Strategies for induction of HIV‐1 envelope‐reactive broadly neutralizing antibodies

Abstract

IntroductionA primary focus of HIV‐1 vaccine development is the activation of B cell receptors for naïve or precursor broadly neutralizing antibodies (bnAbs), followed by expansion and maturation of bnAb B cell lineage intermediates leading to highly affinity‐matured bnAbs. HIV‐1 envelope (Env) encodes epitopes for bnAbs of different specificities. Design of immunogens to induce bnAb precursors of different specificities and mature them into bnAb status is a goal for HIV‐1 vaccine development. We review vaccine strategies for bnAb lineages development and highlight the immunological barriers that these strategies must overcome to generate bnAbs.MethodsWe provide perspectives based on published research articles and reviews.DiscussionThe recent Antibody Mediated Protection (AMP) trial that tested the protective efficacy of one HIV‐1 Env bnAb specificity demonstrated that relatively high levels of long‐lasting serum titers of multiple specificities of bnAbs will be required for protection from HIV‐1 transmission. Current vaccine efforts for induction of bnAb lineages are focused on immunogens designed to expand naïve HIV‐1 bnAb precursor B cells following the recent success of vaccine‐induction of bnAb precursor B cells in macaques and humans. BnAb precursor B cells serve as templates for priming‐immunogen design. However, design of boosting immunogens for bnAb maturation requires knowledge of the optimal immunogen design and immunological environment for bnAb B cell lineage affinity maturation. BnAb lineages acquire rare genetic changes as mutations during B cell maturation. Moreover, the immunological environment that supports bnAb development during HIV‐1 infection is perturbed with an altered B cell repertoire and dysfunctional immunoregulatory controls, suggesting that in normal settings, bnAb development will be disfavoured. Thus, strategies for vaccine induction of bnAbs must circumvent immunological barriers for bnAb development that normally constrain bnAb B cell affinity maturation.ConclusionsA fully protective HIV‐1 vaccine needs to induce durable high titers of bnAbs that can be generated by a sequential set of Env immunogens for expansion and maturation of bnAb B cell lineages in a permitted immunological environment. Moreover, multiple specificities of bnAbs will be required to be sufficiently broad to prevent the escape of HIV‐1 strains during transmission.

Neutralization Sensitivity of HIV-1 CRF07_BC From an Untreated Patient With a Focus on Evolution Over Time

“…With diversification of the Env gene comes diverse antigen stimulation for the immune system, activating naive B cells to induce the maturation of bNAbs ( Williams et al., 2021 ). The results of the phylogenetic tree and genetic distance showed significantly increased host and immunosuppressive effects on virus over time.…”

Immune Response to HIV-1 Infection and Vaccine Development

“…This class of antibodies have high levels of mutations in rare, low-affinity naive B cell receptors [24], and these B-cell receptor (BCR) display atypical structural and binding characteristics that the immune system usually negatively selects against during B cell development [24,25]. Some of the features of BnAbs are similar to those of autoreactive antibodies, indicating that they may evade immune tolerance mechanisms [26,27]. Through the chronic viral replication, BnAbs are generated due to the extensive affinity maturation in germinal centers [27,28].…”

Round up

“…However, precursors for VRC01-class antibodies are highly conservative when compared to precursors targeting other HIV epitopes (which are highly promiscuous). [ 20 21 ] Nevertheless, this study stands as a proof of concept for establishing and developing vaccine regimens that can boost the production of VRC01-class bnAbs against HIV and other pathogens.…”