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Posted by RJG on January 15th, 2014  •  Reticuloendotheliosis virus in Marek's disease vaccine.

Eye of a chicken with Marek's disease Eye of a chicken with Marek's disease (click here to see comparison with a normal chicken eye).

Reticuloendotheliosis virus in a Marek's disease vaccine.

Marek's disease (MD) is one of the most common diseases affecting poultry flocks worldwide. MD is caused by infection with gallid herpesvirus 2 (GHV-2), a virus that belongs to the same subfamily (Alphaherpesvirinae) as varicella zoster virus, which causes chickenpox in humans.

MD was first described by Professor Josef Marek in 1907. Over recent decades the disease has substantially increased in severity of symptoms, evolving from an endemic infection causing a mild paralytic syndrome, into a globally distributed and highly contagious neoplastic disease [1]. MD is estimated to cause annual losses of over $1 billion to the global poultry industry [2].

The first MD vaccines were developed in the late 1960s. One of the most successful vaccines was based on herpesvirus of turkeys (HVT), which is distinct from, but closely related to GHV-2. Widespread use of HVT vaccines in the early 1970s saw a drastic reduction in losses from MD [1]. Over subsequent years, however, the effectiveness of these vaccines declined. Newer vaccines were developed in response, but the effectiveness of these vaccines was also short-lived. This pattern is ongoing, with GHV-2 repeatedly countering new vaccines, while simultaneously increasing in virulence.

Reticuleoendotheliosis virus (REV) is a retrovirus that has been isolated from poultry and wild birds. REV has been found as a contaminant in MD vaccines on multiple occasions, dating back to the early 1970s. We previously presented evidence that REV is not a natural infection of birds, but is in fact a mammalian retrovirus that was accidentally transmitted to birds in the early 20th century [3]. We propose that REV subsequently contaminated avian cell culture systems, and that this likely accounts for the presence of DNA sequences derived from REV in the genomes of some GHV-2 strains. REV sequences have also been identified in the genome of another large DNA virus that infects birds - fowlpox virus (FWPV).

Shortly after the our paper was published, a new REV genome sequence was reported, derived from a strain (REV-MD2) contaminating an HVT-based MD vaccine [4]. We examined this new sequence in the context of our hypothesis of REV origin.

Phylogenetic trees including the newly available REV sequence show that it falls squarely within the diversity of GHV-2-associated and FWPV-associated REV isolates. This indicates that REV-MD2 shares a very recent common ancestor with the prototypic REV isolate, as well as with the strains that inserted into GHV-2 and FWPV genomes. These observations provide yet more evidence that REV is spreading iatrogenicaly. Furthermore, it is clear that REV contamination of MD vaccines is a longstanding and ongoing problem.

Intriguingly, the tumors induced by REV infection are highly similar to those that occur in MD. Furthermore, the emergence of neoplastic MD seems to coincide with the time at which we estimate REV to have spread from contaminated Plasmodium lophurae stocks into US poultry populations, and subsequently into avian cell culture systems. This may be purely coincidental. The paradigm in MD research is that neoplasticity is mediated by a GHV-2-encoded oncogene (meq). Nevertheless, the long-term association of REV with MD vaccines does raise questions about the potential synergistic role of REV and GHV-2 in the emergence of neoplastic MD in poultry flocks throughout the world.



References


1.  Nair V. (2005) Evolution of Marek's disease -- a paradigm for incessant race between the pathogen and the host. Vet J. 170 (2):175-83. [abstract]

2.  Morrow, C. and Fehler, F. (2004) Marek's disease: a worldwide problem. In: Marek's Disease, An Evolving Problem, (Davidson, I. and Nair, V., eds.), pp. 49—61

3.  AM Niewiadomska and RJ Gifford (2013) The extraordinary evolutionary history of the reticuloendotheliosis viruses. PLoS Biology 11 (8): e1001642 [full text]

4.  Li J, Yang C, Li Q, Li H, Xia Y, Liu D, Yu K, Yang H. (2013) Complete genome sequence of reticuloendotheliosis virus strain MD-2, isolated from a contaminated turkey herpesvirus vaccine. Genome Announc. 3;1(5). [full text]