Novel mouse model of HIV broad neutralizing antibody induction

Duke University, Durham NC

Investigators

Linked publications & trials

Abstract

? DESCRIPTION (provided by applicant): Induction of HIV broad neutralizing antibodies (bnAbs) is a major goal of HIV vaccine development. While bnAbs arise in roughly 20% of HIV chronically infected individuals; they do not arise following HIV Envelope vaccination in animal or man. BnAbs tend to have unique traits such as long HCDR3s, extensive somatic hypermutation, and polyreactivity, all traits that predispose antibodies to be controlled by tolerance mechanisms. Thus, development of bnAb B cell lineages may be impeded due to their unique traits. To date the only in vivo models to study development of neutralization breadth are in humans with chronic HIV infection. Recent studies using stably transformed B cell lines expressing germline versions of broad neutralizing and narrow neutralizing (nNab) CD4 binding site antibodies demonstrated that B cells expressing germline versions of non-neutralizing antibodies were more easily activated by HIV Env (29). Furthermore, when pools of cells expressing bnAb and nNAb UCAs were mixed, B cells expressing nNAb UCA were preferentially activated, owing to their higher affinity for HIV Env. Taken together, these in vitr studies provide important hypotheses as to reasons why Env fails to induce bnAbs and provide an in vitro model for events that might transpire in germinal centers during the antibody response to Env. This data however, does not account for in vivo factors that can reduce fitness of bnAb precursors, thus contributing to bnAb subdominance. In this grant, we will establish a novel and relevant in vivo model of bnAb/non-bnAb B cell competition in the germinal center by constructing chimeras comprised of CH01 UCA and CH58 UCA knock-in mouse bone marrow. We will use this model to define the mechanisms of bnAb precursor activation and selection in germinal centers. By constructing mouse chimeras with varying ratios of CH01 UCA and CH58 UCA from knock-in mouse bone marrow, we can study ontogeny of bnAb and strain-specific antibody UCAs and affinity maturation pathways after vaccination. We anticipate this project will define mechanisms of HIV-1 bnAb subdominance, thus informing future directions to create a potent and effective prophylactic HIV-1 vaccine.