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.

具有抗药性的艾滋病毒-1的传播对公共卫生以及 1例HIV-1感染者的治疗和预后。HIV-1感染的治疗选择已经演变 在过去的10年里，许多新感染的患者只需服用2片就可以得到治疗 每日一次，短期和长期毒性均可接受。然而，对于许多人来说，简化了 由于感染了具有抗药性的HIV-1，方案不是一个选择。此外，与抗药性不同 停止治疗的慢性感染者中的病毒，传播的耐药病毒持续存在 在新感染的宿主多年没有治疗的情况下，增加了传播到 易感宿主。事实上，对一类、两类甚至三类耐药病毒的传播增加 在过去的十年里已经被记录在案。这项建议的目标有三个：1. 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.了解耐药病毒的传播潜力 RT、PR和整合酶抑制剂等新药；3.了解MDR病毒的作用机制 补偿RT和PR的突变，这些突变赋予高水平的抵抗力，但仍允许传播。至 为了达到这些目标，我们将继续识别新的HIV-1感染者，并使用聚合酶链式反应技术 对HIV-1基因组的相关部分进行测序。那些含有抗药性赋予氨基的病毒 酸替代将测试对特定试剂的表型抗性。使用具有传染性的分子 从一组传播的MDR HIV-1病毒构建的克隆，我们将产生抗药性的病毒 整合酶抑制剂通过体外连续传代进行深入表征，其基本假设是 具有传播潜力的病毒必须保持与野生型接近的复制动力学 病毒。最后，将使用具有感染性的分子克隆来构建嵌合病毒以了解病毒 MDR病毒补偿预测的适应度损失从而维持复制的决定因素 能力、传播性和致病性。