Functions and Mechanisms of Action of the Adenovirus E3 Proteins

Abstract

In the evolutionary battle between viruses and their hosts, viruses have armed themselves with weapons to defeat the host's attacks on infected cells. Various proteins encoded in the adenovirus (Ad) E3 transcription unit protect cells from killing mediated by cytotoxic T cells and death-inducing cytokines such as tumor necrosis factor (TNF), Fas ligand, and TNF-related apoptosis-inducing ligand (TRAIL). The viral protein E3-gp19 K blocks MHC class-I-restricted antigen presentation, which diminishes killing by cytotoxic T cells. The receptor internalization and degradation (RID) complex (formerly E3-10.4 K/14.5 K) stimulates the clearance from the cell surface and subsequent degradation of the receptors for Fas ligand and TRAIL, thereby preventing the action of these important immune mediators. RID also downmodulates the epidermal growth factor receptor (EGFR), although what role, if any, this function has in immune regulation is uncertain. In addition, RID antagonizes TNF-mediated apoptosis and inflammation through a mechanism that does not primarily involve receptor downregulation. E3-6.7 K functions together with RID in downregulating some TRAIL receptors and may block apoptosis independently of other E3 proteins. Furthermore, E3-14.7 K functions as a general inhibitor of TNF-mediated apoptosis and blocks TRAIL-induced apoptosis. Finally, after expending great effort to maintain cell viability during the early part of the virus replication cycle, Ads lyse the cell to allow efficient virus release and dissemination. To perform this task subgroup C Ads synthesize a protein late in infection named ADP (formerly E3-11.6 K) that is required for efficient virus release. This review focuses on recent experiments aimed at discovering the mechanism of action of these critically important viral proteins.

The human papillomavirus 16 E6 protein can either protect or further sensitize cells to TNF: effect of dose

“…75,76 Viruses can modulate this balance. In the adenovirus system, for example, it has been shown that the existence of several virus-encoded proteins that block TNF-induced apoptosis [77][78][79] may be necessitated by the actions of the adenovirus E1A protein, which sensitizes cells to TNF, likely as a 'side effect' of its other biological activities. 58,80,81 In the experiments reported here, we were unable to observe significant cell death in response to TNF in the absence of cycloheximide in any of the cells tested (control cells, cells expressing high levels of E6 and cells expressing low levels of E6) (data not shown).…”

Anticancer activity of oncolytic adenovirus vector armed with IFN-α and ADP is enhanced by pharmacologically controlled expression of TRAIL

“…The E3 region in these vectors is identical to the E3 region in KD3 allowing for overexpression of ADP in the absence of immunomodulatory E3 genes. 32 The TetON-EGFP and TetON-SEAP vectors were constructed for visualization 33 and quantification 30 of transgene expression, respectively.…”

“…Expression of Ad 'stealth' genes by RD Ad might also decrease immune-mediated clearance of the coinfected cell carriers in the immunocompetent host and lead to further improvement of antitumor efficacy. 32,51,52 Ad genome modifications introduced with the goal of improving the toxicity profile can compromise the oncolytic potency of the vectors due to attenuation of their replication in cancer cells as compared with wildtype (wt) Ad5. However, wt Ad5 can cause lethal outcomes in immunocompromised patients.…”

Clinical development directions in oncolytic viral therapy

“…E3 proteins prevent Ad-infected cells from being cleared by cytotoxoic T lymphocyte, tumor necrosis factor, Fas ligand and tumor necrosis factorrelated apoptosis-inducing ligand and act to decrease systemic viral clearance. 59 Other adenoviral therapeutics have dysfunctional or deleted E3 regions for safety considerations. However, removal of the E3 region and rapid clearance of viral therapeutics may also cripple the antitumor effect.…”