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Eliciting protective titers of HIV-1 broadly neutralizing antibodies (bnAbs) is a goal of HIV-1 vaccine development, but current vaccine strategies have yet to induce bnAbs in humans. Many bnAbs isolated from HIV-1-infected individuals are encoded by immunoglobulin gene rearrangments with infrequent naive B cell precursors and with unusual genetic features that may be subject to host regulatory control. Here, we administer antibodies targeting immune cell regulatory receptors CTLA-4, PD-1 or OX40 along with HIV envelope (Env) vaccines to rhesus macaques and bnAb immunoglobulin knock-in (KI) mice expressing diverse precursors of CD4 binding site HIV-1 bnAbs. CTLA-4 blockade augments HIV-1 Env antibody responses in macaques, and in a bnAb-precursor mouse model, CTLA-4 blocking or OX40 agonist antibodies increase germinal center B and T follicular helper cells and plasma neutralizing antibodies. Thus, modulation of CTLA-4 or OX40 immune checkpoints during vaccination can promote germinal center activity and enhance HIV-1 Env antibody responses.

Original publication

DOI

10.1038/s41467-020-14670-w

Type

Journal article

Journal

Nature communications

Publication Date

19/02/2020

Volume

11

Addresses

Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, 27710, USA. tcbradley@cmh.edu.

Keywords

B-Lymphocytes, T-Lymphocytes, Helper-Inducer, Animals, Mice, Transgenic, Macaca mulatta, Humans, Mice, HIV-1, HIV Infections, AIDS Vaccines, Immunologic Factors, Antibodies, Blocking, HIV Antibodies, Vaccination, Lymphocyte Activation, Receptors, OX40, env Gene Products, Human Immunodeficiency Virus, Antibodies, Neutralizing, CTLA-4 Antigen, Transcriptome, CD4 Antigens