Impact of HIV-1 Fitness on Disease Progression

描述(由申请人提供)：HIV-1适合性是由病毒对给定环境的适应性定义的一个复杂参数。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体外适合性，并探索了与疾病进展以及人类流行病中病毒的全球和时间演变的可能关系。在这项提案中，我们将重点关注在疾病自然病史期间以及在A、C和D亚型感染患者中发生离散传播事件后复制HIV-1适合性的变化。在过去的三年里，我们分析了在急性感染后三个月内招募的266多名津巴布韦和乌干达妇女的样本，并在此之后每三个月跟踪观察她们的进展。这一队列还提供了一个很好的机会来比较艾滋病毒-1亚型对感染和随后的疾病结果的影响。在这项研究之前，我们发表了对HIV类型(1或2)、组(M和O)、亚型(A到F)和重组形式的适合度的相当详尽的比较，并发现体外HIV复制适合度的顺序为：HIV-1组M(亚型A、B、D、F、CRF01_AE、CRF02_AG、CRF012_BF)&GT；亚型C和GT；HIV-2“HIV-1 O组。根据初步数据显示，C亚型感染的疾病进展较慢，C亚型病毒本质上不太适合，我们的研究将讨论这两个观察结果是否有联系，以及C亚型是否代表减弱的HIV-1形式。这些假设将在以下具体目标中得到检验。具体目的1：建立一种基于酵母的包膜病毒快速克隆系统，以生产嵌合包膜病毒。为了进一步检查体外HIV-1适合度是否映射到env基因，并受HIV-1进入宿主细胞的过程控制。具体目标2：探讨HIV-1在急性/早期感染时适应性/多样性之间的关系。具体目标3：检查病毒适应性、遗传多样性和其他临床相关性在疾病进展过程中的变化。若要将更改关联到子类型，请执行以下操作。

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.