Impact of HIV-1 Fitness on Disease Progression

描述（由申请人提供）：HIV-1适应性是由病毒对给定环境的适应性定义的复杂参数。在过去的四年中，我们研究了HIV-1在各种原代人类细胞中的体外适应性，并探索了与疾病进展以及病毒在人类流行病中的全球和时间演变的可能关系。在本提案中，我们将重点关注在疾病的自然史中，以及在A、C和D亚型感染患者中发生离散传播事件后，复制HIV-1适应性的变化。在过去的三年里，我们分析了266名津巴布韦和乌干达妇女在急性感染后三个月内招募的样本，并在此后每三个月跟踪其进展。该队列还提供了一个很好的机会来比较HIV-1亚型对感染和随后疾病结局的影响。作为这项研究的先导，我们已经发表了关于HIV类型（1或2），组（M和O），亚型（A至F），和重组形式，并发现离体HIV复制适合度的顺序为：HIV-1 M组（亚型A、B、D、F、CRF01_AE、CRF02_AG、CRF012_BF）> C亚型> HIV-2“HIV-1 O组。基于初步数据显示C亚型感染的疾病进展较慢，并且C亚型病毒本质上不太适合，我们的研究将解决这两个观察结果是否相关以及C亚型是否代表减毒的HIV-1形式。这些假设将在以下具体目标中得到检验。具体目标1：建立一种基于酵母的快速env克隆系统，生产嵌合env病毒。为了进一步检查离体HIV-1适应性是否映射到env基因，并受HIV-1进入宿主细胞过程的控制。具体目标2：探索急性/早期感染时HIV-1适应性/多样性之间的关系具体目标3：检查疾病进展期间病毒适应性、遗传多样性和其他临床相关性的变化。将更改与子类型关联。

DESCRIPTION (provided by applicant): HIV-1 fitness is a complex parameter defined by the adaptability of the virus to a given environment. Over the past four years we have studied the ex vivo fitness of HIV-1 in various primary human cells and have explored possible relationships with disease progression as well as global and temporal evolution of the virus in the human epidemic. In this proposal we will focus on changes in replicative HIV-1 fitness during the natural history of disease and following discrete transmission events in subtype A, C, and D infected patients. Over the past three years, we have analyzed samples from over 266 Zimbabwean and Ugandan women recruited within three months of acute infections and have followed their progression every three months thereafter. This cohort also provides an excellent opportunity to compare the affects of HIV-1 subtype on infection and subsequent disease outcomes. As a lead up to this study, we have published fairly exhaustive comparisons on the fitness of HIV types (1 or 2), groups (M and O), subtype (A through F), and recombinant forms and found the order of ex vivo HIV replicative fitness to be: HIV-1 group M (subtypes A, B, D, F, CRF01_AE, CRF02_AG, CRF012_BF) > subtype C > HIV-2 " HIV-1 group O. Based on preliminary data that shows slower disease progression in subtype C infections and that subtype C virus is intrinsically less fit, our study will address if these two observations are linked and if subtype C represents an attenuated HIV-1 form. These hypotheses will be tested in the following specific aims. Specific aim 1: To establish a rapid yeast-based env cloning system to produce chimeric env viruses. To further examine if ex vivo HIV-1 fitness maps to the env gene and is controlled by the HIV-1 entry process into host cells. Specific aim 2: To explore the relationships between HIV-1 fitness/diversity at acute/early infection Specific aim 3: To examine changes in viral fitness, genetic diversity, and other clinical correlates during disease progression. To relate changes to subtype.