Expression of herpes simplex virus ICP47 and human cytomegalovirus US11 prevents recognition of transgene products by CD8(+) cytotoxic T lymphocytes

TY - JOUR

T1 - Expression of herpes simplex virus ICP47 and human cytomegalovirus US11 prevents recognition of transgene products by CD8(+) cytotoxic T lymphocytes

AU - Berger, C

AU - Xuereb, S

AU - Johnson, D C

AU - Watanabe, K S

AU - Kiem, H P

AU - Greenberg, P D

AU - Riddell, S R

PY - 2000/5

Y1 - 2000/5

N2 - 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.

AB - 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.

KW - Animals

KW - Antigen Presentation

KW - Cells, Cultured

KW - Cytomegalovirus/genetics

KW - Cytotoxicity, Immunologic

KW - Fibroblasts/metabolism

KW - Gene Expression

KW - Genetic Vectors

KW - Glycoproteins

KW - Herpesviridae/genetics

KW - Humans

KW - Immediate-Early Proteins/genetics

KW - Killer Cells, Natural/immunology

KW - Lymphocyte Activation

KW - Membrane Proteins

KW - Mice

KW - Phosphotransferases (Alcohol Group Acceptor)/genetics

KW - RNA-Binding Proteins/genetics

KW - Recombinant Proteins/immunology

KW - Retroviridae/genetics

KW - T-Lymphocytes, Cytotoxic/immunology

KW - Transgenes

KW - Viral Proteins/genetics

U2 - 10.1128/jvi.74.10.4465-4473.2000

DO - 10.1128/jvi.74.10.4465-4473.2000

M3 - SCORING: Journal article

C2 - 10775582

VL - 74

SP - 4465

EP - 4473

JO - J VIROL

JF - J VIROL

SN - 0022-538X

IS - 10

ER -