Reverse Transcriptase Multi-Class Drug Resistance and Rilpivirine Susceptibility in Diverse HIV-1 Subtypes

不同 HIV-1 亚型中的逆转录酶多类耐药性和利匹韦林敏感性

• 批准号: 9140626
• 负责人: Stefan G Sarafianos
• 金额: $ 37.37万
• 依托单位: UNIVERSITY OF MISSOURI-COLUMBIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9140626
• 关键词: Accounting; Address; Affect; Affinity; Anti-HIV Agents; Biochemical; Clinical Data; Clinical Research; Complex; Development; Drug Design; Drug resistance; Ethiopia; Generations; Goals; HIV; HIV-1; HIV-1 drug resistance; Highly Active Antiretroviral Therapy; Infection; Molecular; Mutation; Nevirapine; Patients; Pattern; Pharmaceutical Preparations; Phenotype; Predisposition; Prevalence; RNA-Directed DNA Polymerase; Resistance; Reverse Transcriptase Inhibitors; Reverse Transcription; Ribonuclease H; Sampling; Structure; Testing; Time; Vertebral column; Virus; base; clinical sequencing; clinically relevant; cohort; efavirenz; effective therapy; experience; fitness; insight; low and middle-income countries; multidrug resistance inhibition therapy; non-nucleoside reverse transcriptase inhibitors; novel therapeutics; pressure; public health relevance; resistance mechanism; resistance mutation; treatment strategy

 DESCRIPTION (provided by applicant): Reverse transcriptase (RT) inhibitors comprise two different classes, nucleos(t)ide RT inhibitors (NRTIs) and nonnucleoside RTIs (NNRTIs), which act by entirely different mechanisms. However, their extensive use has led to the emergence of drug resistance mutations that may affect use of new RTIs. As new drugs like rilpivirine (RPV) become increasingly available to patients infected with HIV strains of subtypes other than B (HIV-nonB), it is important to understand how RPV resistance-associated mutations determined in HIV-1B samples (RAMB) affect susceptibility patterns in both drug-naïve or -treated HIV-nonB patients. This proposal aims to understand differences in drug resistance among different HIV subtypes (HIV-1B vs. HIV-nonB). Recent collaborative clinical data (with A. Sönnerborg and U. Neogi) identified RAMBs in treatment-naïve (6- 11%, depending on subtype) and nevirapine (NVP) or efavirenz (EFV)-based therapy-failed patients (22-34%, depending on subtype). Hence, it is hypothesized that patients who failed NVP/EFV-based therapy are more likely to fail RPV-based therapy. Moreover, patients treated with TDF/FTC/RPV failed therapy through RPV- associated mutations in ~9% of HIV-1B patients compared to ~25% of HIV-nonB patients. Preliminary analysis of RT sequences from clinical cohorts of HIV-1B and HIV-nonB patients that are treatment-naïve or -failed (NVP/EFV-based) showed an increase in prevalence of predicted RAMBs. Hence, it is also hypothesized that RPV resistance emerges through different mechanisms in various subtypes. Furthermore, until recently, it was thought resistance to one class of RTIs was unrelated to the other. However, RT connection subdomain mutations (CSMs), namely N348I in HIV-1B, have been identified, which give multi-class drug resistance (MCDR) to both NRTIs and NNRTIs. It is hypothesized that CSMs affect MCDR differently in various HIV subtypes. The following aims will be addressed: SA 1. Determine how the presence of CSMs and RAMBs affect RPV susceptibility of HIV-1B and -nonB SA 2. Virologically characterize the contribution of CSMs and RAMBs on fitness and multi-class resistance in multiple subtypes SA 3. Unravel biochemical and structural mechanisms of the MCDR phenotype in HIV-1B and HIV-nonB The goal of this application is to elucidate the molecular mechanisms underlying MCDR and how CSMs may impact the RPV susceptibility of different HIV subtypes, providing important insights into the feasibility of RPV as first-line therapy in HIV 1B and HIV-nonB patients.

 描述（由申请人提供）：逆转录酶（RT）抑制剂包括两种不同的类别：核苷（酸）RT抑制剂（NRTI）和非核苷RTI（NNRTI），它们通过完全不同的机制发挥作用。然而，它们的广泛使用导致了耐药突变的出现，可能会影响新的 RTI 的使用。随着利匹韦林 (RPV) 等新药越来越多地可供感染除 B 以外亚型 (HIV-nonB) 的 HIV 毒株的患者使用，了解 HIV-1B 样本 (RAMB) 中确定的 RPV 耐药相关突变如何影响未接受过药物治疗或接受过药物治疗的 HIV-nonB 患者的易感模式非常重要。该提案旨在了解不同 HIV 亚型（HIV-1B 与 HIV-nonB）之间的耐药性差异。最近的合作临床数据（与 A. Sönnerborg 和 U. Neogi）在初治患者（6-11%，取决于亚型）和奈韦拉平（NVP）或依非韦伦（EFV）治疗失败的患者（22-34%，取决于亚型）中发现了 RAMB。因此，假设基于 NVP/EFV 的治疗失败的患者更有可能失败于基于 RPV 的治疗。此外，接受 TDF/FTC/RPV 治疗的患者由于 RPV 相关突变导致治疗失败，其中约 9% 的 HIV-1B 患者与约 25% 的 HIV-nonB 患者相比。对未接受治疗或治疗失败（基于 NVP/EFV）的 HIV-1B 和 HIV-nonB 患者临床队列的 RT 序列的初步分析显示，预测的 RAMB 患病率有所增加。因此，还假设不同亚型中通过不同机制出现 RPV 抗性。此外，直到最近，人们还认为对一类 RTI 的耐药性与另一类无关。然而，RT 连接子域突变 (CSM)，即 HIV-1B 中的 N348I，已被鉴定，该突变使 NRTI 和 NNRTI 产生多类耐药性 (MCDR)。据推测，CSM 在不同的 HIV 亚型中对 MCDR 的影响不同。将实现以下目标： SA 1. 确定 CSM 和 RAMB 的存在如何影响 HIV-1B 和 -nonB 的 RPV 易感性 SA 2. 从病毒学角度表征 CSM 和 RAMB 对多种亚型 SA 的适应性和多类耐药性的贡献 SA 3. 揭示 HIV-1B 和 HIV-nonB 中 MCDR 表型的生化和结构机制 该应用的目标是阐明 MCDR 的分子机制以及 CSM 如何影响不同 HIV 亚型的 RPV 易感性，为 RPV 作为 HIV 一线治疗的可行性提供了重要见解 1B 和非 B 型 HIV 患者。