Mechanisms of Antibody Interception of Virus Following SHIV Challenge

艾滋病毒生命周期中对免疫干预最脆弱的是非常早期的事件 在粘膜暴露于病毒后。特别是，非人灵长类动物的研究表明，抗体可以流产或 在这一早期阶段减轻感染，但对如何以及在哪里实现这一点知之甚少。我们 假设抗体保护涉及抗体、病毒、靶细胞和宿主的复杂相互作用 免疫细胞。我们进一步假设抗体可能参与早期感染的不同阶段。 包括最早的信号事件，以及抗体的存在可能对 对病毒的细胞和先天免疫反应。我们建议通过以下方式来研究这些假设 在广泛存在和不存在的情况下，对SIV挑战猕猴的详细横断面研究 中和抗体B12，我们在HIV的SIV/猕猴模型中进行了广泛的研究 感染。我们建议进行一系列的尸检研究，结合组织学， 通过本计划提供的病毒学、免疫学和系统生物学方法，以揭示 抗体截留病毒的详细情况。 该项目的具体目标是：1.确定SHIV162P3感染在中国的传播过程 大剂量阴道刺激后的猕猴2.确定相关的解剖位置和时间 在SIV挑战3之后完全阻断病毒的抗体。为了确定解剖位置， SIV攻击后不完全抗体截留病毒的时机和后遗症 4.确定抗体效应器功能在截留SIV中的作用。 这个项目的意义在于，它将提供一个比这里更清楚的关于抗体是如何 预防艾滋病毒感染。这对艾滋病毒疫苗的设计很重要，因为它会影响我们对疫苗的重视 具体的免疫策略，例如全身免疫与粘膜免疫，以及 我们试图诱导的抗体。

The greatest vulnerabilities in the life cycle of HIV to immunological intervention are the very early events following mucosal exposure to virus. In particular, nonhuman primate studies suggest antibody can abort or attenuate infection during this early stage but very little is known about how and where this is achieved. We hypothesize that antibody protection involves the complex interplay of antibody, virus, target cells and host immune cells. We further hypothesize that antibody may be involved at different stages of early infection including the earliest signaling events and that the presence of antibody may have profound effects on cellular and innate immune responses to the virus. We propose to investigate these hypotheses through detailed cross-sectional studies of SHIV-challenged macaques in the presence and absence of the broadly neutralizing antibody b12, which we have investigated extensively in the SHIV/macaque model of HIV infection. We propose to carry out serial necropsy studies combined with an arsenal of histological, virological, immunological, and systems biological approaches provided through this Program to reveal the details of antibody interception of virus. The specific aims of the project are: 1 .To determine the course of dissemination of SHIV162P3 infection in macaques following high-dose vaginal challenge 2. To determine the anatomic sites and timing associated with complete antibody interception of the virus following SHIV challenge 3. To determine the anatomic sites, timing and sequelae associated with incomplete antibody interception of the virus following SHIV challenge 4. To determine the role of antibody effector function in interception of SHIV. The significance of this project is that it will provide a much clearer picture than hereto of how antibody prevents HIV infection. This is important for HIV vaccine design as it will influence the emphasis we place on particular immunization strategies, e.g. systemic versus mucosal immunization, and the characteristics of antibody that we try to induce.