Yu Lei, Guan Yongjun
Division of Basic Science and Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine , Baltimore, MD , USA.
Division of Basic Science and Vaccine Research, Institute of Human Virology, University of Maryland School of Medicine , Baltimore, MD , USA ; Department of Microbiology and Immunology, University of Maryland School of Medicine , Baltimore, MD , USA.
Front Immunol. 2014 Jun 2;5:250. doi: 10.3389/fimmu.2014.00250. eCollection 2014.
A large number of potent broadly neutralizing antibodies (bnAbs) against HIV-1 have been reported in recent years, raising hope for the possibility of an effective vaccine based on epitopes recognized by these protective antibodies. However, many of these bnAbs contain the long heavy chain complementarity-determining region 3 (HCDR3), which is viewed as an obstacle to the development of an HIV-1 vaccine targeting the bnAb responses. This mini-review summarizes the current literature and discusses the different potential immunologic mechanisms for generating long HCDR3, including D-D fusion, VH replacement, long N region addition, and skewed D-J gene usage, among which potential VH replacement products appear to be significant contributors. VH replacement occurs through recombinase activated gene-mediated secondary recombination and contributes to the diversified naïve B cell repertoire. During VH replacement, a short stretch of nucleotides from previously rearranged VH genes remains within the newly formed HCDR3, thus elongating its length. Accumulating evidence suggests that long HCDR3s are present in significant numbers in the human mature naïve B cell repertoire and are primarily generated by recombination during B cell development. These new observations indicate that long HCDR3s, though low in frequency, are a normal feature of the human antibody naïve repertoire and they appear to be selected to target conserved epitopes located in deep, partially obscured regions of the HIV-1 envelope trimer. Therefore, the presence of long HCDR3 sequences should not necessarily be viewed as an obstacle to the development of an HIV-1 vaccine based upon bnAb responses.
近年来，已报道了大量针对HIV-1的强效广谱中和抗体（bnAbs），这让基于这些保护性抗体所识别的表位开发有效疫苗的可能性有了希望。然而，这些bnAbs中有许多含有长的重链互补决定区3（HCDR3），这被视为开发针对bnAb应答的HIV-1疫苗的障碍。本综述总结了当前文献，并讨论了产生长HCDR3的不同潜在免疫机制，包括D-D融合、VH替换、长N区添加和偏向性D-J基因使用，其中潜在的VH替换产物似乎是重要的促成因素。VH替换通过重组激活基因介导的二次重组发生，并有助于幼稚B细胞库的多样化。在VH替换过程中，来自先前重排的VH基因的一小段核苷酸保留在新形成的HCDR3内，从而延长其长度。越来越多的证据表明，长HCDR3在人类成熟幼稚B细胞库中大量存在，并且主要在B细胞发育过程中通过重组产生。这些新观察结果表明，长HCDR3虽然频率较低，但却是人类抗体幼稚库的正常特征，并且它们似乎被选择用于靶向位于HIV-1包膜三聚体深层、部分隐蔽区域的保守表位。因此，长HCDR3序列的存在不一定应被视为基于bnAb应答开发HIV-1疫苗的障碍。
