Relevance of Resistance Mutations for the Susceptibility to Broadly Neutralizing Antibodies Against HIV-1

抗性突变与 HIV-1 广泛中和抗体敏感性的相关性

基本信息

批准号：
10258138
负责人：
Nikolaus Jilg
金额：
$ 19.96万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10258138
关键词：
AIDS clinical trial group Address Advisory Committees Affect Africa South of the Sahara Antibodies Antibody Therapy Area Basic Science Binding Botswana Child Chronic Clinical Clinical Data Clinical Trials Collection Combined Modality Therapy Communicable Diseases Data Development Plans Dideoxy Chain Termination DNA Sequencing Disease remission Drug resistance Epidemic Epitopes Europe Failure Fellowship General Hospitals Genotype Goals HIV HIV Infections HIV Seropositivity HIV resistance HIV-1 Hepatitis C Hospitals Individual Infection Interruption Intervention Knowledge Maintenance Massachusetts Mentors Mentorship Minority Mutation Mutation Analysis Names Natural Immunity North America Patients Pattern Phenotype Physicians Plasma Play Polysaccharides Predisposition Prevalence Prevention Process Publishing RNA Research Research Personnel Resistance Resources Role Sampling Scientist Site Testing Time Training Translational Research Treatment Failure Variant Viral Virus Virus Diseases Woman Work antiretroviral therapy career development deep sequencing design early phase clinical trial experience member neutralizing antibody next generation novel novel therapeutic intervention pathogen perinatal HIV programs resistance mutation skills tool treatment strategy viral rebound virology

项目摘要

Project Summary/ Abstract Novel therapeutic strategies to end the HIV epidemic are urgently needed. Broadly neutralizing antibodies (bNAbs) have emerged as highly promising tools in HIV treatment, and early-phase clinical trials have been conducted or are under way. We propose to study resistance mutations to broadly neutralizing antibodies in HIV-1 with a focus on subtypes other than subtype B. While subtype B, prevalent in North America and Europe, has historically been investigated the most, it only affects ~12% of HIV positive people globally. There is a knowledge gap regarding non-subtype B HIV-1 infection which is endemic in resource-limited settings, like sub-Saharan Africa. Minority variant resistance mutations have been found to be associated with treatment failure of ART. There is evidence that similar mechanisms are involved in bNAb resistance, but the role of minority variants for resistance to bNAbs is less defined, particularly in resource-limited areas. We therefore propose to use a large collection of viremic plasma samples obtained from HIV-1 infected individuals from two studies (ACTG A5288 and REVAMP) to determine the prevalence of resistance mutations to bNAbs in HIV-1 subtypes A, C, and D which together represent the majority of infections worldwide. As minority variants typically are missed on routine Sanger sequencing, we propose to use deep sequencing to analyze the plasma samples for majority and minority resistance variants. We will process the obtained sequencing data using a pipeline similar to what has recently been used by our group for resistance mutation analysis which will be adapted to the current project. We will then compare the resistance mutation in these HIV-1 subtype C samples with previously published resistance mutations to at least four widely used bNAbs (VRC01, 3BNC117, PGT121 and 10-1074). For example, we expect to find baseline resistance mutations at the glycan binding N332 and N334 sites as previously described. In a second aim of the study, we will confirm the resistance against these bNAbs in phenotypic tests using subtype-specific pseudoviruses by introducing resistance mutations that we have identified as minority variants. We will use these pseudoviruses to determine the half maximal inhibitory concentrations (IC50) against the named antibodies. In aim 3 we will look for resistance mutations at baseline and with any observed viral rebound in children with perinatal HIV infection that will be treated with dual bNAb therapy and undergo ART treatment interruption. The candidate is a physician-scientist and has completed clinical fellowship training at the combined Massachusetts General Hospital and Brigham and Woman’s Hospital Infectious Diseases Program. He has research experience in basic and translational science in innate immunity, host-pathogen interactions, chronic viral diseases (previous work on hepatitis C) and has now been applying his research skills to the virology of HIV. His goal is to become an independent investigator in translational HIV research and an expert on HIV resistance. The career development plan as outlined in this proposal will provide the necessary additional training, mentoring and time for research to achieve this goal.

项目概要/摘要迫切需要新的治疗策略来结束艾滋病毒的流行。正在成为艾滋病毒治疗中极具前景的工具，早期临床试验已经进行或正在进行。我们建议研究 HIV-1 中广泛中和抗体的耐药突变，重点关注除 B 亚型。虽然 B 亚型在北美和欧洲流行，历史上研究最多，但它仅全球约 12% 的 HIV 阳性人群对非 B 亚型 HIV-1 感染存在知识差距。已发现少数变异抗性突变在资源有限的地区流行。与 ART 治疗失败有关有证据表明 bNAb 耐药性涉及类似的机制，但少数变异对 bNAb 耐药性的作用尚不明确，特别是在资源有限的地区。提议使用两项研究中从 HIV-1 感染者身上获得的大量病毒血症血浆样本（ACTG A5288 和 REVAMP）确定 HIV-1 A、C 和 D 亚型中 bNAb 耐药突变的流行率它们共同代表了全球大多数感染，因为少数变种通常在常规桑格检测中被遗漏。测序，我们建议使用深度测序来分析血浆样本的多数和少数耐药性我们将使用类似于我们最近使用的管道来处理获得的测序数据。小组进行抗性突变分析，该分析将适应当前项目，然后我们将比较抗性。这些 HIV-1 C 亚型样本中的突变具有先前发表的对至少四种广泛使用的抗性突变例如，我们期望在 bNAb（VRC01、3BNC117、PGT121 和 10-1074）处找到基线耐药突变。如前所述，聚糖结合 N332 和 N334 位点在本研究的第二个目标中，我们将确认耐药性。通过引入抗性突变，使用亚型特异性假病毒在表型测试中针对这些 bNAb 我们已确定为少数变体，我们将使用这些假病毒来确定半最大抑制。在目标 3 中，我们将寻找基线和耐药突变。在接受双 bNAb 治疗的围产期 HIV 感染儿童中观察到的任何病毒反弹，以及接受 ART 治疗中断。候选人是一名医师科学家，并已完成临床进修培训。在马萨诸塞州总医院和布莱根妇女医院联合传染病项目中。在先天免疫、宿主-病原体相互作用、慢性病毒等基础和转化科学领域的研究经验疾病（之前研究丙型肝炎），现在将他的研究技能应用于艾滋病毒病毒学。成为艾滋病毒转化研究的独立研究者和艾滋病毒耐药性专家。本提案中概述的发展计划将提供必要的额外培训、指导和时间研究以实现这一目标。