An HIV-1 envelope glycoprotein trimer with an embedded IL-21 domain activates human B cells.

TitleAn HIV-1 envelope glycoprotein trimer with an embedded IL-21 domain activates human B cells.
Publication TypeJournal Article
Year of Publication2013
AuthorsIsik G, P Y Chung N, van Montfort T, Menis S, Matthews K, Schief WR, Moore JP, Sanders RW
JournalPLoS One
Volume8
Issue6
Paginatione67309
Date Published06/24/2013
ISSN1932-6203
KeywordsAntigens, Viral, B-Lymphocytes, Cell Differentiation, Cells, Cultured, env Gene Products, Human Immunodeficiency Virus, HIV Antibodies, HIV-1, Humans, Interleukins, Lymphocyte Activation, Protein Engineering, Protein Multimerization, Protein Structure, Tertiary, Recombinant Fusion Proteins
Abstract

Broadly neutralizing antibodies (bNAbs) that target the HIV-1 envelope glycoproteins (Env) can prevent virus acquisition, but several Env properties limit its ability to induce an antibody response that is of sufficient quantity and quality. The immunogenicity of Env can be increased by fusion to co-stimulatory molecules and here we describe novel soluble Env trimers with embedded interleukin-4 (IL-4) or interleukin-21 (IL-21) domains, designed to activate B cells that recognize Env. In particular, the chimeric Env(IL-21) molecule activated B cells efficiently and induced the differentiation of antibody secreting plasmablast-like cells. We studied whether we could increase the activity of the embedded IL-21 by designing a chimeric IL-21/IL-4 (ChimIL-21/4) molecule and by introducing amino acid substitutions in the receptor binding domain of IL-21 that were predicted to enhance its binding. In addition, we incorporated IL-21 into a cleavable Env trimer and found that insertion of IL-21 did not impair Env cleavage, while Env cleavage did not impair IL-21 activity. These studies should guide the further design of chimeric proteins and Env(IL-21) may prove useful in improving antibody responses against HIV-1.

DOI10.1371/journal.pone.0067309
Alternate JournalPLoS ONE
PubMed ID23826263
PubMed Central IDPMC3691133
Grant ListP0I AI82362 / AI / NIAID NIH HHS / United States
R37 AI036082 / AI / NIAID NIH HHS / United States
R37 AI36082 / AI / NIAID NIH HHS / United States
UM1 AI100663 / AI / NIAID NIH HHS / United States
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