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Targeting HIV-1 envelope glycoprotein trimers to B cells by using APRIL improves antibody responses.

TitleTargeting HIV-1 envelope glycoprotein trimers to B cells by using APRIL improves antibody responses.
Publication TypeJournal Article
Year of Publication2012
AuthorsMelchers M, Bontjer I, Tong T, P Y Chung N, Klasse PJohan, Eggink D, Montefiori DC, Gentile M, Cerutti A, Olson WC, Berkhout B, Binley JM, Moore JP, Sanders RW
JournalJ Virol
Volume86
Issue5
Pagination2488-500
Date Published2012 Mar
ISSN1098-5514
KeywordsAnimals, Antibody Formation, B-Lymphocytes, Cell Line, Cells, Cultured, env Gene Products, Human Immunodeficiency Virus, HIV Antibodies, HIV Infections, HIV-1, Humans, Neutralization Tests, Protein Multimerization, Rabbits, Recombinant Fusion Proteins, Tumor Necrosis Factor Ligand Superfamily Member 13
Abstract

An HIV-1 vaccine remains elusive, in part because various factors limit the quantity and quality of the antibodies raised against the viral envelope glycoprotein complex (Env). We hypothesized that targeting Env vaccines directly to B cells, by fusing them to molecules that bind and activate these cells, would improve Env-specific antibody responses. Therefore, we fused trimeric Env gp140 to A PRoliferation-Inducing Ligand (APRIL), B-cell Activating Factor (BAFF), and CD40 Ligand (CD40L). The Env-APRIL, Env-BAFF, and Env-CD40L gp140 trimers all enhanced the expression of activation-induced cytidine deaminase (AID), the enzyme responsible for inducing somatic hypermutation, antibody affinity maturation, and antibody class switching. They also triggered IgM, IgG, and IgA secretion from human B cells in vitro. The Env-APRIL trimers induced higher anti-Env antibody responses in rabbits, including neutralizing antibodies against tier 1 viruses. The enhanced Env-specific responses were not associated with a general increase in total plasma antibody concentrations, indicating that the effect of APRIL was specific for Env. All the rabbit sera raised against gp140 trimers, irrespective of the presence of CD40L, BAFF, or APRIL, recognized trimeric Env efficiently, whereas sera raised against gp120 monomers did not. The levels of trimer-binding and virus-neutralizing antibodies were strongly correlated, suggesting that gp140 trimers are superior to gp120 monomers as immunogens. Targeting and activating B cells with a trimeric HIV-1 Env-APRIL fusion protein may therefore improve the induction of humoral immunity against HIV-1.

DOI10.1128/JVI.06259-11
Alternate JournalJ. Virol.
PubMed ID22205734
PubMed Central IDPMC3302291
Grant List280829 / / European Research Council / International
AI58763 / AI / NIAID NIH HHS / United States
AI84714 / AI / NIAID NIH HHS / United States
P01 AI061093 / AI / NIAID NIH HHS / United States
P01 AI82362 / AI / NIAID NIH HHS / United States
R01 AI074378 / AI / NIAID NIH HHS / United States
R37 AI036082 / AI / NIAID NIH HHS / United States
R37 AI36082 / AI / NIAID NIH HHS / United States
U01 AI095613 / AI / NIAID NIH HHS / United States
U19 AI096187 / AI / NIAID NIH HHS / United States

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