Department of Pharmacology, New York University School of Medicine, 550 First Avenue MSB 497, New York, NY 10016, USA.
Vaccine. 2011 Sep 9;29(39):6736-41. doi: 10.1016/j.vaccine.2010.12.052. Epub 2011 Jan 7.
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.
尽管频繁观察到 HIV-1 中和表位的掩蔽现象，但以前从未系统地评估过单个病毒呈现的多个表位或多个病毒株的单个表位的掩蔽程度。我们使用最近开发的方法来识别 HIV-1 中和单克隆抗体（mAb）识别所需的氨基酸序列基序，我们可视化了针对 mAb 靶向的特定表位的掩蔽模式，这些表位在多样化的 HIV-1 分离株中。我们还根据 mAb 针对病毒中表位的观察中和活性，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 株中每种 mAb 靶向表位的保守性估计相结合，以估计每种 mAb 的有效中和潜力（E（N））。以 gp120 的 V3 环作为原型中和结构域，我们发现 mAb 2219 靶向的 V3 环表位是掩蔽程度最低的 mAb 之一，其 E（N）最高。有趣的是，尽管 mAb 3074 靶向的 V3 环表位存在于所有病毒的 87%以上，但它被掩蔽 82.2%，因此其 E（N）低于 mAb 2219。值得注意的是，mAb 3074 能够中和的 50%的病毒被归类为 C 型病毒，而 70%或更多的由 mAb 2219、2557 或 447-52D 中和的病毒被归类为 B 型。因此，中和表位（在这种情况下，在 V3 环中）具有不同的掩蔽模式，并且在循环 HIV-1 病毒中也显示出不同的分布模式。这两个因素共同导致任何单个表位/mAb 的实际疫苗价值。在这里，我们为此值开发了一个定量评分。这些结果对于合理设计旨在通过诱导中和 Abs 来设计疫苗具有重要意义，这揭示了最小掩蔽和最大反应性的表位。
