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.

抗药性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发展 在过去的10年中，许多新感染的患者可以接受2片服用的治疗 每天都有可接受的短期和长期毒性。但是，对于许多人来说，简化了 由于获得了耐药性HIV-1，因此不能选择治疗方案。此外，与抗药性不同 慢性感染的人停止治疗的病毒，传播抗药性病毒持续存在 在没有治疗的情况下，在新感染的宿主多年中，将传播的风险增加到 敏感的主人。实际上，增加了对一，两个或三类的抗性病毒的传播 在过去的十年中，已经记录了毒品。该提议的目标是三倍。 1 继续监测耐药性传播的流行，不仅关注传统 诸如逆转录酶（RT）和蛋白酶（PR）之类的靶标，但要包括较新的药物靶标，例如病毒 信封和整合酶； 2。了解抗性病毒对抑制剂的传播潜力 RT，PR和小说剂，例如集成酶抑制剂； 3。了解MDR病毒的机制 补偿RT和PR中的突变，从而赋予高水平的电阻并允许传播。到 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 测序HIV-1基因组的相关部分。那些带有耐药性授予氨基的病毒 酸取代将测试对特定药物的表型耐药性。使用传染性分子 由一组传播的MDR HIV-1病毒构成的克隆，我们将产生抗性病毒 通过序列化体外通过的整合酶抑制剂，以深入表征，并具有基本假设 具有传播潜力的病毒必须保留近似野生型的病毒 病毒。最后，将使用传染性分子克隆来构建嵌合病毒以了解病毒 MDR病毒补偿预测的健身损失，从而维持复制的决定因素 容量，透明度和致病性。