Immunomodulation by viruses: the myxoma virus story

Abstract

Myxoma virus is a poxvirus pathogen of rabbits that has evolved to replicate successfully in the presence of an active immune response by an infected host. To accomplish this, the virus has developed a variety of strategies to avoid detection by or obstruct specific aspects of the antiviral response whose consolidated action is antagonistic to virus survival. We describe two distinct viral strategies carried out by viral proteins with which myxoma virus subverts the host immune response. The first strategy is the production of virus-encoded proteins known as viroceptors or virokines that mimic host receptors or cytokines. These seek to actively block extracellular immune signals required for effective virus clearance and produce a local environment in the infected tissue that is "virus friendly". The second strategy, carried out by intracellular viral proteins, seeks to retard the innate antiviral responses such as apoptosis, and hinder attempts by the infected cell to communicate with the cellular arm of the immune system. By studying these viral strategies of immune evasion, the myxoma system can provide insights into virus-host interactions and also provide new insights into the complex immune system.

Myxoma virus in the European rabbit: interactions between the virus and its susceptible host

“…One particular mechanism conceived by MV to subvert the host immune response is carried out by two related sets of immunomodulatory proteins described as virokines and viroreceptors [74,87]. These virus-encoded proteins target specific pathways of the host immune system used to coordinate antiviral and early inflammatory responses directed against viral infection [64,74].…”

“…This leads to a series of downstream events ultimately resulting in the digestion of key structural proteins in the cytoplasm and degradation of chromosomal DNA. Viruses with larger genomes, such as poxviruses, have evolved immunomodulatory proteins which function to inhibit host-cell apoptotic responses during early stages of viral infection [74,94]. These anti-apoptotic effectors have been shown to manipulate the cell death pathways within the cell in a variety of ways, including the inhibition of caspases and disruption of key mitochondrial checkpoints to prevent apoptosis [22,23,94].…”

“…There are many extensive and excellent reviews on the immunomodulatory proteins of poxviruses [42,50,64,69,74,75,87,91,106]. This review will focus primarily on the interactions of MV and its susceptible host, the European rabbit in vitro and in vivo.…”

Oncolytic viral therapies

“…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.…”