Gene therapy is an important, new and expanding field of experimental medicine and has enormous potential. A significant number of human genes have recently been identified, that are mutated or altered in human diseases. The number of such genes will expand dramatically in the near future as efforts to sequence the entire human genome yields fruit. Gene therapy offers the opportunity to replace mutant genes in individuals suffering from genetic diseases, with corrected forms of the genes. A example, here is cystic fibrosis, where there are widespread attempts to deliver the gene encoding the CFIR protein into the upper respiratory tract of diseased youths. In addition to this more classical gene therapy, there are substantial efforts to to treat other human diseases, such as cancer, heart disease, diabetes, and liver disease by delivering normal or altered genes or proteins that have therapeutic effects. An example, here is the use of endothelial cell growth factors to promote blood vessel growth in the limbs of patients that have occluded arteries. In this case, the effects are substantial, often cases of gangrene related to loss of blood supply can be reversed and patient's limbs can be saved. The major problem that has limited efforts to obtain sustained gene therapy is that there are host immune responses directed to the viruses used as vectors as well as to the therapeutic gene or transgene. It is our hypothesis that a panel of herpesvirus proteins that act as inhibitors of the immune system can be used to prevent this host immunity. We intend to test this hypothesis by introducing herpes simplex virus ICP47, an inhibitor of CD8+ T lymphocytes, into recombinant adenovirus gene therapy vectors. In order to test whether ICP47 can sustain transgene expression, adenoviruses with and without ICP47 will be injected into rhesus macaques and expression of the transgene measured over the course of the succeeding weeks. The studies will also be extended to another family of herpesvirus immune evasion proteins encoded by human cytomegalovirus.
