Development of in vivo secreted antiviral entry inhibitory peptides for the treatment of HIV-infection

• Antragstellerinnen: Professorin Dr. Hildegard Büning; Professorin Dr. Dorothee von Laer
• Fachliche Zuordnung: Virologie
• Förderung: Förderung von 2009 bis 2014
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 131542860

Previously, we have developed a novel gene therapeutic strategy for the treatment of HIV infection. The antiviral gene product (maC46/M87o) is a membrane-anchored antiviral C peptide, which inhibits entry of HIV-1 with great efficacy. However, overall antiviral efficacy in patients depends on a robust selective advantage of the M87o gene-protected cells as initially only a small fraction of potential target cells for HIV can be genetically modified. In a phase I clinical trial, the safety and feasibility of the transfer of autologous M87o gene-modified T lymphocytes was shown in 10 patients. The fraction of gene-modified cells, however, remained below 1% of the T helper population, to low to achieve an overall antiviral effect (van Lunzen et al., 2007). In the proposed project, we want to overcome the limitations of this gene therapy approach by two strategies. Firstly, we will improve our current version of the in vivo secreted antiviral entry inhibitory (iSAVE) peptide that already showed potent in vitro antiviral activity even with low levels of gene-modified cells. The iSAVE peptide is derived from the C heptad repeat of HIV-2EHO and was found to inhibit entry at the level of membrane fusion for HIV-1, HlV-2 and SIV. To further improve the system, we will maximize the level of secretion, while the potential immunogenicity of the C peptide will be minimized. Secondly, this optimal iSAVE peptide will be expressed from a vector system that supports high level gene expression following systemic in vivo application. Potential target tissues are liver or even more advantageous the hematopoietic or lymphatic tissue. Such a directly injectable vector would allow broad application of this gene therapy approach. For this purpose we will select hematopoietic and lymphatic tissue-specific AAV targeting vectors (H. Büning), and compare these to the hepatotropic AAV serotype 8 vectors with regard to antiviral efficacy in the humanized mouse models for HIV infecfion established in the laboratory of D. v. Laer.

• DFG-Verfahren: Sachbeihilfen
• Internationaler Bezug: Österreich