Enhanced Potency of a Broadly Neutralizing HIV-1 Antibody In Vitro Improves Protection against Lentiviral Infection In Vivo
Enhanced Potency of a Broadly Neutralizing HIV-1 Antibody In Vitro Improves Protection against Lentiviral Infection In Vivo
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DOI：
10.1128/jvi.02213-14
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发表时间：
2014-11-01
影响因子：
5.4
通讯作者：
Nabel, Gary J.
中科院分区：
文献类型：
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作者：
Rudicell, Rebecca S.;Do Kwon, Young;Nabel, Gary J.
在过去的5年中，新一代高效和广泛中和的HIV-1抗体已经被发现。这些抗体可以防止非人灵长类动物（NHPs）的慢病毒感染，表明被动抗体转移可以防止HIV-1在人类中的传播。为了提高这种单克隆抗体的保护功效，我们采用新一代测序、计算生物信息学和结构引导设计来增强VRC01的中和效力和广度，VRC01是一种靶向HIV-1包膜CD4结合位点的抗体。其中一种变体VRC07-523的效力是VRC01的5- 8倍，中和了96%的测试病毒，并表现出最小的自身反应性。为了比较其与VRC01的体内保护效果，我们在非人类灵长类动物中进行了一系列猿人免疫缺陷病毒（SHIV）攻击实验，并计算了VRC07-523和VRC01提供50%保护（EC50）的剂量。VRC07-523的浓度比VRC01低5倍。这些结果表明，体外中和效力的增强与体内抗感染能力的增强相关，证明了VRC07-523增强的功能功效及其在保护人类抗HIV-1感染方面的潜在临床意义。在缺乏有效的HIV-1疫苗的情况下，需要其他策略来阻止HIV-1的传播。直接给药HIV-1中和抗体可能能够预防人类HIV-1感染。这种方法对感染HIV-1的高危人群尤其有用，可以与抗逆转录病毒药物一起使用来预防感染。为了优化成功的机会，可以对这些抗体进行修饰，以提高它们的效力、宽度和体内半衰期。本研究利用对一种靶向HIV-1包膜蛋白cd4结合位点的强效中和抗体VRC01结构的了解，设计了一种体外效力提高5至8倍的下一代抗体。当给予非人灵长类动物时，这种抗体的保护浓度比原始抗体低5倍。我们的研究证明了用于评估抗体治疗潜力的体外分析与其体内有效性之间的重要相关性。
Over the past 5 years, a new generation of highly potent and broadly neutralizing HIV-1 antibodies has been identified. These antibodies can protect against lentiviral infection in nonhuman primates (NHPs), suggesting that passive antibody transfer would prevent HIV-1 transmission in humans. To increase the protective efficacy of such monoclonal antibodies, we employed next-generation sequencing, computational bioinformatics, and structure-guided design to enhance the neutralization potency and breadth of VRC01, an antibody that targets the CD4 binding site of the HIV-1 envelope. One variant, VRC07-523, was 5- to 8-fold more potent than VRC01, neutralized 96% of viruses tested, and displayed minimal autoreactivity. To compare its protective efficacy to that of VRC01 in vivo, we performed a series of simian-human immunodeficiency virus (SHIV) challenge experiments in nonhuman primates and calculated the doses of VRC07-523 and VRC01 that provide 50% protection (EC50). VRC07-523 prevented infection in NHPs at a 5-fold lower concentration than VRC01. These results suggest that increased neutralization potency in vitro correlates with improved protection against infection in vivo, documenting the improved functional efficacy of VRC07-523 and its potential clinical relevance for protecting against HIV-1 infection in humans.IMPORTANCEIn the absence of an effective HIV-1 vaccine, alternative strategies are needed to block HIV-1 transmission. Direct administration of HIV-1-neutralizing antibodies may be able to prevent HIV-1 infections in humans. This approach could be especially useful in individuals at high risk for contracting HIV-1 and could be used together with antiretroviral drugs to prevent infection. To optimize the chance of success, such antibodies can be modified to improve their potency, breadth, and in vivo half-life. Here, knowledge of the structure of a potent neutralizing antibody, VRC01, that targets the CD4-binding site of the HIV-1 envelope protein was used to engineer a next-generation antibody with 5- to 8-fold increased potency in vitro. When administered to nonhuman primates, this antibody conferred protection at a 5-fold lower concentration than the original antibody. Our studies demonstrate an important correlation between in vitro assays used to evaluate the therapeutic potential of antibodies and their in vivo effectiveness.