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Principal Investigator: Leonidas Stamatatos
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2024
Award: $349,040
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY / ABSTRACT
An effective HIV-1 vaccine will be one that elicits diverse anti-viral immune responses, including broadly
neutralizing antibodies (bnAbs). Here, we focus on eliciting anti-CD4-binding site (CD4-BS) bnAbs, including
VRC01-class bnAbs, through a guided immunization approach with specifically designed Env-derived
immunogens. We previously reported on the design of a clade C Env-derived immunogen that activates naïve
B cells expressing the bnAb precursors of VRC01-class antibodies in vivo. We also reported on the design of a
second immunogen, derived from a clade B Env, that when administered as a 1st boost, increases the
maturation of the emerging VRC01 B cells. Our proposal is based on our recent identification of two additional
Env immunogens that complete the maturation of VRC01-class antibody responses towards their cross-
neutralizing forms. Thus, after 4 Env immunizations of knock-in mice expressing elements of human VRC01
BCRs, we isolate VRC01-class antibodies that neutralize ~33% of heterologous tier 2 viruses. Here, our efforts
focus on optimizing this immunization schema to improve the neutralizing breadth of the elicited VRC01-class
antibodies. An important aspect of our proposal is that we will not limit our work to well-controlled knock-in
mice, but transgenic mice that express diverse human VH/VL genes, as well. Because the B cell repertoire of
these mice better reflects that of humans, we expect that our optimized immunization schema will not only lead
to the generation of VRC01-class antibodies, as it does in the knock-in mice, but that additional classes of anti-
CD4-BS antibody responses will also be elicited. A second important aspect of our proposal is that we will
examine whether mRNA-based immunogen-delivery platforms accelerate the development of cross-
neutralizing CD4-BS antibody responses.
Terms: <AIDS Virus><Acceleration><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Adjuvant><Affect><Antibodies><Antibody Binding Sites><Antibody Response><Antigens><B blood cells><B cell><B cell receptor><B cell repertoire><B cells><B-Cell Antigen Receptor><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Sites><Combining Site><Data><Development><Elements><Frequencies><Generalized Growth><Generations><Genes><Genetic Alteration><Genetic Change><Genetic defect><Germ Lines><Growth><HIV><HIV-1><HIV-1 vaccine><HIV-I><HIV1><HIV1 vaccine><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><Immune response><Immunization><Immunochemical Immunologic><Immunologic><Immunological><Immunological response><Immunologically><Immunologics><Infection><KI mice><Knock-in Mouse><LAV-HTLV-III><Lead><Light><Lymphadenopathy-Associated Virus><Messenger RNA><Methodology><Mice><Mice Mammals><Modern Man><Molecular Interaction><Murine><Mus><Mutation><Paratopes><Pathway interactions><Pb element><Photoradiation><Production><Proteins><Protocol><Protocols documentation><Reactive Site><Recombinant Proteins><Reporting><Surface><Tissue Growth><Transgenic Mice><Vaccines><Viral><Virus><Virus-HIV><Work><antibody combining site><design><designing><developmental><genome mutation><heavy metal Pb><heavy metal lead><host response><immune system response><immunogen><immunoresponse><improved><in vivo><isolated individuals><isolated people><knockin mice><lonely individuals><lonely people><mRNA><mouse model><murine model><neutralizing antibody><ontogeny><pathway><response><viral testing><virus testing>