Adenovirus region E3 proteins that prevent cytolysis by cytotoxic T cells and tumor necrosis factor

Abstract

Human adenoviruses are providing insights into strategies that viruses may adopt to evade immune surveillance. There are 47 serotypes that form six groups (A to F) with different genetic and biological properties. Adenovirus type 2 (Ad2) and Ad5, two group C types, the most common and best understood in terms of molecular biology, cause respiratory infections in young children and often form persistent infections. Following infection, the linear duplex DNA genome is expressed in two broad phases: "early", when viral proteins function to usurp the cell; and "late", when viral DNA and structural proteins are synthesized and virions are assembled. One of the early transcription units, region E3, encodes two proteins that appear to counteract different branches of the host's anti-viral defenses. A 19,000 Mr protein called gp19K protects cells against cytolysis by adenovirus-specific cytotoxic T lymphocytes (CTL). Gp19K has two properties that are crucial to this function: it is localized in the endoplasmic reticulum, and it binds strongly to class I antigens of the major histocompatibility complex (MHC). The effect of these two properties is to block transport of class I antigens to the cell surface. In order to lyse adenovirus-infected cells, CTL must recognize adenovirus peptide antigens complexed with class I major histocompatability complex antigens displayed on the cell surface. Since gp19K prevents this, it renders the cell effectively invisible to CTL. The second anti-immune E3 protein is a 14,700 Mr protein called 14.7K. The 14.7K protects adenovirus-infected cells against cytolysis by tumor necrosis factor (TNF). TNF is a pleiotropic immunoregulatory protein that has anti-viral properties and is believed to provide a defense against virus infections. The 14.7K presumably counteracts the anti-viral effects of TNF in vivo. The mechanism of action of the 14.7K is unknown. Further studies on gp19K and 14.7K should assist our understanding of the immune system and adenovirus pathogenesis.