HIV mutagenesis and evolution

HIV突变和进化

• 批准号: 8102256
• 负责人: Louis M Mansky
• 金额: $ 4.94万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8102256
• 关键词: Acquired Immunodeficiency Syndrome; Antiretroviral drug resistance; Cell Line; Cells; Cytosine; DNA; DNA biosynthesis; Deamination; Development; Disease Progression; Drug resistance; Evolution; Genetic Recombination; Genetic Variation; HIV; HIV-1; Health; Human; Immune system; Induced Mutation; Investigation; Knowledge; Mutagenesis; Mutate; Mutation; Mutation Analysis; NNRTI-resistance; Nucleosides; Play; Population; Proteins; Proviruses; RNA-Directed DNA Polymerase; Reagent; Role; Shapes; System; Testing; Vaccines; Variant; Viral; Viral Pathogenesis; Virus; drug resistant virus; fitness; improved; novel; prophylactic; public health relevance; research study; transition mutation; vaccine development; vector; viral DNA

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.

描述（由申请方提供）：在人类免疫缺陷病毒1型（HIV-1）人群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和有效疫苗开发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驱动着病毒的进化。繁殖也被认为在形成种群多样性方面发挥着重要作用。HIV-1的复制和进化被认为是免疫系统逐渐崩溃的原因，也是疾病进展为艾滋病的机制。尽管HIV-1变异对治疗和病毒发病机制至关重要，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APOBEC 3蛋白是否会影响HIV-1变异。目前的建议将探索三条调查路线。首先，我们建议研究HIV-1突变率和病毒适应性之间的相互作用。虽然已经进行了研究来分析每一个，但迄今为止还没有研究来分析它们之间的关系。我们建议通过分析一小组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，我们发现在存在和不存在APOBEC 3蛋白的情况下，与野生型病毒相比，这些病毒的突变率增加或减少。其次，我们建议探讨适应性突变如何改变HIV-1的突变率在抗逆转录病毒药物耐药性的选择。我们将研究是否适应性选择的改善病毒的健身与选择具有野生型突变率的病毒。我们还将评估APOBEC 3蛋白是否塑造HIV-1变异。最后，我们将研究HIV-1前病毒中G到A转换突变的起源，以确定APOBEC 3蛋白诱导的频繁但亚致死的胞嘧啶脱氨基作用是否会影响HIV-1变异。HIV-1人群的高度变异导致了耐药性的出现，并使疫苗开发的努力受挫。对HIV-1如何突变和进化的基础研究将增强我们对病毒诱变的理解，这可能间接有助于改善人类健康。