The Transmission and Fitness of Drug Resistant HIV-1

耐药 HIV-1 的传播和适应性

• 批准号: 7892053
• 负责人: Martin H Markowitz
• 金额: $ 55.57万
• 依托单位: AARON DIAMOND AIDS RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2012-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892053
• 关键词: Acquired Immunodeficiency Syndrome; Amino Acid Substitution; Anti-Retroviral Agents; Antiretroviral drug resistance; Antiretroviral resistance; Attention; Berry; Case Study; Clinical; DNA; Drug Delivery Systems; Drug resistance; Failure; Funding; Genetic; Genome; Growth; HIV; HIV-1; HIV-1 drug resistance; In Vitro; Individual; Infection; Integrase; Integrase Inhibitors; Interruption; Kinetics; Link; Molecular Cloning; Monitor; Multi-Drug Resistance; Mutation; Pathogenicity; Patients; Pattern; Peer Review; Peptide Hydrolases; Pharmaceutical Preparations; Planet Mars; Prevalence; Protease Inhibitor; Public Health; Publications; RNA-Directed DNA Polymerase; Research Personnel; Resistance; Reverse Transcriptase Inhibitors; Risk; Serial Passage; Syphilis; T-20; Technology; Testing; Therapeutic; Toxic effect; Treatment Protocols; United States National Institutes of Health; Vaccination; Variant; Viral; Viremia; Virus; Virus Inhibitors; antiretroviral therapy; base; cost; drug resistant virus; experience; fitness; non-nucleoside reverse transcriptase inhibitors; novel; outcome forecast; parkin gene/protein; pill; programs; transmission process

The transmission of drug resistant HIV-1 represents a significant challenge to the public health as well as the treatment and prognosis of an HIV-1 infected individual. Treatment options for HIV-1 infection have evolved over the past 10 years such that many newly infected patients can be treated with as few as 2 pills taken once daily with acceptable short term and long term toxicities. However for many individuals simplified regimens are not an option due to the acquisition of drug resistant HIV-1. Furthermore, unlike drug resistant viruses in chronically infected individuals who discontinue therapy, transmitted drug resistant viruses persist in the newly infected host for years in the absence of treatment, increasing the risk of transmission to a susceptible host. Indeed, increases in the transmission of viruses resistant to one, two or even three classes of drugs have been documented over the past decade. The objectives of this proposal are three-fold; 1. To continue to monitor for the prevalence of drug resistant transmissions with attention not only to traditional targets such as reverse transcriptase (RT) and protease (Pr), but to include newer drug targets such as viral envelope and integrase; 2. To understand the potential for transmission of viruses resistant to inhibitors of RT, Pr and novels agents such as integrase inhibitors; 3. To understand mechanisms by which MDR viruses compensate for mutations in RT and Pr, that confer high level resistance and yet allow for transmission. To accomplish these aims we will continue to identify newly HIV-1 infected individuals and use PCR technology to sequence relevant portions of the HIV-1 genome. Those viruses harboring drug resistant conferring amino acid substitutions will be tested for phenotypic resistance to specific agents. Using infectious molecular clones constructed from a panel of transmitted MDR HIV-1 viruses we will generate viruses resistant to integrase inhibitors by serial in vitro passage for in depth characterization with the underlying hypothesis that viruses with the potential for transmission must retain replication kinetics approximating that of wild type viruses. Finally, chimeric viruses will be constructed using infectious molecular clones to understand viral determinants by which MDR viruses compensate for predicted fitness loss thereby maintaining replication capacity, transmissiblity and pathogenicity.

耐药性HIV-1的传播是对公共卫生以及 HIV-1感染个体的治疗和预后。HIV-1感染的治疗选择已经演变 在过去的10年中，许多新感染的患者只需服用2片药丸就可以治疗 每日一次，短期和长期毒性可接受。然而，对于许多人来说， 由于获得了耐药性HIV-1，因此治疗方案不是一种选择。此外，与耐药性不同， 在停止治疗的慢性感染个体中，传播的耐药病毒持续存在 在新感染的宿主中，多年没有治疗，增加了传播给 易感宿主事实上，对一种、两种甚至三种抗生素具有抗药性的病毒传播的增加， 在过去的十年里，毒品的使用已经被记录在案。该提案的目标有三个方面：1.到 继续监测耐药传播的流行情况，不仅关注传统的 靶点如逆转录酶（RT）和蛋白酶（Pr），但包括较新的药物靶点，如病毒 包膜和整合酶; 2.为了了解病毒传播的可能性， RT、Pr和新型药物如整合酶抑制剂; 3.为了了解MDR病毒 补偿RT和Pr中的突变，这些突变赋予高水平的耐药性，但仍允许传播。到 为了实现这些目标，我们将继续识别新的HIV-1感染者，并使用PCR技术 对HIV-1基因组的相关部分进行测序。这些病毒具有抗药性， 将测试酸置换对特定试剂的表型抗性。利用传染性分子 从一组经传播的MDR HIV-1病毒构建的克隆，我们将产生对 整合酶抑制剂通过连续体外传代进行深入表征，其基本假设是 具有传播潜力的病毒必须保持接近野生型的复制动力学 病毒最后，嵌合病毒将使用感染性分子克隆构建，以了解病毒 MDR病毒通过其补偿预测的适应性损失从而维持复制的决定因素 能力、传染性和致病性。