Virologic Correlates of Heterosexual Transmission

描述(申请人提供)：尽管在了解HIV-1进入细胞的机制方面取得了实质性进展，但对病毒在体内传播的过程知之甚少。病毒包膜蛋白的什么结构和功能特性将传播的病毒与其他变种区分开来，并促进跨粘膜表面的传播？在这项应用中，我们建议从遗传学和生物学上表征在赞比亚一组独特的不和谐夫妇中，在传播事件发生后立即从捐赠者和接受者中分离出的HIV-1病毒种群。这些研究将提供一个独特的机会，利用来自代表全球主要HIV-1亚型(C)的大型、特征良好的不和谐夫妇队列的样本，研究生物相关病毒包膜基因中gp120可变区所指定的异性传播的病毒学决定因素。我们的假设是，我们观察到的极端遗传瓶颈似乎选择了具有更紧密、中和敏感包膜糖蛋白的病毒，选择了一种具有独特生物学特性的病毒，这种病毒具有传播和建立感染的独特优势。一致阳性夫妇的伴侣，特别是两人都感染不同病毒的夫妇，重复感染和随后的病毒重组的风险很高。我们假设，双重感染的风险将取决于病毒的多样性，将因一方的急性感染而增强，将反映对即将到来的病毒的免疫防御能力，对这些事件的研究将了解对自然感染的免疫力所提供的保护的广度。对于这些研究，我们将前瞻性地跟踪卢旺达和赞比亚的两对夫妇的伴侣，在那里我们已经记录了血清阴性伴侣被一种与他们的配偶无关的病毒感染，并监测重叠感染。具体来说，我们将：1.确定新传播的C亚型变异株的哪些生物学特性可以促进在新宿主中建立感染，并将这些特性与这些分离株所特有的Env结构特征相关联；2.确定C亚型感染的供者伴侣的生殖器间隔是否存在遗传瓶颈，或者是否在受体的生殖器间隔内存在传播病毒种群的生物限制；以及3.确定急性/早期感染后HIV重叠感染的频率、动力学以及在双方中的病毒学和免疫学分支。 拟议的研究结果旨在描述新感染的艾滋病毒-1的生物学特性、在急性感染者中观察到的遗传瓶颈的来源以及艾滋病毒-1重叠感染的细节和后果，这些研究结果将增强我们对异性传播过程的理解，并将产生对设计和测试全球有效的候选疫苗至关重要的新信息。

DESCRIPTION (provided by applicant): Although substantial progress has been made on understanding the mechanism of HIV-1 entry into cells, much less is known about the process of virus transmission in vivo. What structural and functional properties of the viral Env protein differentiate the transmitted virus from other variants and facilitate transmission across mucosal surfaces? In this application, we propose to characterize genetically and biologically HIV-1 virus populations isolated from both the donor and recipient immediately following a transmission event in a unique cohort of discordant couples in Zambia. These studies will provide a unique opportunity to investigate the virologic determinants of heterosexual transmission specified by the variable regions of gp120 in biologically relevant viral envelope genes using samples from a large, well-characterized discordant couple cohort that represents the predominant subtype (C) of HIV-1 worldwide. Our hypothesis is that the extreme genetic bottleneck that we have observed, which appears to select for viruses with more compact, neutralization sensitive envelope glycoproteins selects for a virus, which has biological properties that confer unique advantages for transmission and establishment of infection. Partners in concordantly positive couples, particularly those where both are infected by different viruses, are at high risk for superinfection and subsequent virus recombination. We hypothesize that risk of superinfection will depend on virus diversity, will be enhanced by acute infection in one partner, will reflect an inability to immunologically defend against the incoming virus, and that studies of these events will inform on the breadth of protection conferred by immunity to natural infection. For these studies we will follow prospectively, in both Rwanda and Zambia, both partners of couples where we have documented infection of the seronegative partner by a genetically unrelated virus from that in their spouse and monitor for superinfection. Specifically we will: 1. Determine which biological properties of subtype C newly transmitted variants could facilitate establishment of infection in a new host and correlate these with structural features of Env that characterize these isolates, 2. Determine whether a genetic bottleneck occurs in the genital compartment of subtype C infected donor partners or if there is a biological restriction of the transmitted virus population in the genital compartment of the recipients, and 3. Determine the frequency, kinetics and the virologic and immunologic ramifications of HIV superinfection in both partners following acute/early infection. The results of the proposed studies, which are aimed at characterizing the biological properties of newly infecting HIV-1, the origin of the genetic bottleneck observed in acutely infected individuals, and the details and consequences of HIV-1 superinfection, will enhance our understanding of the heterosexual transmission process and will yield novel information that is critical to the design and testing of globally effective vaccine candidates.