Role of Virus Recombination in Multiple Drug Resisitance

病毒重组在多重耐药性中的作用

• 批准号: 6693386
• 负责人: FENG GAO
• 金额: $ 33.88万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-01-01 至 2007-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6693386
• 关键词: Role; Virus; Recombination; Multiple; Drug

DESCRIPTION (provided by applicant): 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 recombination 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 sequencing 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.

描述（由申请人提供）：人类免疫缺陷病毒（HIV）感染位列全球前五位死亡原因之一，对公共健康构成重大威胁。通过使用抗逆转录病毒药物组合（高效抗逆转录病毒疗法），HAART 可有效显着降低 HIV 相关死亡率和发病率。然而，近一半的HIV感染者HAART治疗仍然失败。尽管对这些患者的病毒基因组进行的遗传分析显示pol基因存在多重耐药突变，但出现耐药性的分子机制尚不清楚。因此，为了更有效地控制HIV感染，阐明多重耐药机制非常重要。在这里，我们建议研究HAART期间病毒重组在多重耐药性产生中的作用。我们建立了一个前瞻性临床队列，并开发了分析感染个体内重组病毒基因组的方法。该提案的具体目标是：(i) 我们将在 HAART 治疗前对每位患者的多个克隆进行测序，从而对基线病毒群体进行基因表征，并确定其对治疗失败的预测值。 (ii)为了确定重组在多重耐药性产生中的作用，我们将耐药病毒群体与基线病毒群体进行比较，并鉴定来自HAART失败的患者的病毒群体的重组基因组和重组指数增加。 (iii)获取连续HAART方案中每次治疗失败前后的病毒种群，分析病毒种群的动态变化，以确定反复耐药的机制和耐药病毒的适应性。了解HAART期间病毒种群的变化、耐药机制和病毒适应性将有助于开发更有效的抗逆转录病毒药物、更好的治疗方案和准确预测治疗效果。从这项研究中获得的知识可以广泛应用于理解病毒逃避免疫监视和其他选择性力量的机制。