Drug Resistance and Pathogenesis in Subtype C HIV-1

C 亚型 HIV-1 的耐药性和发病机制

• 批准号: 6892245
• 负责人: David Allenberg Katzenstein
• 金额: $ 29.61万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6892245
• 关键词: AIDS therapy; HIV infections; antiAIDS agent; antiviral agents; clinical research; drug resistance; human immunodeficiency virus 1; human subject; human therapy evaluation; lamivudine; mother /infant health care; nevirapine; pathologic process; patient oriented research; phenotype; polymerase chain reaction; reverse transcriptase inhibitors; vertical transmission; zidovudine

DESCRIPTION (provided by applicant): AIDS care and treatment initiatives are anticipated to provide antiretroviral (ARV) treatment for 3 million people living with HIV/AIDS (PLWHA) in resource limited countries by 2005, the majority is infected by subtype C HIV-1, a widely dispersed virus responsible for HIV-1 infection in high prevalence populations in Southern Africa, Ethiopia, India and China. Reverse transcriptase inhibitor (RTI) ARV drugs, currently recommended as first-line therapy for HIV infection, are widely used in prevention of mother-to-child transmission (MTCT) as short-course regimens or single dose Nevirapine (SD NVP). Although SD NVP reduces MTCT by approximately 50%, rapid, complex selection of drug resistant virus has been documented in the majority of subtype C infected women and infected infants exposed to SD NVP. While drug resistant virus disappears (as detected by sequencing) from plasma RNA, archival resistant proviral DNA persists is thought to persist, potentially for years following exposure to NVP and other antiretroviral drugs (ARV). ARV therapy is expected to dramatically increase in developing countries, and viral drug resistance evolution will inevitably take place. Viruses from patients exposed to ARV drugs demonstrate phenotypic changes in drug susceptibility and envelope chemokine receptor tropism. Resistance to ARV drugs and the syncytia inducing (SI) phenotype are associated with distinct genotypic mutations in gag-pol and the V-3 loop of the env gene, respectively. These phenotypes are associated with rapid disease progression and mortality in HIV-1. The aim is to study the pathogenesis of subtype C HIV-1 in women and infants after ARV including SD NVP to optimize clinical benefits of ARV treatment and prevention of MTCT.

描述（由申请人提供）：预计到2005年，艾滋病护理和治疗倡议将为资源有限国家的300万艾滋病毒/艾滋病（PLWHA）感染者提供抗逆转录病毒（ARV）治疗，其中大多数感染C亚型HIV-1，这是一种广泛传播的病毒，导致南部非洲、埃塞俄比亚、印度和中国高流行率人群中的HIV-1感染。逆转录酶抑制剂（RTI）抗逆转录病毒药物，目前被推荐为艾滋病毒感染的一线治疗，被广泛用于预防母婴传播（MTCT）作为短期方案或单剂量奈韦拉平（SD NVP）。尽管SD NVP可使MTCT降低约50%，但在大多数暴露于SD NVP的C亚型感染妇女和感染婴儿中已记录了耐药病毒的快速复杂选择。虽然耐药病毒从血浆RNA中消失（如通过测序检测到的），但认为存档的耐药前病毒DNA持续存在，可能在暴露于NVP和其他抗逆转录病毒药物（ARV）后持续多年。预计发展中国家的抗逆转录病毒治疗将大幅增加，病毒耐药性演变将不可避免地发生。来自暴露于抗逆转录病毒药物的患者的病毒表现出药物敏感性和包膜趋化因子受体趋向性的表型变化。对ARV药物的抗性和合胞体诱导（SI）表型分别与gag-pol和env基因V-3环的不同基因型突变相关。这些表型与HIV-1的快速疾病进展和死亡率相关。 目的是研究抗逆转录病毒治疗（包括SD NVP）后妇女和婴儿中C亚型HIV-1的发病机制，以优化抗逆转录病毒治疗和预防母婴传播的临床获益。