Adenovirus proteins and MHC expression

Adenoviruses are able to specifically down-regulate the cell surface expression of MHC class I antigens. Most viral serotypes achieve these ends by synthesizing a protein that binds to class I antigens in the endoplasmic reticulum (ER) and impedes the transport of these molecules to the cell surface. However, viruses belonging to the highly oncogenic subgenus A do not affect the class I antigen expression during acute infection. Instead, they are distinct from other adenoviruses in that they specifically down-regulate the level of mRNAs, encoding MHC class I antigens, in virally transformed cells. The virus-induced reduction of class I antigen expression drastically diminishes the ability of CTLs to recognize cells infected or transformed by adenovirus. A number of issues concerning these viral mechanisms for class I antigen modulation need to be addressed. The molecular mechanism by which the E1A gene product of subgenus A viruses diminishes class I mRNA levels has not been elucidated. Also, the details of the interaction between the E19 protein and class I molecules should be studied, preferably by X-ray crystallography of the complexes. This would clarify the role of the antigen-binding site as well as other portions of the class I molecule in the binding to the E19 protein. Of general importance for our understanding of the sorting and intracellular transport of proteins is the exact delimitation of the signal for ER localization, which is present in the COOH-terminus of the E19 protein. The putative interaction of this peptide sequence with components of the ER membrane should also be studied. Finally, the study of the pathophysiological role of the MHC class I down-regulation will undoubtedly yield new insights into how the immune system combats virally infected and transformed cells.