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Resistance of human cells to the adenovirus E3 effect on class I MHC antigen expression. Implications for antiviral
1Robert W. Lisle Research Laboratory in Immunology and Tumor Cell Biology, Department of Medicine, National Jewish Center for Immunology and Respiratory Medicine, Denver, CO 80206.
Abstract:
Group C human adenovirus (Ad) serotypes (e.g., Ad2 and Ad5) cause persistent infections in man. One proposed mechanisms to explain human adenovirus persistence is an ineffective CTL response due to reduced cell surface expression of class I MHC Ag on virally infected cells, an effect mediated by the 19-kDa glycoprotein encoded by Ad early region 3 (E3). In the present study, the generality of this phenomenon was tested by analyzing E3 19-kDa glycoprotein down-regulation of cell surface class 1 MHC Ag on a variety of human cell types. With the exception of the Ad5 early region 1 (E1) transformed cell line, 293, Ad2/5 infection of fibroblastic, epithelial, and lymphoid cells did not cause major decreases in surface class I Ag until the terminal stages of infection when cell death is imminent. Furthermore, newly synthesized class I Ag continued to be surface expressed on most cell types at times when infected cells contained large amounts of Ad E3 19-kDa glycoprotein. These data indicate that most types of human cells are resistant to the E3 19-kDa glycoprotein effect, suggesting that virus-specific CTL recognition and lysis of most Ad2/5-infected human cells should not be limited by E3 19-kDa-mediated reduction in class I MHC Ag expression.
Insights
Human adenovirus persistence may not be due to ineffective CTL responses. The E3 19-kDa glycoprotein did not significantly reduce MHC class I expression on most infected human cells, suggesting CTLs can still recognize them.
Area of Science:
- Immunology
- Virology
- Molecular Biology
Background:
- Group C human adenoviruses (Ad) establish persistent infections.
- Reduced cell surface MHC class I antigen expression on infected cells is a proposed mechanism for adenovirus persistence, mediated by the Ad E3 19-kDa glycoprotein.
- This reduction is thought to impair cytotoxic T lymphocyte (CTL) responses.
Purpose of the Study:
- To investigate the generality of the E3 19-kDa glycoprotein's effect on MHC class I expression across various human cell types.
- To determine if this mechanism limits CTL recognition during adenovirus infection.
Main Methods:
- Infection of diverse human cell types (fibroblastic, epithelial, lymphoid) with Ad2/5.
- Analysis of cell surface class I MHC antigen expression.
- Quantification of Ad E3 19-kDa glycoprotein levels in infected cells.
Main Results:
- Ad2/5 infection did not significantly decrease surface class I MHC Ag in most cell types until late stages of infection.
- Newly synthesized class I MHC Ag remained expressed on the cell surface even when high levels of E3 19-kDa glycoprotein were present.
- The Ad5 E1-transformed cell line 293 was an exception to these findings.
Conclusions:
- Most human cell types are resistant to the MHC class I down-regulatory effects of the Ad E3 19-kDa glycoprotein.
- Adenovirus persistence is unlikely to be explained by this glycoprotein-mediated immune evasion mechanism in the majority of human cells.
- Virus-specific CTL recognition and lysis of Ad2/5-infected cells are likely not hindered by reduced MHC class I expression.