An impediment encountered in many viral-based gene therapy clinical trials has been the rapid destruction of the transgene by the host's immune response. The processing and presentation of antigens through the class I major histocompatibility complex (MHC) pathway is the initial specific response to @entity1800 . Disruption of the class I MHC pathway by herpes simplex virus (HSV) or the @entity4538 ) results in a decrease of the @entity405 (+) cytotoxic T lymphocyte (CTL) response and prolongs survival of infected cells in the host. Two viral immune suppression genes that interfere with the class I MHC presentation pathway, the HSV type I ICP47 gene and HCMV US11 gene, were cloned and each incorporated into a retroviral vector. HSV ICP47 and HCMV US11 transgenes were expressed in multiple cells lines and compared for their abilities to reduce antigen presentation on the cell surface by class I MHC. Retroviral supernatants were used to transduce @entity1 , @entity235 , and @entity35 cell lines. Fluorescence-activated cell sorter (FACS) analysis of US11- and ICP47-transduced cell lines demonstrated substantial reductions in class I MHC cell surface expression in most cell lines except in rodent cells where ICP47 is nonfunctional. The decrease in the level of class I MHC expression for ICP47 transduced cell lines ranged from 31-98% relative to negative controls. US11 decreased class I cell surface MHC by 67-96%. When both ICP47 and US11 are expressed in @entity1 cells, a further reduction of class I MHC was observed. Next, @entity1 A375 @entity320 cells were tested to determine if the resulting reduction in cell surface class I MHC would reduce in vitro @entity137 by CTL. A375 cells expressing either ICP47 or US11 demonstrated a twofold to threefold reduction of specific lysis by primed @entity405 (+) CTL. These data clearly establish an ability to convey immune protection to @entity1 cells by viral genes. However, further analysis demonstrated that @entity379 could reverse part or all of the downregulation of class I MHC induced by the ICP47 or US11 genes. The ICP47 and US11 genes, when expressed in target cells, decrease class I MHC presentation and as such might be used in strategies to create local immunosuppression against transgenes or allografts.

Effective suppression of class I major histocompatibility complex expression by the US11 or ICP47 genes can be limited by cell type or XXXX exposure.

@entity1 :: ('9606', 'Species') :: ['human'] @entity137 :: ('MESH:D064420', 'Disease') :: ['cytotoxicity'] @entity235 :: ('9615', 'Species') :: ['canine'] @entity4538 :: ('10359', 'Species') :: ['human cytomegalovirus (HCMV'] @entity1800 :: ('MESH:D014777', 'Disease') :: ['viral infection'] @entity379 :: ('3458', 'Gene') :: ['interferon (IFN)-gamma'] @entity35 :: ('10116', 'Species') :: ['rat'] @entity405 :: ('925', 'Gene') :: ['CD8'] @entity320 :: ('MESH:D008545', 'Disease') :: ['melanoma']
@entity379 :: (3458,Gene) :: ['interferon-gamma']
