Humanized Immunoglobulin Mice

Abstract

A vaccine that can effectively prevent HIV-1 transmission remains paramount to ending the HIV pandemic, but to do so, will likely need to induce broad neutralizing antibody (bnAb) responses. A major technical hurdle towards achieving this goal has been a shortage of animal models with the ability to systematically pinpoint roadblocks to bnAb induction and to rank vaccine strategies based on their ability to stimulate bnAb development. Over the past six years, immunoglobulin (Ig) knock-in (KI) technology has been leveraged to express bnAbs in mice, an approach that has enabled elucidation of various B-cell tolerance mechanisms limiting bnAb production and evaluation of strategies to circumvent such processes. From these studies, in conjunction with the wealth of information recently obtained regarding the evolutionary pathways and paratopes/epitopes of multiple bnAbs, it has become clear that the very features of bnAbs desired for their function will be problematic to elicit by traditional vaccine paradigms, necessitating more iterative testing of new vaccine concepts. To meet this need, novel bnAb KI models have now been engineered to express either inferred pre-rearranged V(D)J exons (or unrearranged germline V, D, or J segments that can be assembled into functional rearranged V(D)J exons) encoding predecessors of mature bnAbs One encouraging approach that has materialized from studies using such newer models is sequential administration of immunogens designed to bind progressively more mature bnAb predecessors. In this review, insights into the regulation and induction of bnAbs based on the use of KI models will be discussed, as will new Ig KI approaches for higher-throughput production and/or altering expression of bnAbs in vivo, so as to further enable vaccine-guided bnAb induction studies.

The molecular immune modulator adenosine deaminase-1 enhances HIV specific humoral and cellular responses to a native-like HIV envelope trimer DNA vaccine

“…We demonstrated neutralization against the Tier 1A virus Q461e2TAIV; however, we were unable to achieve neutralization in any immunization groups against the Tier 1B virus Q23env17 and or the autologous BG505 virus. Future investigation is needed in other animal models, such as human immunoglobulin, bNAb knock-in mice [ 61 – 65 ], or NHP to evaluate the extent to which ADA-1 can induce bNAb’s for HIV-1.…”

The Mechanism of bnAb Production and Its Application in Mutable Virus Broad-Spectrum Vaccines: Inspiration from HIV-1 Broad Neutralization Research

“…Animal models can effectively detect the success of the induction of a bnAb strategy. Studies with knockout B cells with bnAb UCA BCR into mice can preliminarily speculate on the role of a bnAb induction strategy in their amplification [ 76 , 77 ]. Recently, the bnAb induction model of simian human immunodeficiency virus (SHIV) infection in monkeys has provided a tool for the study of antibody environment co-evolution, and can serve as a guide for inducing bnAb [ 63 ].…”