HIV mutagenesis and evolution

描述（由申请人提供）：人类免疫缺陷病毒 1 型 (HIV-1) 群体中发现的高水平遗传变异对于抗逆转录病毒药物耐药性的出现以及有效疫苗开发过程中遇到的挑战至关重要。病毒的高突变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着重要作用。 HIV-1复制和进化被认为是导致免疫系统逐渐崩溃的原因，也是疾病进展为艾滋病的机制。尽管 HIV-1 变异对于治疗和病毒发病机制具有根本重要性，但仍有许多基本概念尚未探索或了解甚少。一个重要的概念是 APOBEC3 蛋白是否会影响 HIV-1 变异。目前的提案将探讨 3 条调查路线。首先，我们建议检查 HIV-1 突变率和病毒适应性之间的相互作用。尽管已经进行了研究来分析每一项，但迄今为止还没有进行任何研究来分析它们之间的关系。我们建议通过分析一小群核苷和非核苷逆转录酶抑制剂抗性病毒来研究 HIV-1 复制的这些方面，我们发现这些病毒与 wt 病毒相比，在存在和不存在 APOBEC3 蛋白的情况下突变率增加或减少。其次，我们建议探索适应性突变如何在抗逆转录病毒耐药性选择过程中改变HIV-1突变率。我们将研究改进的病毒适应性的适应性选择是否与具有wt突变率的病毒的选择相一致。我们还将评估 APOBEC3 蛋白是否影响 HIV-1 变异。最后，我们将研究 HIV-1 原病毒中 G 到 A 转变突变的起源，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。公共卫生相关性 HIV-1 群体的高度变异导致了耐药性的出现，并阻碍了疫苗开发的努力。 HIV-1如何突变和进化的基础研究将增强我们对病毒突变的理解，从而间接帮助改善人类健康。

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.