Immune evasion by adenoviruses

Abstract

Adenovirus is a human pathogen that infects mainly respiratory and gastrointestinal epithelia. While the pathology caused by this virus is generally not life threatening in immunocompetent individuals, there is a large literature describing its ability to establish a persistent infection. These persistent infections typically occur in apparently healthy individuals with no outward signs of disease. Such a long term and benign interaction between virus and immune system requires adenoviruses to dampen host antiviral effector mechanisms that would otherwise eliminate the virus and cause immune-mediated pathology to the host. Adenovirus devotes a significant portion of its genome to gene products whose sole function seems to be the modulation of host immune responses. This review focuses on what is currently understood about how these immunomodulatory mechanisms work and how they might play a role in maintaining the virus in a persistent state.

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).…”

Oncolytic viral therapies

“…The early genes generate regulatory proteins that set the stage for viral DNA replication by blocking host cell antiviral mechanisms. 90,91 E1A proteins are potent transactivators that provoke the infected cell to enter the cell cycle and progress to S phase. 92 In S phase, the virus takes advantage of the cell's DNA replication machinery and replicates its own genome.…”

“…108,109 Furthermore, it has also been demonstrated that viral manufactured soluble binding proteins specific to TNF and other viral toxic cytokines such as interferon are also produced by other viruses including poxviruses, cytomegalovirus, herpesviruses, and adenoviruses. 91,[110][111][112][113][114][115] Late viral genes encode structural proteins for the capsid and viral internal core. 89 A great deal of preclinical work has been carried out utilizing modified capsid components to improve cancer targeting and reduce nontarget cell uptake.…”

Pilot trial of intravenous infusion of a replication-selective adenovirus (ONYX-015) in combination with chemotherapy or IL-2 treatment in refractory cancer patients

“…67,68 Interestingly, several wild-type viruses actually produce soluble binding proteins specific to TNF. [69][70][71][72][73][74][75] Viral-produced TNF binding proteins have a similar extracellular domain as the human TNF receptor, but lack both the membrane anchor and cytoplasmic domains. [76][77][78] Given the evidence that TNF induction may affect adenoviral survival, particularly with ONYX-015 which does not contain the E3 region expressive of 14.7 protein, we have initiated a pilot trial testing the combination of ONYX-015 with Enbrel (soluble TNF receptor) in cancer patients.…”