Adenoviruses (Ad) contain genes that appear dedicated to the control of the host immune and cytokine responses in such a way as to facilitate either the efficiency of acute infection or the persistence of the virus. Many of these genes are clustered in early region 3 (E3), which codes for a gp19kDa protein that inhibits transport of the class I major histocompatibility complex (MHC) to the plasma membrane, a 14.7 kDa protein that inhibits tumor necrosis factor alpha (TNFa) cytolysis and a heterotrimeric complex of 2 polypeptides (10.4kDa and 14.5 kDa) that also inhibit the action of TNFa. The applicant postulated that the E3 genes, expressed under the control of a strong promoter, might downregulate the immune response to Ad-based, gene-therapy vectors and promote long term expression of Ad-delivered therapeutic genes. Recent experiments from our lab have proven that this postulate was correct. Remarkably, the overexpression of Ad E3 genes not only inhibited class I based cytotoxic T lymphocyte (CTL) responses but also profoundly inhibited the formation of neutralizing antibodies to the virus. This surprising observation has lead the applicant to a series of questions that ask (a) which of the Ad E3 genes are responsible for the abrogation of the antibody response, (b) whether the Ad E3 gene(s) can control the immune response to foreign proteins, synthesized and secreted from the liver and (c) how the E3 genes could be delivered and function in hepatocytes to facilitate allogeneic hepatocyte transplantation.
