Recent identification of large numbers of new broadly neutralizing antibodies (bnAbs) against HIV-1 is leading a vaccine path based on their epitopes. However, majority of the newly identified bnAbs have apparent unusually high levels of mutation, which raises a high bar for a vaccine to generate this type of Ab response. Here we show by phylogenetic analysis that these highly mutated bnAbs cluster into two families of VH genes that are distant from known VH germline genes. It is recognized that the number of human Ab germline genes is not always the same due to genetic polymorphism. Our studies on diversity of VH germline genes also find that diversity of VH germline genes is common. These observations indicate that the diversity of Ab germline genes may limit the induction of these bnAbs at the population level. Here we describe a new potent bnAb, N60-B1.1 that neutralizes 40% of a panel of 118 tier 2,3 viruses with an average IC50 of 0.44 ug/ml. The neutralization pattern of N60-B1.1 is complementary to other bnAbs in that it potently neutralizes viruses that are more resistant to these other antibodies. This bnAb is encoded by VH4-39*07 that is somatically mutated 13.3% at the nucleotide level, which is within the normal somatic mutation rate for vaccine induced antibodies. It uses a single point mutated light chain of germline (CDRL3) VK3-15*01. Theoretically, the induction of “N60-B1.1-like” bnAb will not be limited by the somatic mutation bottleneck that is required for other bnAbs against HIV-1. Therefore, rational design of Env immunogens that preferentially expose “N60-B1.1-like” epitopes to elicit bnAb responses is a promising direction for the development of a protective HIV-1 vaccine.
© 2013 Lippincott Williams & Wilkins, Inc.