Havenar-Daughton Colin, Lee Jeong Hyun, Crotty Shane
Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, CA, USA.
Scripps Center for HIV/AIDS Vaccine Immunology and Immunogen Discovery (CHAVI-ID), La Jolla, CA, USA.
Immunol Rev. 2017 Jan;275(1):49-61. doi: 10.1111/imr.12512.
The generation of HIV bnAbs may be one of the greatest feats of the human immune system and our best hope of finally creating an HIV vaccine. The striking amount of somatic hypermutation in HIV bnAbs led to the hypothesis that T follicular helper (Tfh) cells and germinal centers (GC) play a critical role in the ability of the immune system to generate these uncommon antibodies. In this review, we first summarize what is known about the immunological process of HIV bnAb development, the challenges of eliciting bnAbs via immunizations, and the putative central roles of Tfh cells and GC in the generation of HIV bnAbs. Next, we explore factors that have impeded our understanding of the GC and Tfh-cell processes involved in bnAb generation, including the difficulty of quantifying antigen-specific GC Tfh cells and the difficulty of tracking GC in human and non-human primate vaccine studies. Finally, we discuss antibody immunodominance pertaining to neutralizing antibody generation and the GC response, propose models to explain the negative effects of immunodominance on neutralizing antibody generation, and consider means of optimizing Tfh and GC responses to potentially overcome these problems.
HIV广谱中和抗体(bnAbs)的产生可能是人类免疫系统最伟大的成就之一,也是我们最终研制出HIV疫苗的最大希望。HIV bnAbs中显著的体细胞超突变现象引发了这样一种假说,即滤泡辅助性T细胞(Tfh)和生发中心(GC)在免疫系统产生这些罕见抗体的能力中起着关键作用。在这篇综述中,我们首先总结关于HIV bnAb产生的免疫过程、通过免疫接种引发bnAbs所面临的挑战,以及Tfh细胞和GC在HIV bnAbs产生中假定的核心作用的已知信息。接下来,我们探讨阻碍我们理解bnAb产生过程中GC和Tfh细胞过程的因素,包括量化抗原特异性GC Tfh细胞的困难,以及在人类和非人类灵长类动物疫苗研究中追踪GC的困难。最后,我们讨论与中和抗体产生和GC反应相关的抗体免疫优势,提出解释免疫优势对中和抗体产生负面影响的模型,并考虑优化Tfh和GC反应以潜在克服这些问题的方法。
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