Mechanisms of HIV-1 Variation

描述(由申请人提供)：在人类免疫缺陷病毒1型(HIV-1)人群中发现的高水平基因变异对于抗逆转录病毒耐药性的出现和在开发有效的预防性或预防性疫苗方面遇到的挑战至关重要。病毒的高变异率和感染细胞的高周转率都推动了病毒的进化。重组也被认为在塑造种群多样性方面发挥了重要作用。HIV-1的复制和进化被认为是免疫系统逐渐崩溃的原因，也是疾病发展为艾滋病的机制。尽管HIV-1变异对治疗和病毒发病机制具有根本的重要性，但仍有许多基本概念仍未被探索或了解得很少。在这项提案中，我们寻求资金来继续十多年前开始的研究。目前的提案将探索3条调查路线。首先，我们建议研究HIV-1变异率和病毒适合性之间的相互作用。虽然已经对它们进行了分析，但到目前为止还没有进行过分析它们之间关系的研究。我们建议通过分析一小部分核苷和非核苷逆转录酶抑制剂耐药病毒来研究HIV-1复制的这些方面，我们发现与wt病毒相比，这些病毒的突变率增加或降低。其次，我们建议在抗逆转录病毒耐药性的选择中探索适应性突变如何改变HIV-1变异率。我们将调查改进的病毒适合度的适应性选择是否与具有wt突变率的病毒的选择一致。最后，我们将调查HIV-1前病毒G-A转换突变的来源，以确定是否频繁但亚致死性的胞嘧啶脱氨作用塑造了HIV-1变异。与公共卫生的相关性艾滋病毒-1人群的高水平变异导致了耐药性的出现，并挫败了疫苗开发的努力。对HIV-1如何变异和进化的基本了解应该有助于开发新的治疗方法以及改进现有的治疗方法。

DESCRIPTION (provided by applicant): The high level of genetic variation found in human immunodeficiency virus type 1 (HIV-1) populations is of fundamental importance to the emergence of antiretroviral drug resistance and to the challenges encountered in the development of an effective preventative or prophylactic vaccine. Both the high virus mutation rate and the high turnover rate of infected cells drive virus evolution. Recombination is also thought to play a significant role in shaping population diversity. HIV-1 replication and evolution is thought to be responsible for the gradual breakdown of the immune system and is the mechanism of disease progression to AIDS. Despite the fundamental importance of HIV-1 variation to therapy and viral pathogenesis, there are many basic concepts that remain unexplored or poorly understood. In this proposal, we seek funding to continue studies began over a decade ago. The current proposal will explore 3 lines of investigation. First, we propose to examine the interplay between the HIV-1 mutation rate and viral fitness. Although studies have been performed to analyze each, no studies have been performed to date to analyze their relationship to one another. We propose to investigate these aspects of HIV-1 replication by analysis of a small group of nucleoside and non-nucleoside reverse transcriptase inhibitor-resistant viruses that we have discovered have increased or decreased mutation rates compared to wt virus. Second, we propose to explore how adaptive mutations can alter the HIV-1 mutation rate during the selection of antiretroviral drug resistance. We will investigate whether the adaptive selection of improved viral fitness coincides with the selection for viruses that possess a wt mutation rate. Finally, we will investigate the origins of G-to-A transition mutations in HIV-1 proviruses to determine if frequent, yet sublethal cytosine deamination shapes HIV-1 variation. PUBLIC HEALTH RELEVANCE The high level variation in HIV-1 populations has led to the emergence of drug resistance and has frustrated efforts in vaccine development. A basic understanding of how HIV-1 mutates and evolves should aid in the development of new therapeutic approaches as well as improving existing ones.