title: A rationally engineered anti-HIV peptide fusion inhibitor with greatly reduced immunogenicity.
abstract: Peptides derived from the C-terminal heptad repeat 2 (HR2) region of the HIV-1 gp41 envelope glycoprotein, so-called C peptides, are very efficient HIV-1 fusion inhibitors. We previously developed innovative gene therapeutic approaches aiming at the direct in vivo production of C peptides from genetically modified host cells and found that T cells expressing membrane-anchored or secreted C peptides are protected from HIV-1 infection. However, an unwanted immune response against such antiviral peptides may significantly impair clinical efficacy and pose safety risks to patients. To overcome this problem, we engineered a novel C peptide, V2o, with greatly reduced immunogenicity and excellent antiviral activity. V2o is based on the chimeric C peptide C46-EHO, which is derived from the HR2 regions of HIV-2(EHO) and HIV-1(HxB2) and has broad anti-HIV and anti-simian immunodeficiency virus activity. Antibody and major histocompatibility complex class I epitopes within the C46-EHO peptide sequence were identified by in silico and in vitro analyses. Using rational design, we removed these epitopes by amino acid substitutions and thus minimized antigenicity and immunogenicity considerably. At the same time, the antiviral activity of the deimmunized peptide V2o was preserved or even enhanced compared to that of the parental C46-EHO peptide. Thus, V2o is an ideal candidate, especially for those novel therapeutic approaches for HIV infection that involve direct in vivo production of antiviral C peptides.
authors.affiliation: Applied Virology and Gene Therapy, Institute for Biomedical Research Georg-Speyer-Haus, Frankfurt am Main, Germany.
authors.forename: Frances
authors.initials: F
authors.lastname: Brauer
authors.forename: Kerstin
authors.initials: K
authors.lastname: Schmidt
authors.forename: Roland C
authors.initials: RC
authors.lastname: Zahn
authors.forename: Cornelia
authors.initials: C
authors.lastname: Richter
authors.forename: Heinfried H
authors.initials: HH
authors.lastname: Radeke
authors.forename: Jörn E
authors.initials: JE
authors.lastname: Schmitz
authors.forename: Dorothee
authors.initials: D
authors.lastname: von Laer
authors.forename: Lisa
authors.initials: L
authors.lastname: Egerer
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D002460:Cell Line; D003198:Computer Simulation; D018604:Epitope Mapping; D000939:Epitopes / Q000276:immunology; D057809:HEK293 Cells; D015483:HIV Antibodies / Q000097:blood; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D023581:HIV Fusion Inhibitors / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D015658:HIV Infections / Q000276:immunology; D015497:HIV-1 / Q000235:genetics; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma; D008253:Macaca mulatta; D010446:Peptide Fragments / Q000737:chemistry / Q000276:immunology* / Q000494:pharmacology; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology; D015302:Simian Immunodeficiency Virus; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology
chemical_list: C515020:C46 HIV-1 fusion inhibitory peptide; D000939:Epitopes; D015483:HIV Antibodies; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D007371:Interferon-gamma