Glycan dependent epitopes of HIV broadly neutralizing antibodies

NIH Pandemic-Era Grants

Pandemic Era Grants

2020

↗ Live URL (may be dead)

Document text

Principal Investigator: JAMES C PAULSON
Organization: SCRIPPS RESEARCH INSTITUTE, THE
Fiscal Year: 2020
Award: $887,498
Funding agency: National Institute of Allergy and Infectious Diseases

PROJECT SUMMARY/ABSTRACT
There is as yet no effective vaccine to HIV despite concerted efforts by numerous groups worldwide to produce
one. The target for vaccines is the envelope spike protein (gp120/gp41), which mediates binding to receptors
on the surface of CD4 T cells. The problem from a vaccine perspective is that the spike protein is heavily
glycosylated, with up to 25 or more N-linked glycans, creating a `glycan shield' that prevents an immune
response to the underlying protein. Yet, many HIV infected individuals develop broadly neutralizing antibodies
(bnAbs) that utilize glycans as part of their binding epitopes or accommodate glycans for binding to conserved
features of the underlying protein. In the past project period, we have developed methods for analyzing site
specific glycosylation of the N-linked glycans of the envelope protein produced recombinantly and isolated from
virus grown in peripheral blood lymphocytes. We have observed that site specific glycan processing of native
virus envelope trimer differs significantly from the corresponding SOSIP trimers being evaluated as vaccine
candidates. In this project we will increase the sensitivity of the methods to analyze glycosylation of native virus
from blood of HIV patients. For representative strains, we will develop soluble trimers that have glycosylation
similar to the envelope of native virus and compare them with SOSIP stabilized trimers for their ability to elicit
neutralizing antibodies in animal models. The results will help assess the importance of establishing native-like
glycosylation for optimally eliciting neutralizing antibodies of HIV.

Terms: <AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Animal Model><Animal Models and Related Studies><Antibodies><Antigenic Determinants><Binding><Binding Determinants><Blood><Blood Reticuloendothelial System><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cell Body><Cells><Chronic><Cleaved cell><Clinical Trials><Complex><D-Mannose><Embryo><Embryonic><Envelope Protein><Epitopes><Exhibits><Future><Genetic Alteration><Genetic Change><Genetic defect><Glycans><HIV><HIV Antibodies><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV Infections><HIV env Protein gp120><HIV vaccine><HIV-Associated Antibodies><HIV/AIDS Vaccines><HTLV-III Antibodies><HTLV-III Infections><HTLV-III gp120><HTLV-III-LAV Antibodies><HTLV-III-LAV Infections><Human><Human Immunodeficiency Viruses><Human T-Lymphotropic Virus Type III Antibodies><Human T-Lymphotropic Virus Type III Infections><Hybrids><Immune response><Immunize><Immunological response><Individual><Kidney><Kidney Urinary System><LAV Antibodies><LAV-HTLV-III><Laboratory Study><Link><Lymphadenopathy-Associated Antibodies><Lymphadenopathy-Associated Virus><Mannopyranose><Mannopyranoside><Mannose><Mediating><Membrane><Membrane Protein Gene><Membrane Proteins><Membrane-Associated Proteins><Metabolic Glycosylation><Methods><Modern Man><Molecular Interaction><Mutation><PBMC><Patients><Peripheral Blood Lymphocyte><Peripheral Blood Mononuclear Cell><Polysaccharides><Primates><Primates Mammals><Proteins><Receptor Protein><Recombinants><Series><Site><Structure><Surface><Surface Proteins><T4 Cells><T4 Lymphocytes><Testing><Tissues><Transgenic Mice><Translating><Vaccination><Vaccine Design><Vaccines><Viral Diseases><Virus><Virus Diseases><Virus-HIV><cleaved><design><designing><env Antigens><env Gene Products><env Polyproteins><env Protein><genome mutation><glycosylation><gp120><gp120 ENV Glycoprotein><gp120(HIV)><host response><human immunodeficiency virus vaccine><humanized mice><humanized mouse><immunogenicity><immunoresponse><improved><membrane structure><model of animal><model organism><mouse model><murine model><neutralizing antibody><non-human primate><nonhuman primate><prevent><preventing><receptor><renal><tool><vaccine candidate><viral infection><virus envelope><virus infection><virus-induced disease>