Human Adenoviruses: Evading Detection by Cytotoxic T Lymphocytes

Abstract

Human adenoviruses cause lytic and persistent respiratory, enteric, and other infections. Adenoviruses can transform primary rodent cells and certain serotypes of human adenoviruses (such as adenovirus type 12 from subgenus A) induce tumors in newborn rodents. In both cases, adenovirus gene products mediate evasion of the cellular immune system by infected and tumor cells. In viral infection, a product of the early regionE3gene, a glycoprotein termed E3-19K, binds to and retains newly synthesised major histocompatibility complex (MHC) class I molecules in the endoplasmic reticulum thus rendering infected cells resistant to lysis by cytotoxic T lymphocytes. In addition, other products of theE3region confer on infected cells resistance to tumor necrosis factor-α-mediated lysis. Not all human adenovirus serotypes encode an E3-19K protein: viruses from subgenus A (such as adenovirus 12) and F (the enteric adenoviruses 40 and 41) do not encode an E3-19K molecule. In the case of Ad12, products of the viral E1A gene repress MHC class I heavy chain gene transcription. This leads to loss of MHC class I molecules from the surface of adenovirus 12-transformed cells and contributes to their evasion from cytotoxic T lymphocytes. Considerable progress has been made toward identifying the targets for E1A-mediated repression of the class I heavy chain promoter. In addition, adenovirus 12 mediates transcriptional repression of other genes in the MHC complex involved in antigen presentation, namely the transporter associated with antigen presentation (TAP) genes and MHC-encoded proteasome components, the low molecular weight proteins termed LMPs. Overall, adenoviruses display a variety of differing mechanisms for posttranslational (E3-19K) and transcriptional (E1A) repression of MHC class I expression that operate in all human viral serotypes studied, suggesting that evasion of cytotoxic T cell lysis forms an important part of the infection and oncogenic transformation strategies adopted by human adenoviruses.