Department of Electronic and Computer Engineering, Hong Kong University of Science and Technology, Kowloon, Hong Kong.
Institute for Advanced Study, Hong Kong University of Science and Technology, Kowloon, Hong Kong.
Proc Natl Acad Sci U S A. 2018 Jan 23;115(4):E564-E573. doi: 10.1073/pnas.1717765115. Epub 2018 Jan 8.
HIV is a highly mutable virus, and over 30 years after its discovery, a vaccine or cure is still not available. The isolation of broadly neutralizing antibodies (bnAbs) from HIV-infected patients has led to renewed hope for a prophylactic vaccine capable of combating the scourge of HIV. A major challenge is the design of immunogens and vaccination protocols that can elicit bnAbs that target regions of the virus's spike proteins where the likelihood of mutational escape is low due to the high fitness cost of mutations. Related challenges include the choice of combinations of bnAbs for therapy. An accurate representation of viral fitness as a function of its protein sequences (a fitness landscape), with explicit accounting of the effects of coupling between mutations, could help address these challenges. We describe a computational approach that has allowed us to infer a fitness landscape for gp160, the HIV polyprotein that comprises the viral spike that is targeted by antibodies. We validate the inferred landscape through comparisons with experimental fitness measurements, and various other metrics. We show that an effective antibody that prevents immune escape must selectively bind to high escape cost residues that are surrounded by those where mutations incur a low fitness cost, motivating future applications of our landscape for immunogen design.
HIV 是一种高度易变的病毒，在发现它 30 多年后，仍然没有疫苗或治愈方法。从感染 HIV 的患者中分离出广谱中和抗体（bnAbs），为开发能够对抗 HIV 这一致命疾病的预防性疫苗带来了新的希望。一个主要的挑战是设计免疫原和接种方案，以引发针对病毒刺突蛋白中区域的 bnAbs，这些区域的突变逃逸可能性较低，因为突变的适应性代价很高。相关的挑战包括选择用于治疗的 bnAbs 的组合。作为其蛋白质序列（适应度景观）的函数的病毒适应性的准确表示，明确考虑突变之间的耦合的影响，可以帮助解决这些挑战。我们描述了一种计算方法，该方法使我们能够推断出 HIV 多蛋白 gp160 的适应度景观，该多蛋白包含抗体靶向的病毒刺突。我们通过与实验适应性测量以及其他各种指标进行比较来验证推断的景观。我们表明，一种有效的预防免疫逃逸的抗体必须选择性地结合高逃逸成本的残基，这些残基被包围在那些突变适应性代价较低的残基周围，这为我们的景观在免疫原设计中的未来应用提供了动力。
