Immunologic basis for long HCDR3s in broadly neutralizing antibodies against HIV-1

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 minireview 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 naive 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 naive 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 naive 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.