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Quantitative assessment of masking of neutralization epitopes in HIV-1

机译：掩盖HIV-1中和表位的定量评估

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Despite the frequent observation of masking of HIV-1 neutralization epitopes, its extent has not been previously systematically assessed either for multiple epitopes presented by individual viruses or for individual epitopes across multiple viral strains. Using a recently developed method to identify amino acid sequence motifs required for recognition by HIV-1-neutralizing monoclonal antibodies (mAbs), we visualized the patterns of masking of specific epitopes targeted by mAbs in a diverse panel of HIV-1 isolates. We also calculated a specific masking intensity score for each virus based on the observed neutralization activity of mAbs against the epitopes in the virus. Finally, we combined these data with estimates of the conservation of each mAb-targeted epitope in circulating HIV-1 strains to estimate the effective neutralization potential (E-N) for each mAb. Focusing on the V3 loop of gp120 as a prototype neutralization domain, we found that the V3 loop epitope targeted by mAb 2219 is one of the least masked mAbs and it has the highest E-N. Interestingly, although the V3 loop epitope targeted by mAb 3074 is present in over 87% of all viruses, it is 82.2% masked, so its E-N is lower than that for mAb 2219. Notably, 50% of the viruses that mAb 3074 is able to neutralize are classified as subtype C viruses, while 70% or more of the viruses neutralized by mAbs 2219, 2557 or 447-52D are classified as subtype B. Thus, neutralization epitopes (in this case, in the V3 loop) have differential patterns of masking and also display distinct patterns of distribution among circulating HIV-1 viruses. Both factors combine to contribute to the practical vaccine value of any single epitope/mAb. Here we have developed a quantitative score for this value. These results have important implications for rational design of vaccines designed to induce neutralizing Abs by revealing epitopes that are minimally masked and maximally reactive with neutralizing Abs
机译：尽管经常观察到掩盖HIV-1中和表位的情况，但以前尚未系统评估单个病毒呈现的多个表位或跨多个病毒株的单个表位的程度。使用一种最新开发的方法来识别被HIV-1中和单克隆抗体（mAb）识别所需的氨基酸序列基序，我们在多种HIV-1分离株中可视化了mAb靶向的特定表位的掩蔽模式。我们还根据观察到的mAb对病毒表位的中和活性，为每种病毒计算了特定的掩蔽强度评分。最后，我们将这些数据与循环HIV-1菌株中每个mAb靶向表位的保守性估算结合起来，以估算每个mAb的有效中和潜力（E-N）。着眼于gp120的V3环作为原型中和域，我们发现mAb 2219靶向的V3环表位是被掩盖的mAb最少的一种，并且E-N最高。有趣的是，尽管mAb 3074靶向的V3环抗原决定簇存在于所有病毒中的超过87％，但被82.2％的病毒掩盖，因此其EN低于mAb 2219的EN。值得注意的是，mAb 3074能够感染的病毒占50％被中和的抗原被归类为C型病毒，而被单抗2219、2557或447-52D中和的病毒中有70％或更多被归类为B型。因此，中和表位（在这种情况下，在V3环中）具有差异模式也可以显示正在传播的HIV-1病毒之间的不同分布模式。这两个因素共同为任何单个表位/ mAb的实用疫苗价值做出了贡献。在这里，我们为该值制定了定量分数。这些结果对于揭示诱导与中和抗体的掩盖作用最小并具有最大反应性的抗原决定簇的疫苗的合理设计具有重要意义。

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