title: C peptides as entry inhibitors for gene therapy.
abstract: Peptides derived from the C-terminal heptad repeat 2 region of the HIV-1 gp41 envelope glycoprotein, so-called C peptides, are very potent HIV-1 fusion inhibitors. Antiviral genes encoding either membrane-anchored (ma) or secreted (iSAVE) C peptides have been engineered and allow direct in vivo production of the therapeutic peptides by genetically modified host cells. Membrane-anchored C peptides expressed in the HIV-1 target cells by T-cell or hematopoietic stem cell gene therapy efficiently prevent virus entry into the modified cells. Such gene-protection confers a selective survival advantage and allows accumulation of the genetically modified cells. Membrane-anchored C peptides have been successfully tested in a nonhuman primate model of AIDS and were found to be safe in a phase I clinical trial in AIDS patients transplanted with autologous gene-modified T-cells. Secreted C peptides have the crucial advantage of not only protecting genetically modified cells from HIV-1 infection, but also neighboring cells, thus suppressing virus replication even if only a small fraction of cells is genetically modified. Accordingly, various cell types can be considered as potential in vivo producer cells for iSAVE-based gene therapeutics, which could even be modified by direct in vivo gene delivery in future. In conclusion, C peptide gene therapeutics may provide a strong benefit to AIDS patients and could present an effective alternative to current antiretroviral drug regimens.
authors.affiliation: Division of Virology, Department of Hygiene, Microbiology and Social Medicine, Medical University of Innsbruck, Peter Mayr-Str. 4b, Innsbruck, 6020, Austria, lisa.egerer@i-med.ac.at.
authors.forename: Lisa
authors.initials: L
authors.lastname: Egerer
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Kiem
authors.forename: Dorothee
authors.initials: D
authors.lastname: von Laer
mesh_terms: D000818:Animals; D000077560:Enfuvirtide; D015316:Genetic Therapy / Q000379:methods*; D015700:HIV Envelope Protein gp41 / Q000235:genetics*; D015658:HIV Infections / Q000628:therapy*; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008561:Membrane Fusion / Q000235:genetics; D010446:Peptide Fragments / Q000235:genetics*; D053586:Virus Internalization
chemical_list: D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; D000077560:Enfuvirtide