Quantifying the fitness cost of HIV-1 resistance to broadly neutralizing antibodies

项目摘要/摘要： 用单抗(MAbs)进行免疫治疗已在自身免疫和 癌症，因此，抗体的治疗选择特别是重新设计的分子基于广泛的 应在艾滋病毒-1的背景下探索中和抗体(BNAbs)。需要注意的是，HIV-1病毒有能力 通过在其可变的env基因中产生突变来快速逃脱抗体。因此，当务之急是 需要深入了解HIV-1从bNAbs中逃脱的情况，以帮助制定更有效的组合抗体策略 用于HIV-1的治疗、治疗和预防。由于bNAbs已经在临床试验中进行测试，因此 当务之急是不仅要评估最佳抗体组合的中和能力，而且还要评估它们的中和能力 它们被不同的病毒“轻松逃脱”。这项提案的总体目标是衡量 基因不同的HIV毒株逃脱广谱中和抗体并设计抗体鸡尾酒 能够限制逃生的。为了实现这一目标，林奇博士是艾滋病毒-1逃避bNAbs的专家 已经组建了一个合作团队，利用分子病毒学进行跨学科研究(林奇博士) 研究HIV-1的计算方法(Barton博士和Fischer博士)和人源化小鼠模型(Klein博士) 逃走。我们的中心假设是，当HIV-1从联合的bNAbs中逃脱时，将受到限制 逃脱所有bNAb所需的突变在不同的 病毒，因此，复制不能轻易地通过补偿突变恢复。我们会 通过(I)定义不同病毒中单个bNAbs的可行逃逸路径文库来检验这一假设 体外和体内方法，(Ii)确定病毒-bNAb配对逃逸的适宜成本或“容易” 生物信息学，以及(Iii)确定使健康成本最大化的抗体的最佳组合 在不同的HIV-1亚型中的耐药性，并在体外和体内测试这种组合。我们的结果将是 限制不同HIV-1病毒逃逸能力的最佳组合抗体鸡尾酒的鉴定 抗体压力。这些发现将通知所有使用bNAbs或基于bNAb的分子的临床试验，以及 最终，这些研究将确定一条合理的管道，以确定未来抗体逃逸途径的特征。

PROJECT SUMMARY/ABSTRACT: Immunotherapy with monoclonal antibodies (mAbs) has been successful in settings such as autoimmunity and cancers, and therefore, treatment options with antibodies especially re-designed molecules based on broadly neutralizing antibodies (bNAbs) should be explored in the context of HIV-1. A caveat is that HIV-1 has the ability to rapidly escape from antibodies by generating mutations in its variable env gene. Therefore, there is an urgent need to gain insight into HIV-1 escape from bNAbs to aid in more effective combination antibody strategies to be used towards HIV-1 therapy, cure and prevention. As bNAbs are already being tested in clinical trials, it is imperative that optimal antibody combinations are evaluated not only for their neutralization capability but also their ‘ease of escape’ by diverse viruses. The overall objective of this proposal is to measure the ability of genetically diverse strains of HIV to escape from broadly neutralizing antibodies and design an antibody cocktail capable of restricting escape. To accomplish this goal, Dr. Lynch, who is an expert in HIV-1 escape from bNAbs has put together a collaborative team for an interdisciplinary approach using molecular virology (Dr. Lynch), computational methods (Drs. Barton and Fischer) and a humanized-mouse model (Dr. Klein) to study HIV-1 escape. Our central hypothesis is that HIV-1 escape from combination bNAbs will be limited when the mutations required to escape all bNAbs exert the maximum replicative fitness cost across diverse viruses and, therefore, replication cannot easily be restored through compensatory mutations. We will test this hypothesis by (i) defining a library of viable escape pathways for single bNAbs in diverse viruses with in vitro and in vivo approaches, (ii) determining the fitness cost or “ease” of escape for virus-bNAb pairings bioinformatically, and (iii) identifying the optimal combination of antibodies that maximize fitness costs of resistance in diverse HIV-1 subtypes and testing this combination in vitro and in vivo. Our outcome will be the identification of optimal combination antibody cocktails to limit the ability of diverse HIV-1 viruses to escape from antibody pressure. These findings will inform all clinical trials using bNAbs or bNAb-based molecules, and ultimately, these studies will define a rational pipeline to characterize antibody escape pathways in the future.