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

• 批准号: 10685999
• 负责人: Nikolaus Jilg
• 金额: $ 19.98万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 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/10685999
• 关键词: AIDS clinical trial group; Advisory Committees; Affect; Africa South of the Sahara; Antibodies; Antibody Therapy; 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; Education; 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; Persons; Phenotype; Physicians; Plasma; Play; Polysaccharides; Predisposition; Prevalence; Prevention; Process; Publishing; RNA; Research; Research Personnel; Resistance; Resource-limited setting; 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; viral rebound; virology

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.

项目总结/摘要 迫切需要新的治疗策略来结束艾滋病毒的流行。广泛中和抗体（bNAb）具有 作为治疗艾滋病毒的非常有前途的工具，已经进行或正在进行早期临床试验。 我们建议研究HIV-1中对广泛中和抗体的耐药突变，重点关注除 B亚型。虽然流行于北美和欧洲的亚型B在历史上被研究得最多，但它只 影响全球约12%的HIV阳性人群。关于非B亚型HIV-1感染， 在资源有限的地区，如撒哈拉以南非洲，已发现少数变异耐药突变 有证据表明，类似的机制涉及bNAb抗性， 但少数变异体对bNAb耐药性的作用还不太明确，特别是在资源有限的地区。因此我们 我建议使用从两项研究的HIV-1感染者中获得的大量病毒血症血浆样本 (ACTG A5288和REVAMP），以确定HIV-1亚型A、C和D中bNAb耐药突变的流行率 它们共同代表了世界上大多数的感染。由于少数变异通常错过了例行桑格 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 变体。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。 耐药突变分析小组将根据当前项目进行调整。然后我们将比较电阻 这些HIV-1 C亚型样本中的突变与先前公布的耐药突变，至少有四个广泛使用的 bNAb（VRC 01、3BNC 117、PGT 121和10-1074）。例如，我们希望在这些基因组中找到基线耐药突变。 如前所述的聚糖结合N332和N334位点。在研究的第二个目的中，我们将确认 在表型试验中使用亚型特异性假病毒通过引入抗性突变来对抗这些bNAb， 我们已经确定为少数变异。我们将使用这些假病毒来确定半最大抑制 在一些实施方案中，使用针对指定抗体的浓度（IC 50）来测定抗体的浓度。在目标3中，我们将在基线时寻找耐药突变， 在将接受bNAb双重治疗的围产期HIV感染儿童中观察到的任何病毒反弹， 中断抗逆转录病毒治疗。候选人是一名医生-科学家，并已完成临床奖学金培训 在联合马萨诸塞州总医院和布里格姆妇女医院传染病项目。他 在先天免疫、宿主-病原体相互作用、慢性病毒感染、 疾病（以前的工作对丙型肝炎），现在已经应用他的研究技能，艾滋病毒的病毒学。他的目标是 成为翻译HIV研究的独立调查员和HIV耐药性专家。职业 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。