critical for understanding unique aspects of HIV-1 transmission in women, and for finding approaches to decrease transmission that consider issues that are relevant to women. PROJECT 1: Incidence, Timing and Cofactors that Contribute to the High Risk of HIV-1 Infection in Peri and Post Partum Women (Project Leader: John-Stewart, G) PROJECT 1 DESCRIPTION (provided by applicant): Pregnancy and the postpartum period have been associated with increased risk of HIV-1. In Africa, where both HIV-1 seroprevalence and fertility rates are high, the pregnancy/postpartum period may be one in which HIV-1 acquisition contributes substantially to HIV-1 in women. Pregnancy, delivery, and the postpartum period are associated with hormonal, genital mucosal, and genital flora changes that could predispose to acquisition of HIV-1. Project 1 will enroll 2,000 HIV-1 uninfected women identified during pregnancy and followed to 9 months postpartum to determine risk and cofactors of HIV-1 incidence. Women who acquire HIV-1 will be compared to women who do not in order to determine the role of genital coinfections, ulcers, delivery practice, lactation, partner characteristics, vaginal flora changes, HSV-2, genital innate immune factors, and systemic immune activation on HIV-1 transmission. In addition, changes in cofactors over the course of pregnancy and postpartum may influence susceptibility to HIV-1. Thus, in a subset of 100 women we will compare genital innate immune factors, and systemic cellular immune activation longitudinally during pregnancy, early postpartum, and later postpartum. These comparisons will provide opportunity to determine patterns of change in the genital tract during this dynamic period of change in women. In quantifying co-infections, mucosal innate immune responses, and systemic cellular immune activation, we will be able to determine interactions between these important determinants in 3 different but inter-related areas (co-infection, mucosal innate milieu, systemic cellular) that affect susceptibility to HIV-1. Project 1 will have scientific links to Project 2 (effects of changes in vaginal flora on HIV-1 transmission), Project 3 (which will involve cytokine profile analyses within women from the Project 1 cohort) and Project 4 (adaptive humoral mucosal responses in HIV-1 uninfected women with HIV-1 infected partners). Because of the complexity of the female genital ecosystem and the variety of factors that could alter susceptibility to HIV-1, each Project will focus on complementary factors that may modify transmission of HIV-1. Together, these will lead to a multi-faceted evaluation of transmission in women in different important groups of women at risk for HIV-1, (pregnant/postpartum, female sex workers, and discordant couples), that conceivably share some cofactors for HIV-1 susceptibility but are distinct in others. RELEVANCE: Women may be at increased risk for HIV-1 during and after pregnancy. This study will determine the risk of and cofactors for acquiring HIV-1 during and after pregnancy in a cohort of women in Kenya. Factors including genital infections and immunity will be assessed. These data will be directly relevant to developing appropriate strategies to protect women from HIV-1 during and after pregnancy.