title: An HIV-1 envelope glycoprotein trimer with an embedded IL-21 domain activates human B cells.
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.
authors.affiliation: Laboratory of Experimental Virology, Department of Medical Microbiology Center for Infection and Immunity Amsterdam, University of Amsterdam, Amsterdam, The Netherlands.
authors.forename: Gözde
authors.initials: G
authors.lastname: Isik
authors.forename: Nancy P Y
authors.initials: NP
authors.lastname: Chung
authors.forename: Thijs
authors.initials: T
authors.lastname: van Montfort
authors.forename: Sergey
authors.initials: S
authors.lastname: Menis
authors.forename: Katie
authors.initials: K
authors.lastname: Matthews
authors.forename: William R
authors.initials: WR
authors.lastname: Schief
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
authors.forename: Rogier W
authors.initials: RW
authors.lastname: Sanders
mesh_terms: D000956:Antigens, Viral / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D015483:HIV Antibodies / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D007378:Interleukins / Q000737:chemistry*; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D015202:Protein Engineering; D055503:Protein Multimerization; D017434:Protein Structure, Tertiary; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000494:pharmacology; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry* / Q000494:pharmacology*; D000098546:Interleukin-21
chemical_list: D000956:Antigens, Viral; D015483:HIV Antibodies; D007378:Interleukins; D011993:Recombinant Fusion Proteins; D054299:env Gene Products, Human Immunodeficiency Virus; D000098546:Interleukin-21