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

 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RT抑制剂（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可能影响新RTI使用的耐药突变的出现。随着利匹韦林（RPV）等新药越来越多地用于感染非B亚型HIV毒株（HIV-nonB）的患者，了解HIV-1B样本（RAMB）中确定的RPV耐药相关突变如何影响未经药物治疗或接受过药物治疗的HIV-nonB患者的敏感性模式非常重要。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）或依法韦仑（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基于RPV的治疗失败。此外，接受TDF/FTC/RPV治疗的患者中，约9%的HIV-1B患者因RPV相关突变而治疗失败，而HIV-非B患者约为25%。对来自HIV-1B和HIV-非B患者临床队列的RT序列进行初步分析，这些患者均为未经治疗或治疗失败（基于NVP/EFV），结果显示预测的RAMB患病率增加。因此，还假设RPV抗性在不同亚型中通过不同机制出现。此外，直到最近，人们还认为对一类RTI的耐药性与另一类RTI无关。然而，HIV-1B中的RT连接亚结构域突变（CSM），即N348 I，已被鉴定，其对NRTI和NNRTI产生多类耐药（MCDR）。假设CSM在不同的HIV亚型中对MCDR的影响不同。将讨论以下目标：SA 1。确定CSM和RAMB的存在如何影响RPV对HIV-1B和-nonB SA 2的易感性。从病毒学上表征CSM和RAMB对多种亚型SA 3中适应性和多类耐药的贡献。揭示HIV-1B和HIV-nonB中MCDR表型的生化和结构机制本申请的目的是阐明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重要见解。 1B和HIV-非B患者。

 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.