Owl monkeys as a model for exploring novel biology of transmitted/founder HIV-1

项目概要/摘要： HIV-1传播给新的个体会对现有的病毒群体产生强烈的选择性瓶颈， 通常只有一种或几种非常特殊的病毒变体会建立每种新的感染。直到最近， T/F HIV-1变体因其独特的特性而受到赞赏。重要的是，绝大多数 的HIV-1研究是利用实验室适应的或晚期HIV-1变体进行的， 概括了细胞嗜性，对干扰素和限制性因子的独特抗性，以及 T/F HIV-1变异体。至关重要的是，目前用于HIV-1感染和疫苗研究的动物模型，恒河猴， 猕猴不支持T/F HIV-1的复制甚至细胞进入。然而，我们的实验室发现 第一种猴子是斯皮克斯猫头鹰猴，其中一些（但不是全部）个体编码一种CD 4受体， 允许T/F HIV-1变异体的主要全球亚型。这很有说服力因为猫头鹰猴 已知对HIV-1具有最小限制因子。此外，可以制备具有单点突变的HIV-1， 在猫头鹰猴肾细胞中复制，表明猫头鹰猴中所有必需的细胞辅因子都是 与这种病毒兼容。已知猫头鹰猴T细胞中有两种限制因素对T细胞的生长有显着影响 抑制HIV-1复制、Tetherin和TRIM-Cyp。有趣的是，TRIM-Cyp块可以用单个 HIV-1基因组中的突变。此外，我们和其他人已经确定了CD 4和tetherin循环的等位基因， 在猫头鹰猴种群中，既能阻断HIV-1，也不能阻断HIV-1。因此，原始猫头鹰猴T细胞 我开发的培养和感染系统提供了一个独特的机会， 成功控制T/F HIV-1感染的决定因素。本提案的目的是证明 宿主基因型对T/F HIV-1感染的重要性。本研究建议的具体目标是：1） 确定在四个猫头鹰猴群体中，由循环CD 4和CCR 5等位基因编码的受体是否起作用， T/F HIV-1 Env全球相关亚型的功能性受体，2）了解猫头鹰之间的相互作用 猴系链蛋白等位基因和T/F HIV-1，和3）开发一种猫头鹰猴嗜性版本的HIV-1，用于研究 T/F HIV-1生物学在原代细胞中，并最终在动物中。我提出的初步数据表明， 这些研究将扩大我们对T/F HIV-1生物学的理解。

Project Summary/Abstract: HIV-1 transmission to a new individual elicits a strong selective bottleneck on the existing virus population, and typically only one or a few very special viral variants will establish each new infection. Only very recently have transmitted/founder (T/F) HIV-1 variants been appreciated for their unique properties. Importantly, a vast majority of HIV-1 research has been performed utilizing lab-adapted or late-stage HIV-1 variants, which do not recapitulate the cell-tropism, unique resistance to interferon and restriction factors, and antigenic properties of T/F HIV-1 variants. Critically, the current animal model for HIV-1 infection and vaccine research, the rhesus macaque, does not support replication or even cellular entry of T/F HIV-1. However, our lab has discovered the first monkey, the Spix’s owl monkey, in which some (but not all) individuals encode a CD4 receptor that is broadly permissive for major global subtypes of T/F HIV-1 variants. This is quite compelling because owl monkeys are known to have minimal restriction factors against HIV-1. Further, HIV-1 with a single point mutation can be made to replicate in owl monkey kidney cells, indicating that all necessary cellular cofactors in owl monkey are compatible with this virus. There are two restriction factors in owl monkey T cells that are known to significantly inhibit HIV-1 replication, tetherin and TRIM-Cyp. Interestingly, the TRIM-Cyp block can be bypassed with a single mutation in the HIV-1 genome. Further, we and others have identified alleles of both CD4 and tetherin circulating within owl monkey populations that both do and do not block HIV-1. Therefore, the primary owl monkey T cell culture and infection system that I have developed provides a unique opportunity to map critical determinants for successful control of T/F HIV-1 infection. The objectives of this proposal are to demonstrate the importance of host genotype on T/F HIV-1 infection. The specific aims of this research proposal are to: 1) Determine whether receptors encoded by circulating CD4 and CCR5 alleles in four owl monkey colonies act as functional receptors for globally relevant subtypes of T/F HIV-1 Env, 2) Understand the interaction between owl monkey tetherin alleles and T/F HIV-1, and 3) Develop an owl monkey-tropic version of HIV-1 for investigating the T/F HIV-1 biology in primary cells and eventually in animals. I present preliminary data demonstrating that these studies will expand our understanding of T/F HIV-1 biology.