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)抑制剂包括两类不同的药物，即逆转录酶抑制剂(NRTI)和非核苷类RTI(NNRTI)，它们的作用机制完全不同。然而，它们的广泛使用导致了抗药性突变的出现，这可能会影响新的RTI的使用。随着利培韦林(RPV)等新药越来越多地可用于感染非B亚型HIV毒株(HIV-non B)的患者，了解在HIV-1B样本(RAMB)中确定的RPV耐药相关突变如何影响药物初治或治疗的HIV-non B患者的易感性模式是很重要的。这项建议旨在了解不同HIV亚型(HIV-1B与HIV-Non-B)之间的耐药性差异。最近的合作临床数据(与A.Sönnerborg和U.Neogi)发现，在单纯治疗(6%-11%，取决于亚型)和奈韦拉平(NVP)或依沙韦仑(EFV)治疗失败的患者中(22%-34%，取决于亚型)。因此，假设基于NVP/EFV治疗失败的患者更有可能失败基于RPV的治疗。此外，接受TDF/FTC/RPV治疗的患者中，约9%的HIV-1B患者通过RPV相关突变治疗失败，而在HIV-Non-B患者中，这一比例为约25%。初步分析来自HIV-1B和HIV-non B患者的临床队列的RT序列，这些患者是治疗幼稚或失败的(基于NVP/EFV)，显示预测的RAMB的患病率增加。因此，还假设RPV抗性在不同的亚型中通过不同的机制出现。此外，直到最近，人们还认为对一类RTIs的耐药性与另一类无关。然而，RT连接亚域突变(CSMS)，即HIV-1B中的N348I，已被发现，使其对NRTIs和NNRTIs产生多类耐药(MCDR)。假设CSMS在不同的HIV亚型中对MCDR的影响是不同的。SA 1.确定CSMS和RAMB的存在如何影响HIV-1B和非B亚型RPV的敏感性SA 2.病毒学表征CSMS和RAMB对多个亚型SA的适合性和多类耐药性的贡献3.揭示HIV-1B和HIV-non B中MCDR表型的生化和结构机制本应用的目的是阐明MCDR背后的分子机制以及CSMS如何影响不同HIV亚型的RPV敏感性，为RPV作为HIV一线治疗的可行性提供重要的见解 1B和HIV-Non 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.