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Principal Investigator: Pamela J Bjorkman
Organization: CALIFORNIA INSTITUTE OF TECHNOLOGY
Fiscal Year: 2024
Award: $1,724,205
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY
SHIV-infected rhesus macaques (RMs) develop HIV-1 broadly neutralizing antibodies (bNAbs) via Env-antibody
(Ab) co-evolutionary pathways that recapitulate events in HIV-1 infected humans. This includes the frequency of
bNAb induction, the viral epitopes targeted, and the immunogenetic and structural features of bNAbs, which are
all similar in RMs and humans. Thus, we hypothesize that SHIV-infected RMs can serve as a guide for HIV-1
immunogen design, allowing for an iterative analysis of Env-Ab coevolution and the design of lineage-based
immunogens in a way not previously possible. There are three main hurdles to inducing bNAbs in monkeys and
humans: (i) efficient priming of rare HIV bNAb germline (GL) B cells; (ii) immunofocused boosting of B cell
responses targeting conserved bNAb epitopes and away from off-target epitopes; and (iii) affinity-guided,
antigen-driven maturation of B cell lineages. We hypothesize that we can find solutions to all of these inter-
related challenges by using the SHIV animal model to guide the design of new priming and boosting immunogens
that target V3 glycan and CD4 binding site (CD4bs) bNAb epitopes. Specifically, we will work with the Bjorkman
laboratory and Core A to incorporate selective glycan deletions and other GL-targeted mutations into our SHIV
designs to immunofocus early B cell responses to the V3 glycan and CD4bs bNAb epitopes. We will also develop
lineage-maturing SHIVs designed to boost bNAb responses that are primed by GL-targeted Env trimer
nanoparticles or mRNA-LNPs vaccines and then allow the natural process of Env-Ab coevolution in the setting
of an evolving SHIV quasispecies to affinity-mature the primed bNAb lineages to neutralization breath. In both
instances, we will decipher SHIV Env-Ab co-evolution where, unlike in humans, we can analyze multiple animals
infected by the same SHIVs and identify maturation pathways that are shared among different outbred animals.
We hypothesize that such analyses, when combined with work by the Bjorkman and Nussenzweig laboratories,
can provide a “blueprint” for lineage-based immunogens by identifying key Env variants that bind bNAb
precursors and intermediate stage antibodies required for affinity maturation. In the last year of the Project, we
will determine the protective capacity of the best lineage-based protein and/or mRNA-LNP immunization regimen
against a heterologous tier 2 SHIV challenge. Throughout these studies, we will work closely with the Bjorkman
and Nussenzweig laboratories to assess the impact of antibody feedback on bNAb development in both
vaccinated and SHIV-infected RMs.
Terms: <AIDS Virus><Abbreviations><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Affinity><Animal Model><Animal Models and Related Studies><Animals><Antibodies><Antibody Affinity><Antibody Response><Antigenic Determinants><Antigens><Apical><Autologous><Automobile Driving><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Binding Sites><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cell Lineage><Clinical><Clinical Treatment Moab><Collaborations><Combining Site><Development><Dose><Envelope Protein><Epitope Mapping><Epitopes><Event><Feedback><Frequencies><Generations><Genetic Alteration><Genetic Change><Genetic defect><Germ Lines><Glycans><HIV><HIV-1><HIV-I><HIV1><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Immunization><Immunogenetics><Infection><LAV-HTLV-III><Laboratories><Lymphadenopathy-Associated Virus><M mulatta><M. mulatta><Macaca mulatta><Maps><Membrane><Messenger RNA><Modeling><Modern Man><Molecular><Molecular Interaction><Monkeys><Monoclonal Antibodies><Mutation><Pathway interactions><Pattern><Peptides><Polysaccharides><Process><Proteins><Reactive Site><Rectum><Regimen><Rhesus><Rhesus Macaque><Rhesus Monkey><SHIV><Specificity><T4 Cells><T4 Lymphocytes><Testing><Translating><Vaccinated><Vaccination><Vaccines><Variant><Variation><Viral><Virus-HIV><Work><antigen antibody affinity><design><designing><developmental><driving><env Antigens><env Gene Products><env Polyproteins><env Protein><genome mutation><immunogen><immunogenicity><improved><lipid based nanoparticle><lipid nanoparticle><mAbs><mRNA><mRNA lipid nano particle vaccine><mRNA-LNP based vaccine><mRNA-LNP combination vaccines><mRNA-LNP vaccines><membrane structure><model of animal><monoclonal Abs><nano particle><nano-sized particle><nanoparticle><nanosized particle><neutralizing antibody><novel><pathway><pre-clinical trial><preclinical trial><protective efficacy><response><simian HIV><simian human immunodeficiency virus><success><vector>