Impact of HIV-1 Fitness on Disease Progression

描述（由申请人提供）：HIV-1适应度是一个复杂的参数，由病毒对给定环境的适应性定义。在过去的四年里，我们研究了HIV-1在各种原代人类细胞中的离体适应性，并探索了HIV-1在人类流行病中与疾病进展以及病毒的全球和时间进化的可能关系。在本研究中，我们将重点关注在A、C和D亚型感染患者的疾病自然史期间和离散传播事件后复制HIV-1适应度的变化。在过去的三年中，我们分析了超过266名津巴布韦和乌干达妇女的样本，这些妇女在急性感染三个月内招募，并在此后每三个月跟踪她们的进展。这个队列也提供了一个很好的机会来比较HIV-1亚型对感染和随后的疾病结局的影响。在这项研究之前，我们发表了相当详尽的比较HIV类型（1或2）、组（M和O）、亚型（a到F）和重组形式的适应性，并发现离体HIV复制适应性的顺序为：HIV-1组M（亚型A， B， D， F, CRF01_AE, CRF02_AG, CRF012_BF） >亚型C > HIV-2“HIV-1组O.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种观察结果是否相关，以及C亚型是否代表一种减毒的HIV-1形式。这些假设将在以下具体目标中进行检验。目的1：建立基于酵母的环境病毒快速克隆系统，制备嵌合环境病毒。为了进一步研究体外HIV-1适应度是否映射到env基因，并由HIV-1进入宿主细胞的过程控制。特异性目的2：探讨急性/早期感染时HIV-1适应度/多样性之间的关系特异性目的3：研究疾病进展过程中病毒适应度、遗传多样性和其他临床相关因素的变化。将更改关联到子类型。

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.