Expression of herpes simplex virus ICP47 and human cytomegalovirus US11 prevents recognition of transgene products by CD8(+) cytotoxic T lymphocytes.
The in vivo persistence of gene-modified cells may be limited by the development of a host immune response to vector-encoded proteins. Herpesviruses evade cytotoxic T-lymphocyte (CTL) recognition by expressing genes which interfere selectively with presentation of viral antigens by class I major histocompatibility complex (MHC) molecules. Here, we studied the use of retroviral vectors encoding herpes simplex virus ICP47, human cytomegalovirus (HCMV) US3, or HCMV US11 to decrease presentation of viral proteins and transgene products to CD8(+) CTL. Human fibroblasts and T cells transduced to express the ICP47, US3, or US11 genes alone exhibited a decrease in cell surface class I MHC expression. The combination of ICP47 and US11 rendered fibroblasts negative for surface class I MHC and allowed a class I MHC-low population of T cells to be sorted by flow cytometry. Fibroblasts and T cells expressing both ICP47 and US11 were protected from CTL-mediated lysis and failed to stimulate specific memory T-cell responses to transgene products in vitro. Our findings suggest that expression of immunoregulatory viral gene products could be a potential strategy to prolong transgene expression in vivo.
Berger
C
C
Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
Xuereb
S
S
Johnson
D C
DC
Watanabe
K S
KS
Kiem
H P
HP
Greenberg
P D
PD
Riddell
S R
SR
D000818:Animals; D017951:Antigen Presentation; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D015870:Gene Expression; D005822:Genetic Vectors; D006023:Glycoproteins; D006564:Herpesviridae / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000276:immunology; D008213:Lymphocyte Activation; D008565:Membrane Proteins; D051379:Mice; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D011994:Recombinant Proteins / Q000276:immunology / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D019076:Transgenes; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
D006023:Glycoproteins; C105843:ICP47 protein, Herpes simplex virus; D017874:Immediate-Early Proteins; D008565:Membrane Proteins; D016601:RNA-Binding Proteins; D011994:Recombinant Proteins; C074546:US11 protein, herpesvirus; C095111:US3 protein, cytomegalovirus; D014764:Viral Proteins; D017853:Phosphotransferases (Alcohol Group Acceptor); C063242:hygromycin-B kinase