1. Increased, Durable B-Cell and ADCC Responses Associated with T-Helper Cell Responses to HIV-1 Envelope in Macaques Vaccinated with gp140 Occluded at the CD4 Receptor Binding Site
- Author
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Petra Mooij, Willy M. J. M. Bogers, Daniella Mortier, Niels Beenhakker, Herman Oostermeijer, Rachel P. J. Lai, Indresh K. Srivastava, David C. Montefiori, Brian Burke, David Davis, Grégoire Martin, Susan W. Barnett, Gerrit Koopman, Ivonne G. Nieuwenhuis, Edmund Remarque, Antu K. Dey, Guido Ferrari, Jonathan L. Heeney, Loïc Martin, Yide Sun, Heeney, Jonathan [0000-0003-2702-1621], Apollo - University of Cambridge Repository, Novartis Vaccines, Centre de recherche du CEA/DSV/iBiTec-S/SIMOPRO, Novartis Vaccines and Diagnostics [Siena], Department of Anatomy and Cell Biology, The University of Florida College of Medicine, Duke Human Vaccine Institute [Durham, North Carolina, USA], Duke Human Vaccine Institute, and Duke School of Medicine
- Subjects
0301 basic medicine ,CD4 mimetic ,[CHIM.THER]Chemical Sciences/Medicinal Chemistry ,HIV Antibodies ,chemistry.chemical_compound ,ComputingMilieux_MISCELLANEOUS ,AIDS Vaccines ,B-Lymphocytes ,human immunodeficiency virus ,Immunogenicity ,ELISPOT ,Vaccination ,env Gene Products, Human Immunodeficiency Virus ,T-Lymphocytes, Helper-Inducer ,T helper cell ,vaccines ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biomolecules [q-bio.BM] ,3. Good health ,medicine.anatomical_structure ,[SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology ,CD4 Antigens ,CD4 antigen ,nonhuman primates ,030106 microbiology ,Immunology ,B-cell responses ,Biology ,CD4 occluded ,Microbiology ,Affinity maturation ,03 medical and health sciences ,Antigen ,Virology ,Vaccines and Antiviral Agents ,medicine ,Animals ,[SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry, Molecular Biology/Biochemistry [q-bio.BM] ,B cell ,[SDV.BA.MVSA]Life Sciences [q-bio]/Animal biology/Veterinary medicine and animal Health ,Antibody-Dependent Cell Cytotoxicity ,Germinal center ,[SDV.IMM.IMM]Life Sciences [q-bio]/Immunology/Immunotherapy ,Antibodies, Neutralizing ,Macaca mulatta ,030104 developmental biology ,chemistry ,Insect Science ,T-cell responses ,HIV-1 ,Binding Sites, Antibody ,[SDV.IMM.VAC]Life Sciences [q-bio]/Immunology/Vaccinology - Abstract
Strategies are needed to improve the immunogenicity of HIV-1 envelope (Env) antigens (Ag) for more long-lived, efficacious HIV-1 vaccine-induced B-cell responses. HIV-1 Env gp140 (native or uncleaved molecules) or gp120 monomeric proteins elicit relatively poor B-cell responses which are short-lived. We hypothesized that Env engagement of the CD4 receptor on T-helper cells results in anergic effects on T-cell recruitment and consequently a lack of strong, robust, and durable B-memory responses. To test this hypothesis, we occluded the CD4 binding site (CD4bs) of gp140 by stable cross-linking with a 3-kDa CD4 miniprotein mimetic, serving to block ligation of gp140 on CD4 + T cells while preserving CD4-inducible (CDi) neutralizing epitopes targeted by antibody-dependent cellular cytotoxicity (ADCC) effector responses. Importantly, immunization of rhesus macaques consistently gave superior B-cell ( P < 0.001) response kinetics and superior ADCC ( P < 0.014) in a group receiving the CD4bs-occluded vaccine compared to those of animals immunized with gp140. Of the cytokines examined, Ag-specific interleukin-4 (IL-4) T-helper enzyme-linked immunosorbent spot (ELISpot) assays of the CD4bs-occluded group increased earlier ( P = 0.025) during the inductive phase. Importantly, CD4bs-occluded gp140 antigen induced superior B-cell and ADCC responses, and the elevated B-cell responses proved to be remarkably durable, lasting more than 60 weeks postimmunization. IMPORTANCE Attempts to develop HIV vaccines capable of inducing potent and durable B-cell responses have been unsuccessful until now. Antigen-specific B-cell development and affinity maturation occurs in germinal centers in lymphoid follicles through a critical interaction between B cells and T follicular helper cells. The HIV envelope binds the CD4 receptor on T cells as soluble shed antigen or as antigen-antibody complexes, causing impairment in the activation of these specialized CD4-positive T cells. We proposed that CD4-binding impairment is partly responsible for the relatively poor B-cell responses to HIV envelope-based vaccines. To test this hypothesis, we blocked the CD4 binding site of the envelope antigen and compared it to currently used unblocked envelope protein. We found superior and durable B-cell responses in macaques vaccinated with an occluded CD4 binding site on the HIV envelope antigen, demonstrating a potentially important new direction in future design of new HIV vaccines.
- Published
- 2017