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（由适用提供）：逆转录酶（RT）抑制剂包括两个不同类别的核（T）IDE RT抑制剂（NRTIS）和非核苷RTI（NNRTIS），它们通过完全不同的机制起作用。但是，它们的广泛使用导致了可能影响新RTI的使用的耐药性突变的出现。随着诸如Rilpivirine（RPV）之类的新药越来越多于感染了B（HIV-NONB）以外的其他亚型HIV菌株（HIV-NONB）的患者，重要的是要了解如何在HIV-1B样品（RAMB）中确定RPV抗性相关突变（RAMB）如何影响两种药物为吸毒或耐药的HIV-NononB患者。该建议旨在了解不同HIV亚型（HIV-1B与HIV-NONB）之间耐药性差异。最近的合作临床数据（与A.Sönnerborg和U. Neogi）在治疗中（6-11％，取决于亚型）和Nevirapine（NVP）或Efavirenz（EFV）（EFV）基于治疗的治疗患者（22-34％，取决于22-34％，取决于亚型），确定了RAMB。因此，假设基于NVP/EFV的治疗失败的患者更有可能失败基于RPV的治疗。此外，通过RPV相关的突变治疗了约9％的HIV-1B患者，接受了TDF/FTC/RPV治疗的患者，而HIV-NONB患者中有约25％。对接受治疗或fail的HIV-1B和HIV-NONB患者的RT序列的初步分析（基于NVP/EFV）显示出预测的RAMBS的患病率有所增加。因此，还假设RPV耐药性通过各种亚型的不同机制出现。此外，直到最近，人们认为对一类RTI的抵抗力与另一类无关。然而，已经鉴定出RT连接子域突变（CSM），即HIV-1B中的N348i，它给NRTIS和NNRTIS提供了多级耐药性（MCDR）。假设CSM在各种HIV亚型中对MCDR的影响不同。将解决以下目的：SA 1。确定CSM和RAMB的存在如何影响HIV-1B和-NONB SA 2的RPV敏感性。病毒学从病毒学上表征CSM和RAMB对多个子类型中的适应性和多级耐药性的贡献SA 3。 MCDR的基础机制以及CSM如何影响不同HIV亚型的RPV敏感性，从而提供了对RPV作为HIV一线治疗的可行性的重要见解 1B和HIV-NONB患者。