Expression of gp19K increases the persistence of transgene expression from an adenovirus vector in the mouse lung and liver

Activation of the cellular immune system and subsequent lysis of vector-transduced cells by adenovirus-or transgene-specific cytotoxic T lymphocytes have been shown to limit transgene expression in animal models, The adenovirus gp19K gene product associates with major histocompatibility complex class I proteins and prevents their maturation by sequestering them in the endoplasmic reticulum. gp19K has been shown to block the ability of adenovirus-specific cytotoxic T lymphocytes to recognize virus-infected cells in vitro. To determine if gp19K( expression in an adenovirus vector would increase transgene persistence, a vector that replaces the El region of adenovirus with an expression cassette encoding both gp19K and beta-glucuronidase was constructed. This vector produced high levels of functional gp19K; in infected cells. RNase protection analysis revealed efficient expression of the gp19K gene in the mouse lung, Enhanced persistence and increased beta-glucuronidase activity were observed in the lung and liver following delivery of the gp19K-expressing adenovirus vector in B10.HTG mice but not in BALB/c mice. Since gp19K binds to both class I alleles on B10.HTG mice but only one allele on BALB/c mice, these results suggest that the major histocompatibility complex class I haplotype of mice is important in determining the effectiveness of gp19K in vivo. Since gp19K has previously been shown to interact with every human major histocompatibility complex class I allele tested, the inclusion of gp19K in gene therapy vectors mag increase vector persistence in human gene therapy trials.