Document text
Principal Investigator: Yoann Aldon
Organization: FRED HUTCHINSON CANCER CENTER
Fiscal Year: 2024
Award: $832,117
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
This research proposal aims to develop new immunogens for an HIV-1 vaccine by utilizing advanced protein design
techniques and deep learning methods. Conventional structure-guided approaches have limitations in achieving
desired structural characteristics. Therefore, this study proposes using RFdiffusion, ProteinMPNN, and AlphaFold2,
to generate new germline-targeting gp120 cores based on the pre-fusion native-like structure of the HIV-1 strain
426c. The designed immunogens prioritize maintaining the structural integrity of the pre-fusion gp120 while
removing the bridging sheet and re-designing specific regions to maintain the pre-fusion native-like backbone
structure. In addition, particular attention is directed towards masking off-target epitopes. In vitro characterization
will be performed to evaluate the binding characteristics of these immunogens with germline, broadly neutralizing,
and non-neutralizing antibodies. Subsequently, transgenic mice expressing human germline VRC01-class BCRs
will be utilized to assess the immunogenicity of selected immunogens presented on nanoparticles and analyze their
impact on germinal center B cell responses and memory B cell repertoire. Monoclonal antibodies (mAbs) obtained
from immunized animals will be structurally characterized, shedding light on antibody maturation pathways
influenced by the immunogen structure. Additionally, this research plan aims to expand the immunogen repertoire
by designing gp120 cores based from diverse HIV-1 clades/strains. Furthermore, to enhance immunogenicity,
membrane-bound and nanoparticles delivery through self-amplifying mRNA will be explored. The ultimate objective
of this research is to gain valuable insights into novel antigen design techniques and their application in HIV-1
vaccine strategies for broadly neutralizing antibodies development. The findings from this study will contribute to
the development of immunogens that closely resemble the pre-fusion gp120 state, potentially leading to enhanced
B-cell responses capable of generating broadly neutralizing antibody lineages. By addressing the complex features
of the HIV-1 Env protein and advancing immunogen design strategies, this research aims to make significant
contributions towards the development of an effective HIV-1 vaccine.
Terms: <Address><Adjuvant><Animals><Antibodies><Antibody Response><Antigen Presentation><Antigenic Determinants><Antigens><Attention><B blood cells><B cell><B cell repertoire><B cells><B-Cell Activation><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Binding Sites><C4 b><C4b><Cell Body><Cell Ontogeny><Cells><Characteristics><Clinical Treatment Moab><Clinical Trials><Combining Site><Complement 4b><Complement C4b><Complex><Core Protein><Data><Development><Elements><Engineering><Envelope Protein><Epitopes><Evaluation><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Fostering><Germ Lines><Germinal Center><HIV 1 Envelope Protein gp120><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV env Protein gp120><HIV-1><HIV-1 vaccine><HIV-I><HIV1><HIV1 vaccine><HTLV-III gp120><Human><Human Immunodeficiency Virus Type 1><Human immunodeficiency virus 1><Immune response><Immunization><Immunize><Immunological response><In Vitro><Incidence><Infection><Investigation><KI mice><Kinetics><Knock-in Mouse><Light><Mammalian Cell><Membrane><Memory B Cell><Memory B-Lymphocyte><Messenger RNA><Modern Man><Molecular Interaction><Monoclonal Antibodies><Pathway interactions><Photoradiation><Polishes><Prevention><Process><Property><Protein Engineering><Proteins><Reactive Site><Regimen><Research><Research Proposals><Role><Shapes><Spinal Column><Spine><Structure><Structure of germinal center of lymph node><Techniques><Testing><Transgenic Mice><Vaccinee><Vaccines><Vertebral column><activated B cells><alpha helix><backbone><biophysical characteristics><biophysical characterization><biophysical measurement><biophysical parameters><biophysical properties><deep learning><deep learning method><deep learning strategy><deliver mRNA><deliver messenger RNA><delivery system for mRNA><design><designing><develop a vaccine><develop vaccines><development of a vaccine><developmental><env Antigens><env Gene Products><env Polyproteins><env Protein><flow cytophotometry><genetic protein engineering><gp120><gp120 ENV Glycoprotein><gp120(HIV)><host response><immune system response><immunogen><immunogenic><immunogenicity><immunoresponse><improved><in vivo><innovate><innovation><innovative><insight><knockin mice><mAbs><mRNA><mRNA delivery><membrane structure><messenger RNA delivery><monoclonal Abs><mouse model><murine model><nano particle><nano particle delivery><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><neutralizing antibody><novel><pathway><preservation><protein design><response><screening><screenings><social role><tool><vaccinated individual><vaccinated participant><vaccinated patient><vaccinated person><vaccinated subject><vaccine development><vaccine strategy><α-helix>