756. Targeting Viral Entry in Gene Therapy of HIV-Infection
Authors: Jan van Lunzen, Tobias Glaunsinger, Felix Hermann, Klaus Kuehlcke, Alexander Alexandrov, Dorothee von Laer
Journal: Molecular Therapy (2006)

Despite significant improvements of the survival of HIV-infected patients during HAART, treatment limitations such as the development of drug-resistant HIV strains and long-term toxicities call for innovative treatment strategies. In this study, a novel antiviral gene that effectively inhibits virus entry was tested in a phase I/II clinical trial. The antiviral gene is expressed from a retroviral vector (M87o) and encodes for the membrane-anchored antiviral peptide C46. C46 comprises 46 amino acids, is derived from the second heptad repeat of the HIV-1 envelope glycoprotein gp41 and effectively inhibits fusion of the viral and cellular membranes during virus entry. The membrane-anchored form (maC46) was shown to effectively block entry of a broad range of HIV isolates, including viruses resistant to the fusion inhibitory peptide C36 (T20). C36 (T20) corresponds to the 36 C-terminal amino acids of C46. The gene was introduced into autolous CD4 T lymphocytes from 10 patients with severe immunodeficiency and HAART failure. Cells were expanded by co-stimulation with anti-CD3 and anti-CD28 immobilized on beads. Between 2 and 15 × 10E9 cells were infused. No major toxicities were observed and neither cellular nor humoral immune responses to the transgene product were detected. While a significant rise in T helper cell counts was seen, viral load was not affected. Gene marking could be detected throughout the one-year follow-up, but the levels were too low to account for the marked rise in CD4 counts. Despite significant improvements of the survival of HIV-infected patients during HAART, treatment limitations such as the development of drug-resistant HIV strains and long-term toxicities call for innovative treatment strategies. In this study, a novel antiviral gene that effectively inhibits virus entry was tested in a phase I/II clinical trial. The antiviral gene is expressed from a retroviral vector (M87o) and encodes for the membrane-anchored antiviral peptide C46. C46 comprises 46 amino acids, is derived from the second heptad repeat of the HIV-1 envelope glycoprotein gp41 and effectively inhibits fusion of the viral and cellular membranes during virus entry. The membrane-anchored form (maC46) was shown to effectively block entry of a broad range of HIV isolates, including viruses resistant to the fusion inhibitory peptide C36 (T20). C36 (T20) corresponds to the 36 C-terminal amino acids of C46. The gene was introduced into autolous CD4 T lymphocytes from 10 patients with severe immunodeficiency and HAART failure. Cells were expanded by co-stimulation with anti-CD3 and anti-CD28 immobilized on beads. Between 2 and 15 × 10E9 cells were infused. No major toxicities were observed and neither cellular nor humoral immune responses to the transgene product were detected. While a significant rise in T helper cell counts was seen, viral load was not affected. Gene marking could be detected throughout the one-year follow-up, but the levels were too low to account for the marked rise in CD4 counts.