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Aerial view of Madagascar

Posted by RJG and AMN on August 27th, 2013  •  Origin and evolution of reticuloendotheliosis virus (REV)

Bronx Zoo, c1911. Digital ID: 810170. New York Public Library Visitors arriving at the gates of the New York Zoological Park in 1911

The extraordinary evolutionary history of the REVs

Their story unites mammals from Madagascar with birds from South East Asia, and links the distant evolutionary past to a more recent history of environmental and technological change.

The reticuloendotheliosis viruses (REVs) are retroviruses that were identified in the 1950s as the agents of virulent disease in gamebirds and waterfowl. Remarkably, DNA sequences derived from REVs are present in the genomes of two other, unrelated viruses - gallid herpesvirus-2 (GHV-2), the cause of Marek's disease, and fowlpox virus (FWPV), the cause of fowlpox.

In a study published today in PLoS Biology [1], we shed new light on the origin and evolution of REVs, accounting for their unusual distribution in nature.

REV-like viruses infected ancient mammals

While investigating viral diversity in Malagasy mammals we identified an endogenous retrovirus closely related to REV in the genome of the ring-tailed mongoose (Galidia elegans), a Malagasy carnivore. We recovered the complete genome of this ancient virus, revealing that it shares an unusal genome structure with REV. Genetic analysis of this 'viral fossil' allowed us to establish that REV-like viruses derive from a common ancestor, and entered the germline of Malagasy carnivores approximately 7.8 million years ago (Ma). See here for further details of the paleoviruses we characterized in our study.

We next conducted a paleovirological investigation which affirmed that, in general, retroviruses do not tend to cross between distantly related host groups, such as mammals and birds. REVs are a glaring exception to this general rule - they infect birds yet clearly originate in mammals. We wanted to understand how REVs have successfully negotiated this 'long-distance' transfer. Investigating the history of REV infection, we discovered a connection to an obscure malaria parasite called Plasmodium lophurae.

New guinea jungle New Guinea mountains and jungle.

The history of Plasmodium lophurae

In the late 1920s, dauntless ornithologist Lee Saunders Crandall journeyed to New Guinea, where he would sample exotic fauna inhabiting the difficult, jungle-clad terrain of the Owen Stanley range. Despite being shipwrecked on his return voyage [2], he arrived in New York several weeks later with all his captive specimens intact. These animals - which included 40 birds of paradise, about 200 other birds, and several mammals - were housed in the New York Zoological Park (now Bronx Zoo).

On an excursion to Ceylon (Sri Lanka) in the 1930s, Pasteur Institute parasitologist Émile Brumpt identified Plasmodium gallinaceum, a parasite causing malarial disease in domestic fowl. Since quarantine regulations prevented P. gallinaceum from being introduced to the United States (US), scientists seeking a model organism for malaria research examined some of the South East Asian birds that Crandall had imported to the New York Zoological Park a decade earlier. They identified a malaria parasite, which they named 'Plasmodium lophurae', in the blood of a crested fireback pheasant (Lophura ignita) [3].

A few years after this, the US entered World War II (WWII), and an intense, secretive search for malaria drugs and vaccines began. During the 1940s, P.lophurae was widely used as an experimental organism in the US. In later years, however, it was superseded by other experimental systems, and research use began to decline. By the late 1980s, P.lophurae stocks, which no longer produced gametocytes, had been completely exhausted. Field expeditions have since failed to identify the organism in wild birds.

Malaria parasite A malaria parasite (Plasmodium).

Plasmodium lophurae and the origins of the avian REVs

In 1959, William Trager identified a strain of REV called 'spleen necrosis virus' (SNV) as the cause of a highly pathogenic disease in ducks that were experimentally infected with P.lophurae. By the 1970s, it had become clear that P.lophurae stocks were widely contaminated with this virus [3], which was assumed to occur naturally in birds. In our manuscript, we use genetic data to argue that these stocks in fact provided the route by which REV crossed into birds, and that REVs originated from a mammal housed in the New York Zoological Park.

The precise details of what happened next are not entirely clear, but it appears that REV escaped from P.lophurae stocks and spread into avian cell culture systems, inserting it's genetic material into the GHV-2 and FWPV genomes along the way. These viruses, and vaccines created to target them, have since provided vehicles for further dissemination of REV into the environment. This process appears to be ongoing, impacting wild birds as well as domestic poultry.

REV and the development of avian cell culture

In the decades following WWII, GHV-2 began to inflict severe losses on poultry farms in the US. An urgent search for a GHV-2 vaccine occurred in parallel with some the earliest advances in avian cell culture [4]. REV was widely adopted as an experimental tool during this period, and since contamination was not yet well-understood, opportunities for it to spread surreptitiously in cell culture are likely to have occurred. The virus 'chimeras' that have apparently arisen as a result now circulate naturally in birds.

One of these viruses - an FWPV strain containing an entire copy of the REV genome - has been independently isolated in numerous locations throughout the world, and genetic data indicate it sporadically gives rise to outbreaks of REV infection in captive and wild birds. More research is needed to establish the nature of these outbreaks, and to determine whether FWPV-REV represents a newly-evolved, synergistic relationship between a poxvirus and a retrovirus.

Black swan A black swan (Cygnus atratus), one of REV's potential victims.

The case for phylogenetic surveillance of viruses

The case of REV illustrates how the development of new technologies can have unpredictable consequences on viral ecology and evolution. Due to their inherently high mutation rates, viruses are uniquely able to adapt and exploit opportunities that arise as a result of technological and environmental change. Unfortunately, we see in the case of REV and other viruses [5-7] how biomedical interventions have sometimes played an unintentional role in enabling the emergence of disease epidemics. As with many aspects of viral emergence [8], these iatrogenic events cannot reliably be anticipated [9].

Nevertheless, we can take steps to protect against these risks. Modern DNA sequencing technologies can be used to establish mechanisms for monitoring viral diversity using genetic sequence data. Our study shows that sequence-based approaches can efficiently identify conspicuous changes in the ecology and evolution of viral species. Exponential increases in the power and affordability of DNA sequencing techniques over recent years mean that strategies that have so far only been applied to prominent viruses such as HIV-1 and influenza could feasibly be expanded to many other human, animal and plant viruses.


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

2.  Conway WG (1972) In Memoriam: Lee Saunders Crandall. Auk 89: 420-248.

3.  Coggeshall LT (1938) Plasmodium lophurae, a new species of malaria pathogenic for the domestic fowl. Am J Hyg 27: 615–618. [abstract]

4.  Burmester BR, Purchase HG. The history of avian medicine in the United States. V. Insights into avian tumor virus research. Avian Dis. 1979 Jan-Mar;23(1):1-29. [abstract]

5.  Pybus OG, Drummond AJ, Nakano T, Robertson BH, Rambaut A. (2003) The epidemiology and iatrogenic transmission of hepatitis C virus in Egypt: a Bayesian coalescent approach. Mol Biol Evol. Mar;20(3):381-7. [full text]

6. de Oliveira T, Pybus OG, Rambaut A, Salemi M, Cassol S, Ciccozzi M, Rezza G, Gattinara GC, D'Arrigo R, Amicosante M, Perrin L, Colizzi V, Perno CF; Benghazi Study Group. (2006) Molecular epidemiology: HIV-1 and HCV sequences from Libyan outbreak. Nature Dec 14;444(7121):836-7 [pubmed citation]

7.  Pépin J, Labbé AC (2008) Noble goals, unforeseen consequences: control of tropical diseases in colonial Central Africa and the iatrogenic transmission of blood-borne viruses. Trop Med Int Health. Jun;13(6):744-53. [full text]

8.  Holmes EC. (2013) What can we predict about viral evolution and emergence? Curr Opin Virol. (2):180-4. [pubmed citation]

9.  Taleb NN. (2001) Fooled by Randomness: The Hidden Role of Chance in Life and in the Markets. London : Texere [home page]