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

项目摘要/摘要： 艾滋病毒-1向新个体的传播在现有病毒群体上引起了强烈的选择性瓶颈，以及 通常情况下，只有一个或几个非常特殊的病毒变异会确定每个新的感染。只是最近才有 传播/创立者(T/F)HIV-1变种因其独特的性质而受到赞赏。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变种进行的，这些变种不 概述其细胞嗜性、对干扰素和限制性因子的独特抵抗力以及抗原性。 T/F HIV-1变种。至关重要的是，目前用于HIV-1感染和疫苗研究的动物模型是恒河猴 猕猴，不支持T/F HIV-1的复制甚至进入细胞。然而，我们的实验室发现了 第一只猴子，斯皮克斯的猫头鹰猴子，其中一些(但不是所有)个体编码一种广泛的 允许T/F HIV-1变种的全球主要亚型。这很有说服力，因为猫头鹰猴子 已知对HIV-1有最小的限制因素。此外，可以制造具有单点突变的HIV-1 在猫头鹰猴肾细胞中复制，表明猫头鹰猴体内所有必要的细胞辅助因子都是 与该病毒兼容。已知猫头鹰猴子T细胞中有两个限制因素 抑制HIV-1复制、Tetherin和Trim-Cyp。有趣的是，Trim-Cyp阻塞可以通过一个 HIV-1基因组中的突变。此外，我们和其他人已经确定了cd4和Tetherin循环的等位基因。 在猫头鹰猴子种群中，既能阻止HIV-1，又不能阻止HIV-1。因此，原代猫头鹰猴T细胞 我开发的文化和感染系统提供了一个独特的机会来绘制关键的 成功控制T/F HIV-1感染的决定因素。这项提案的目标是证明 宿主基因在T/F HIV-1感染中的重要性这项研究建议的具体目的是：1) 确定四个猫头鹰猴群中循环中的CD4和CCR5等位基因编码的受体是否起作用 全球相关亚型HIV-1env的功能受体，2)了解猫头鹰与猫头鹰之间的相互作用 猴子Tetherin等位基因与T/F HIV-1，以及3)开发猫头鹰嗜猴版本的HIV-1用于研究 T/F HIV-1在原代细胞中的生物学，并最终在动物中。我提供的初步数据表明 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.