DEVELOPMENT OF IMMUNE MODULATORY VIRAL VECTORS

University Of Virginia Charlottesville, Charlottesville VA

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Abstract

Viral vectors provide powerful tools as vehicles for gene therapy. Lentivirus vectors show great promise in this respect, since they can deliver genes to non-dividing cells and have the potential for long- term stable expression. However, if a "foreign" transgene is delivered, immune responses will likely lead to eventual elimination of transduced cells, especially if repeat administration is required. This pilot grant proposal will evaluated the potential for modulation of such responses by the incorporation of "immunosuppresive" genes into the lentivirus vector itself. To this end, we will insert adenovirus E3 genes or the HIVCNef gene into a lentivirus vector containing a lacZ gene and analyze the effects the expression of the se genes on transgene expression and immune responses to transduced cells. These experiments will include gene delivery to the vasculature and liver using rat and mouse animal model systems. The specific aims are: 1) To analyze transgene expression and immune responses after gene delivery to the vasculature and liver using lentivirus vectors. We will evaluate the potential of novel lentivirus vectors that we have developed in comparison with gene delivery using an adenovirus vector. 2) To construct lentivirus vectors carrying potential immune- modulatory genes and evaluate these vectors vitro. We will analyze the expression of transgenes and immune-modulatory genes and the effects of expression of these genes on immune recognition of transduced cells 3) to analyze the effects of immune-modulatory genes on transgene expression and immune responses after delivery to the vessel wall and liver. Vectors that show promise based on the experiments in Specific Aim 2 will be further analyzed in animal experiments. These experiments will include an analysis of the effects of the immune- modulatory genes on the duration of transgene expression.