TUMOR-NECROSIS-FACTOR-ALPHA INCREASES EXPRESSION OF ADENOVIRUS E3 PROTEINS

Human adenovirus can cause persistent infections in man. Implicated in this phenomenon is the early transcription unit 3 (E3) of the virus w hich encodes proteins that are primarily devoted to counteract the lyr ic attack by the host immune system: Several E3 proteins (14.7K, 10.4K and 14.5K) protect infected cells from the lyric activity of tumor ne crosis factor a (TNF) while the most abundant E3 protein, E3/19K, inhi bits lysis by cytotoxic T cells. E3/19K interacts with class I histoco mpatibility (MHC) antigens in the rough endoplasmic reticulum, thereby preventing transport of MHC molecules to the ceil surface and, conseq uently, MHC-restricted T cell recognition. In addition, the 10.4K and 14.5K proteins downregulate cell surface expression of the epidermal g rowth factor receptor. Interestingly, adenovirus-mediated pneumonia in mice is accompanied by induction of TNF, a cyrokine known to enhance MHC expression. We previously showed that TNF is unable to restore MHC class I expression in E3/19K: transfected cells but rather leads to a further reduction of MHC antigens. This effect correlated with an inc reased production of E3/19K mRNA and protein. We now find in addition an upregulation of other E3 proteins in transfected as well as in infe cted cells. This coordinated upregulation of E3 proteins indicates tha t TNF stimulates the E3 promoter, probably by activating the transcrip tion factor NF-kappa B. Thus, a novel interaction between the immune s ystem and adenovirus is described in which the virus takes advantage o f an immune mediator to promote expression of several immunosubversive proteins supporting its escape from immunosurveillance.