Document text
Principal Investigator: Cynthia Ann Derdeyn
Organization: EMORY UNIVERSITY
Fiscal Year: 2021
Award: $223,125
Funding agency: National Institute of Allergy and Infectious Diseases
Project Summary/Abstract
HIV research efforts are strongly focused on developing vaccines that can elicit highly protective antibody
responses. There is evidence from human and nonhuman vaccine studies that both neutralizing and non-
neutralizing antibody activities contribute to protection against acquisition. Importantly, the only phase III vaccine
efficacy trial to show a signal of protection in human volunteers demonstrated that antibody dependent cell-
mediated cytotoxicity (ADCC) was associated with reduced acquisition, compelling us to know more about this
Fc-mediated antiviral function. We previously recovered a unique collection of more than 300 monoclonal
antibodies from 6 recently HIV-1 infected individuals from Zambia and Rwanda and found that a subset of these
antibodies mediated ADCC against target cells coated with the envelope gp120 protein from the autologous,
transmitted/founder (T/F) variant. This activity was associated with antibodies that had shorter CDRH3 regions
and lower neutralization activity against the T/F envelope pseudovirus than antibodies lacking ADCC activity.
Modeling and competition studies suggested that some of the ADCC-mediating antibodies recognize novel
epitopes. Here, we will test these monoclonal antibodies for ADCC against target cells infected with the authentic
T/F variant created by molecular cloning, and compare the results with ADCC against target cells coated with
the T/F gp120 protein and neutralization of the T/F Env, the latter being the hallmark of antibody binding to the
functional, virion-associated envelope spike. By using a large number of autologous T/F envelope-antibody
combinations, where the envelope presents the exact epitope or a very close approximation to that which the
antibody was selected against, and two widely used ADCC assays, our studies have the potential to reveal
previously unappreciated mechanistic features of ADCC and identify novel epitopes that can be further
developed and explored for vaccines.
Terms: <AIDS Virus><AIDS/HIV><AIDS/HIV problem><Ab-dependent cellular cytotoxicity><Ab-mediated immunity><Ab-mediated protection><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Africa South of the Sahara><Antibodies><Antibody Response><Antibody immunity><Antibody protection><Antibody-mediated protection><Antigenic Determinants><Antiviral Agents><Antiviral Drugs><Antivirals><Assay><Autologous><B blood cells><B cell><B cells><B-Cells><B-Lymphocytes><B-cell><Binding><Binding Determinants><Bioassay><Biologic Assays><Biological Assay><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><Cell Body><Cell Coat><Cell Communication and Signaling><Cell Isolation><Cell Segregation><Cell Separation><Cell Separation Technology><Cell Signaling><Cells><Chemokine (C-C Motif) Receptor 5><Chemokine (C-C) Receptor 5><Chemokine (C-C) Receptor 5 Gene><Clinical Treatment Moab><Collection><Cryofixation><Cryopreservation><Detection><Disease Progression><Effector Cell><Enrollment><Epitopes><Evaluation><Event><Genetic><Glycocalyx><Goals><HIV><HIV Envelope Glycoprotein gp120><HIV Envelope Protein gp120><HIV env Protein gp120><HIV vaccine><HIV-1><HIV-1 Fusion Co-Receptor><HIV-1 Fusion Co-Receptor Gene><HIV-I><HIV/AIDS><HIV/AIDS Vaccines><HIV/AIDS problem><HIV1><HTLV-III gp120><Heterosexuals><Human><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human Volunteers><Human immunodeficiency virus 1><Individual><Infection><Intracellular Communication and Signaling><LAV-HTLV-III><Lymphadenopathy-Associated Virus><Maps><Measures><Mediating><Mediator><Mediator of Activation><Mediator of activation protein><Modeling><Modern Man><Molecular Cloning><Molecular Interaction><Monoclonal Antibodies><Northern Rhodesia><PBMC><Patients><Peripheral Blood Mononuclear Cell><Phase><Proteins><Recombinants><Research><Ruanda><Rwanda><SHIV><Signal Transduction><Signal Transduction Systems><Signaling><Site><Statistical Data Analyses><Statistical Data Analysis><Statistical Data Interpretation><Sub-Saharan Africa><Subsaharan Africa><Surface><Testing><Transmission><Vaccinated><Vaccination><Vaccines><Variant><Variation><Viral><Virion><Virus><Virus Particle><Virus-HIV><Zambia><anti-viral agents><anti-viral drugs><anti-virals><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody-dependent cell cytotoxicity><antibody-dependent cellular cytotoxicity><antibody-mediated cytotoxicity><antibody-mediated immunity><base><biological signal transduction><cell sorting><cohort><cold preservation><cold storage><cross reactivity><efficacy trial><enroll><gp120><gp120 ENV Glycoprotein><gp120(HIV)><human immunodeficiency virus vaccine><innovate><innovation><innovative><insight><mAbs><neutralizing antibody><non-human primate><nonhuman primate><novel><response><simian HIV><simian human immunodeficiency virus><statistical analysis><transmission process><vaccination study><vaccination trial><vaccine efficacy><vaccine study><vaccine trial>