Document text
Principal Investigator: HEATHER R DESAIRE
Organization: UNIVERSITY OF KANSAS LAWRENCE
Fiscal Year: 2019
Award: $671,763
Funding agency: National Institute of Allergy and Infectious Diseases
DESCRIPTION (provided by applicant): Preventing human immunodeficiency virus (HIV-1) transmission by vaccination is a highly desirable, but elusive, goal. Vaccine-induced antibodies that bind the HIV-1 envelope glycoprotein (Env) spike and neutralize the virus are thought to be a desirable component of a protective immune response; as a consequence, recombinantly expressed immunogens containing the exterior portion of Env are generally regarded as an essential element of a prophylactic vaccine. The HIV-1 Env is highly glycosylated, with glycans accounting for about 50% of the glycoprotein mass. These glycans contribute significantly to a number of viral functions, including the ability of HIV-1 to evade antibody responses. The presence and type of glycans on Env-based vaccine candidates influence both immunogenicity and antigenicity of the protein, and several of the gp120 and gp41 glycans serve as epitopes or components of epitopes targeted by potent HIV-1-neutralizing antibodies. If there is any hope of eliciting these types of antibodies during vaccination, the glycans on the Env vaccine must be of the same type as those found on the virus. Therefore, two critical questions facing the field of HIV-1 vaccine development with respect to Env glycosylation are: (1) What is the glycan profile of native HIV-1 Env? and (2) How can that glycan profile be recapitulated in an Env-based vaccine? Answering these two fundamental questions would represent a significant advance in HIV-1 vaccine research: If the glycan profile of a vaccine candidate could match that of native virus, the chances of eliciting effective antibodies that contain glycan-based epitopes would be increased. The two goals of this application are to characterize the glycosylation of Env from the most native source possible, from T-lymphocytes, and to identify ways to express Env with the correct glycosylation in a more tractable cell line that could be used in GMP manufacturing of Env for human clinical trials. This project will be run by a synergistic, collaborative team wit complementary strengths. The group has recently published the glycosylation profile of an HIV-1 membrane Env trimer, taking advantage of highly relevant technical innovations in Env glycoprotein production, sample preparation, and glycosylation analysis; these recent developments provide a strong foundation for the studies proposed herein. The successful completion of the project will provide all vaccine developers with the tools they need to generate native glycosylation profiles on their Env of choice.
Terms: <AIDS Vaccines><AIDS Virus><AIDS vaccine><ATGN><Accounting><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Amino Acid Sequence><Antibodies><Antibody Response><Antigenic Determinants><Antigens><Binding><Binding Determinants><C-C CKR-5><C-C CKR-5 Gene><C-C Chemokine Receptor Type 5><C-C Chemokine Receptor Type 5 Gene><CC Chemokine Receptor 5><CC-CKR-5><CC-CKR-5 Gene><CC-CKR5><CCCKR5><CCCKR5 Gene><CCR-5><CCR-5 Gene><CCR5><CCR5 Protein><CCR5 Receptors><CCR5 gene><CD195 Antigen><CD195 Antigen Gene><CHEMR13><CHEMR13 Gene><CKR-5><CKR-5 Gene><CKR5><CKR5 Gene><CKR5 Receptors><CMKBR5><CMKBR5 Gene><Carbohydrates><Cell Body><Cell Line><Cell membrane><CellLine><Cells><Chemokine (C-C Motif) Receptor 5><Chemokine (C-C) Receptor 5><Chemokine (C-C) Receptor 5 Gene><Clinical Trials><Complex><Cytoplasmic Membrane><D-Mannose><Development><Elements><Epitopes><Foundations><General Viruses><Glycans><Glycobiology><Glycoproteins><Goals><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV env Protein gp120><HIV vaccine><HIV-1 Fusion Co-Receptor><HIV-1 Fusion Co-Receptor Gene><HIV/AIDS Vaccines><HTLV-III gp120><Health Priorities><Human><Human Immunodeficiency Viruses><Immune response><Immune system><Immunological response><LAV-HTLV-III><Lectin><Lymphadenopathy-Associated Virus><Macaca mulatta><Mannopyranose><Mannopyranoside><Mannose><Mediating><Membrane><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Metabolic Glycosylation><Methods><Modality><Modern Man><Molecular Interaction><Plasma Membrane><Polysaccharides><Preparation><Preventative vaccine><Preventive vaccine><Primary Protein Structure><Production><Prophylactic vaccine><Proteins><Publishing><Receptor Cell><Recombinants><Rhesus><Rhesus Macaque><Rhesus Monkey><Running><SHIV><Sampling><Site><Source><Strains Cell Lines><Surface><Surface Proteins><System><T-Cells><T-Lymphocyte><Transmission><Vaccination><Vaccine Clinical Trial><Vaccine Research><Vaccines><Variant><Variation><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Physiology><Virion><Virus><Virus Diseases><Virus Particle><Virus-HIV><Wit><Work><allergic/immunologic body system><allergic/immunologic organ system><base><cultured cell line><develop a vaccine><development of a vaccine><developmental><global health><glycosylation><gp120><gp120 ENV Glycoprotein><gp120(HIV)><host response><human immunodeficiency virus vaccine><immunogen><immunogenicity><immunoresponse><inhibitor><inhibitor/antagonist><innovate><innovation><innovative><membrane structure><neutralizing antibody><plasmalemma><prevent><preventing><protein sequence><public health relevance><simian HIV><simian human immunodeficiency virus><thymus derived lymphocyte><tool><transmission process><vaccination study><vaccination trial><vaccine candidate><vaccine development><vaccine formulation><vaccine study><vaccine trial><viral infection><viral transmission><virus envelope><virus infection><virus transmission><virus-induced disease>