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.

说明（由申请人提供）：艾滋病护理和治疗计划预计到 2005 年将为资源有限国家的 300 万艾滋病毒/艾滋病患者 (PLWHA) 提供抗逆转录病毒 (ARV) 治疗，其中大多数感染 C 亚型 HIV-1是一种广泛传播的病毒，导致南部非洲、埃塞俄比亚、印度和中国的高流行人群中 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作为 HIV 感染的一线治疗药物，作为短程治疗方案或单剂量奈韦拉平 (SD NVP) 广泛用于预防母婴传播 (MTCT)。尽管 SD NVP 可使 MTCT 减少约 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，已记录到耐药病毒的快速、复杂的选择。虽然耐药病毒从血浆 RNA 中消失（通过测序检测到），但档案耐药的原病毒 DNA 被认为会持续存在，可能在接触 NVP 和其他抗逆转录病毒药物 (ARV) 后持续数年。抗逆转录病毒治疗在发展中国家预计将大幅增加，病毒耐药性进化将不可避免地发生。来自接触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 药物的耐药性和合胞体诱导 (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 疾病的快速进展和死亡率相关。 目的是研究 ARV（包括 SD NVP）后妇女和婴儿 C 亚型 HIV-1 的发病机制，以优化 ARV 治疗和预防 MTCT 的临床效益。