Document Type

Article

Publication Date

2-19-2020

Identifier

DOI: 10.1038/s41467-020-14670-w; PMCID: PMC7031230

Abstract

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.

Journal Title

Nat Commun

Volume

11

Issue

1

MeSH Keywords

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

Keywords

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

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