Mouse Models Expresssing Precursors of Broadly Neutralizing Antibodies Against HIV

Abstract

An effective HIV vaccine would undoubtedly be the best solution for controlling the AIDS pandemic. Unfortunately, none of the numerous HIV-1 vaccine development efforts have succeeded to date. The enormous diversity of HIV-1, the capacity of the virus to evade immune responses, and the early establishment of latent viral reservoirs pose formidable challenges for vaccine development. The traditional vaccination method is to immunize human subjects with microbial antigens. However, this strategy has proven ineffective in protecting people against HIV infection in clinical trials, because the antibodies elicited by the vaccination do not target the conserved part of HIV antigens. The recent discovery of broadly neutralizing antibodies (bnAbs) in HIV patients against a wide spectrum of HIV strains holds the promise of effective community-based prevention via vaccination. These antibodies recognize conserved and functionally crucial structures of the HIV surface antigen: specifically, the gp120/gp41 complex, rendering the ability of HIV-1 to infect cells and replicate. In light of these findings, the current goal of HIV vaccine development is to devise vaccination strategies to elicit bnAbs. However, existing vaccination strategies have failed to elicit bnAbs in human subjects for several reasons. One of which is that bnAbs come from rare B cell precursors that have accumulated high levels of somatic hypermutation resulting from prolonged exposures to viral variants. Secondly, most bnAbs against envelope glycoprotein gp120 CD4 binding site share a germline VH gene segment (IGVH1-2*02). As such, to induce this class of bnAbs, the vaccine needs to activate the rare B cells expressing IGVH1-2*02 as part of their antigen receptor. To address this issue, we developed a system that allows a germline human IGHV1-2*02 to undergo normal V(D)J recombination in mice. We also deleted the IGCR-1 regulatory element to promote high-frequency expression and usage of this human VH segment, which is inserted in place of the proximal mouse VH segment. A unique aspect of our model is that, analogous to physiological situations, IGHV1-2*02 is expressed in association with diverse variants of complementarity determining region 3 (CDR3). Our collaborators then successfully immunized our mouse models, which also express a VRC01-antibody precursor light chain, with a series of modified gp120 glycoproteins to guide the maturation of VRC01 precursor antibodies into HIV-neutralizing antibody lineages.