HIV mutagenesis and evolution

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。一个重要的概念是APOBEC3蛋白是否可以影响HIV-1的变异。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。我们建议通过对一小群核苷和非核苷逆转录酶抑制因子耐药病毒的分析来研究HIV-1复制的这些方面，我们发现在存在和不存在APOBEC3蛋白的情况下，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。我们还将评估APOBEC3蛋白是否会形成HIV-1变异。最后，我们将研究HIV-1前病毒G-A转换突变的来源，以确定APOBEC3蛋白诱导的频繁但亚致死的胞嘧啶脱氨是否会影响HIV-1变异。与公共卫生的相关性艾滋病毒-1人群的高度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础研究将增强我们对病毒突变的理解，这可能间接有助于改善人类健康。

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 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. One important concept is whether the APOBEC3 proteins can impact HIV-1 variation. 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 in the presence and absence of APOBEC3 proteins. 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. We will also assess whether APOBEC3 proteins shape HIV-1 variation. Finally, we will investigate the origins of G-to-A transition mutations in HIV-1 proviruses to determine if frequent, yet sublethal cytosine deamination induced by APOBEC3 proteins impact HIV-1 variation. PUBLIC HEALTH RELEVANCE The high level of variation in HIV-1 populations has led to the emergence of drug resistance and has frustrated efforts in vaccine development. Basic studies of how HIV-1 mutates and evolves will enhance our understanding viral mutagenesis, which could indirectly aid in improving human health.