Role of Virus Recombination in Multiple Drug Resisitance

人类免疫缺陷病毒(HIV)感染是全球前五大死亡原因之一 并对公众健康构成重大威胁。通过使用抗逆转录病毒药物组合(高活性 抗逆转录病毒疗法)，HAART在显著降低艾滋病毒相关死亡率和 发病率。然而，近一半的艾滋病毒感染患者仍然未能通过HAART。尽管遗传分析表明 来自这些患者的病毒基因组显示Poll基因的多重耐药突变，分子 耐药性产生的机制尚不清楚。因此，重要的是要划定 研究多重耐药机制，以便更有效地控制艾滋病毒感染。在这里，我们 建议研究病毒联合在HAART多药耐药形成中的作用。我们 已经建立了一个预期的临床队列，并开发了分析重组病毒基因组的方法 在一个受感染的人体内。这项建议的具体目标是：(I)我们将从基因上描述 基线病毒种群，并通过对多个序列的检测来确定它们对治疗失败的预测值 HAART治疗前每个患者的克隆。(二)确定重组在世代中的作用 对于多重耐药性，我们将把耐药病毒种群与基线病毒进行比较 重组基因组的鉴定和重组指数的增加 未通过HAART的患者。(Iii)我们将在每次治疗失败之前和之后获取病毒种群 连续HAART机制并分析病毒种群的动态变化以确定机制 反复耐药和耐药病毒的适合性。了解病毒种群的变化， HAART期间的耐药机制和病毒适合性将使更多的 有效的抗逆转录病毒药物，更好的治疗方案和准确的治疗效果预测。 本研究所获得的知识可广泛应用于了解病毒的致病机制。 逃避免疫监视和其他选择性力量。

Human immunodeficiency virus (HIV) infection ranks among the top five causes of death globally and presents a major threat to public health. By using antiretroviral drug combination (Highly Active Antiretroviral Therapy), HAART has been effective in dramatically reducing HIV-related mortality and morbidity. However, nearly half of HIV-infected patients still fail HAART. Although genetic analyses of viral genomes from these patients show multiple-drug resistance mutations in the pol gene, the molecular mechanisms for the emergence of drug-resistance are not yet known. Therefore, it is important to delineate the mechanisms for multiple-drag resistance in order to more efficiently control HIV infection. Here, we propose to study the role of viral rccombination in generation of multiple-drug resistance during HAART. We have established a prospective clinical cohort and developed methods to analyze recombinant viral genomes within an infected individual. Specific aims of this proposal are: (i) We will genetically characterize the baseline viral population and determine their predictive values for treatment failure by scquencing multiple clones from each patient before HAART treatment. (ii) To determine the role of recombination in generation of multiple-drug resistance, we will compare the drug-resistant viral population with the baseline viral population and identify recombinant genomes and recombinant index increase of the viral population from patients who fail HAART. (iii) We will obtain viral populations before and after each treatment failure in the consecutive HAART regimes and analyze the dynamic changes of viral populations to determine mechanisms of repeated drug-resistance and fitness of drug-resistance viruses. Understanding the viral population changes, drug-resistance mechanisms and viral fitness during HAART will allow for the development of more effective antiretroviral agents, better treatment regimens and accurate prediction of treatment efficacy. Knowledge obtained from this study can be broadly applied toward understanding mechanisms of viral escape from immune surveillance and other selective forces.