Minimally Mutated HIV-1 Broadly Neutralizing Antibodies to Guide Reductionist Vaccine Design.
Minimally Mutated HIV-1 Broadly Neutralizing Antibodies to Guide Reductionist Vaccine Design.
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DOI：
10.1371/journal.ppat.1005815
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发表时间：
2016-08
期刊：
影响因子：
6.7
通讯作者：
Schief WR
中科院分区：
文献类型：
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作者：
Jardine JG;Sok D;Julien JP;Briney B;Sarkar A;Liang CH;Scherer EA;Henry Dunand CJ;Adachi Y;Diwanji D;Hsueh J;Jones M;Kalyuzhniy O;Kubitz M;Spencer S;Pauthner M;Saye-Francisco KL;Sesterhenn F;Wilson PC;Galloway DM;Stanfield RL;Wilson IA;Burton DR;Schief WR
最佳的HIV疫苗应该诱导广泛中和抗体（bnAb），中和不同的病毒株和亚型。然而，有效的bnAb仅在一小部分HIV感染者中产生，所有bnAb都含有罕见的特征，如广泛的突变，插入，缺失和/或长互补决定区，有些是多反应性的，这使人怀疑是否可以通过疫苗接种可靠地诱导针对HIV的bnAb。我们设计了两种有效的VRC 01类bnAb，最大限度地减少了罕见的功能。根据定量特征频率分析，这些最低限度突变的bnAb之一的特征集与分析的所有68种HIV bnAb相比是有利的，并且与普通疫苗引起的抗体相似。这种相同的最小突变bnAb在四种不同的测定中缺乏多反应性。然后，我们将最小的突变分成空间簇，并通过突变和晶体学分析结合中和测定来解剖与这些簇相互作用的表位组分。最后，通过综合现有的数据，我们开发了一个工作概念的提升策略，以选择突变集群的逻辑顺序后，生殖系靶向总理。因此，我们开发了有效的HIV bnAbs，与现有的bnAbs相比，它们可能是更易处理的疫苗目标，并且我们提出了一种策略来引发它们。这种以抗体和抗原结构为指导的疫苗设计的还原主义方法可以应用于设计其他HIV bnAb或针对其他病原体的保护性Ab的候选疫苗。许多HIV疫苗设计工作旨在引发所谓的广泛中和抗体，这些抗体结合并中和不同的病毒株和亚型。然而，这些努力是由从艾滋病毒感染者中分离出的非常不寻常的抗体指导的。这些抗体具有罕见的特征，限制了它们作为直接疫苗模板的使用，因为任何疫苗都不可能持续地引发类似的抗体。我们设计了HIV广泛中和抗体，最大限度地减少了这些罕见的特征，因此可能成为HIV疫苗设计的更好线索。抗体通常通过在自然成熟过程中积累突变来获得对其靶表位的亲和力。弄清楚如何使用疫苗来引发具有特定类型的有用突变的特定类型的抗体，是疫苗设计的一个尚未解决的重大挑战。我们能够确定我们的新抗体中哪些突变是最重要的，以及诱导这些突变所需的表位结构。这种分析使我们能够推导出一种逻辑策略，该策略仍有待测试，用于如何通过接种疫苗来引导这些类型的抗体成熟。我们建议，这种简化的疫苗设计方法，分子结构和工程导向的指导下，允许优化，有希望设计针对艾滋病毒和许多其他病原体的疫苗。
An optimal HIV vaccine should induce broadly neutralizing antibodies (bnAbs) that neutralize diverse viral strains and subtypes. However, potent bnAbs develop in only a small fraction of HIV-infected individuals, all contain rare features such as extensive mutation, insertions, deletions, and/or long complementarity-determining regions, and some are polyreactive, casting doubt on whether bnAbs to HIV can be reliably induced by vaccination. We engineered two potent VRC01-class bnAbs that minimized rare features. According to a quantitative features frequency analysis, the set of features for one of these minimally mutated bnAbs compared favorably with all 68 HIV bnAbs analyzed and was similar to antibodies elicited by common vaccines. This same minimally mutated bnAb lacked polyreactivity in four different assays. We then divided the minimal mutations into spatial clusters and dissected the epitope components interacting with those clusters, by mutational and crystallographic analyses coupled with neutralization assays. Finally, by synthesizing available data, we developed a working-concept boosting strategy to select the mutation clusters in a logical order following a germline-targeting prime. We have thus developed potent HIV bnAbs that may be more tractable vaccine goals compared to existing bnAbs, and we have proposed a strategy to elicit them. This reductionist approach to vaccine design, guided by antibody and antigen structure, could be applied to design candidate vaccines for other HIV bnAbs or protective Abs against other pathogens. Many HIV vaccine design efforts aim to elicit so-called broadly neutralizing antibodies that bind and neutralize diverse strains and subtypes of the virus. However, these efforts are guided by very unusual antibodies isolated from HIV-infected individuals. These antibodies have rare features that limit their use as direct vaccine templates, because it is unlikely that any vaccine could consistently elicit similar antibodies. We engineered HIV broadly neutralizing antibodies that minimized these rare features and may therefore serve as better leads for HIV vaccine design. Antibodies generally gain affinity for their target epitope by accumulating mutations in a natural process of maturation. Figuring out how to use vaccines to elicit particular kinds of antibodies, with particular kinds of helpful mutations, is a major unsolved challenge for vaccine design. We were able to determine which mutations in our new antibodies are most important and which epitope structures are needed to induce those mutations. This analysis allowed us to deduce a logical strategy, which remains to be tested, for how to guide the maturation of these types of antibodies by vaccination. We propose that this reductionist approach to vaccine design, guided by molecular structure and engineering-oriented to allow for optimization, has promise for designing vaccines against HIV and many other pathogens.