Directing the Evolution of Common Human Precursors into HIV-1 Broadly Neutralizing Antibodies

About This Grant

Project Summary An effective HIV vaccine will likely elicit broadly neutralizing antibodies (bnAbs). Doing so, however, remains a major challenge because bnAbs usually require multiple rare and unusual changes that emerge after years of active infection. It is not clear that a practical number of immunizations can consistently recapitulate this process. Although investigators have successfully expanded defined precursors of known bnAbs, they have not moved these diversified precursors to a specific target in humans. Importantly here, the severity of this problem increases rapidly with the number changes needed. The problem further deepens if the required changes are in slow-to-mutate antibody framework regions or require specific indels. The need to move from precursor to bnAb in the fewest steps motivates our focus on the V2 apex epitope of the HIV-1 envelope glycoprotein (Env). Apex bnAbs are qualitatively different from other bnAb classes. They require far fewer mutations, located in their rapidly evolving heavy-chain CDR3 (HCDR3) regions. These HCDR3s are unusually important to their ability to neutralize virus. For example, we have shown that a diverse repertoire of mouse B cell receptors can be modified with apex bnAb HCDR3s, and the resulting mouse B cells generated potent neutralizing sera. Thus, apex precursors can largely be defined by their HCDR3s alone and are far more common than other defined bnAb precursors. Interestingly, these HCDR3 are very similar to those of another class of antibodies that recognize the CD4-induced co-receptor-binding site (CoRBS). Both antibody classes have unusually long HCDR3s with sulfated tyrosines at their tips. Unlike apex bnAbs, these non-neutralizing CoRBS antibodies are readily elicited through vaccination. We have recently shown that apex precursors also bind the CoRBS, suggesting that some apex bnAbs emerge from CoRBS antibodies. Thus, the first step of sequential vaccine strategies, expanding and diversifying a defined precursor pool, is straightforward. Here we divide the remaining goals into two: moving from a precursor that does not bind Env to one that does so and then broaden it to recognize the majority of circulating isolates. We have already made significant progress in the first step: we have shown in our original mouse vaccine model that we can generate potent apex- specific neutralizing antisera. However the breadth of this sera remains limited. Building on these studies, we will pursue three goals: (1) Define the essential mutations that transform a CoRBS antibody into one that binds the Env apex and then generate antigens that select for these mutations. (2) Define mutations and generate antigens that expand the breadth of these antibodies, transforming them to bnAbs, and (3) Evaluate these antigens in a novel system that models key features of the human apex response in mice, and iteratively refine this process using antibodies and HCDR3s drawn from a wide panel of HIV-naïve persons. In short, these studies develop original concepts and tools that can accelerate development of an HIV-1 vaccine and deepen our understanding of the antibody response to vaccines and pathogens.