THE CONSTITUTIVE EXPRESSION OF THE IMMUNOMODULATORY GP19K PROTEIN IN E1(-), E3(-) ADENOVIRAL VECTORS STRONGLY REDUCES THE HOST CYTOTOXIC T-CELL RESPONSE AGAINST THE VECTOR

The immune response against cells infected by gene therapy vectors may be a major hindrance for gene therapy, destroying infected cells thus limiting the length of exogene expression and quickly eliminating inf ected cells on repeal administration. Adenoviruses and many other path ogens have evolved strategies for escape from immune surveillance, inc luding the gp 19k gene, found in the adenovirus E3 region, known to do wn-regulate major histocompatibility complex class 1 expression on the cell surface, and thus reduce lysis of the infected cells by cytotoxi c T cells. We have constructed an adenoviral vector expressing the gen es for beta-galactosidase and gp 19k both under the control of constit utive promoters, and compared the capacity of lymphocytes from DBA/2 m ice previously injected with the virus or with Ad-beta gal, a virus ex pressing beta-galactosidase but not gp 19k, to lyse target cells infec ted with various viruses. Lymphocytes raised against Ad-beta gal fail to lyse target cells infected with Ad-beta gal-gp 19k significantly wh ereas Ad-beta gal infected target cells and a beta-galaclosidase expre ssing cell line are strongly lysed. The administration of Ad-beta gal- gp 19k fails to stimulate the proliferation of anti-vector lymphocytes , and thus these lymphocytes show poor cytotoxic activity against Ad-b eta gal or Ad-beta gal-gp 19k infected cells.