RHD - The Unknown & Unpredictable Virus
The Following Comments Were Gathered By Rabbit Information Service
Jeffrey E. Barlough, DVM, PhDDiplomate, ACVM
Department of Medicine and Epidemiology
School of Veterinary Medicine
University of California
In comparison with other virus families such as the herpesviruses and retroviruses, the caliciviruses are a very poorly studied group. Our knowledge of their molecular biology and natural history is relatively meager. This situation is magnified in particular for the rabbit agent, which has been recognized since only about 1984 and which still cannot be propagated in cell culture. We do not know where it came from and to a large extent we cannot predict where it will be going.
Fachhochschule Hildesheim/Holzminden
Gottingen, Germany
I am afraid, the virus might cross unforeseen species barriers. And I am not sure whether experimental work can absolutely give security. Even the ELISA test, from my opinion, will give no guarantee. It will only inform about the presence of antibodies, but not whether the animal/species will be affected from the infection with the virus. Last but not least , one should not forget the evolution also of viruses; any virus will produce new varieties (think of the Aids virus!) and we do not know what will happen when reaching a new species.
Mr M. Glenn
Mr A. Radford
Faculty of Veterinary Science,
University of Liverpool
Wirral, UK
We are not aware of any evidence for replication of RCD virus in other species. However, the nature of RNA viruses is to evolve extremely rapidly. We do not know where the majority of caliciviruses came from (spread from marine organisms has been postulated by some) and equally, we do not know where they are going. One thing would appear to be clear - RNA viruses like RCD virus are ideally suited to finding and exploiting new and divergent host species.
National Institute for Public Health
and Environmental Protection,
Virology Laboratory,
Bilthoven, The Netherlands
So far there is no clear evidence of interspecies transmission of rabbit caliciviridae to other animals or humans. In view of the knowledge of other caliciviruses - where interspecies transmission has occurred - this should be an area of constant alertness. It has been shown that some animals other than rabbits did seroconvert following ingestion of infected rabbits (fox) or following experimental infection (from memory, I think Kiwi was one of them). This does raise the question whether the antibodies in foxes result from infection or merely from exposure to bulk amounts of the viruses without replication (the latter being the current hypothesis). I have seen no experimental evidence proving either option. In my opinion this matter should be resolved as it is crucial...
Assistant Director (recently retired)
Program Planning & Development
USDA/APHIS
I believe there is much more known about the disease (symptoms, lesions, etc) than about the etiology. I am not aware of any form of disease this virus causes in any species except rabbits, but I am not aware of any meaningful studies to determine pathogenesis in other species. I understand caliciviruses can be readily adapted to growth in a variety of cell culture systems. This might indicate that as they survive in fish cells at ambient temperature, they retain the capacity to infect a variety of mammalian cells as various opportunities arise. THIS NEEDS FURTHER INVESTIGATION.
Emeritus Professor of Zoology
University of Canterbury
New Zealand
Parasites may produce different symptoms in different hosts. Plague is benign in many rodents, but often lethal to man. AIDS (another RNA virus) lives quietly in monkeys, but not in man. Host specificity is a problem. Will the RHD virus stick with rabbits alone? No-one knows. RNA viruses are inherently unstable. Host switching, or extending host range is fairly common in viruses. The movement of AIDS and Ebola from monkeys to humans are recent examples. Knowledge of viral host ranges is usually incomplete. Many viruses are symptomless, and poorly known, so their presence is easily overlooked. San Miguel Sea Lion Virus (another calicivirus) is illustrative. First known in Eastern Coast swine, and later in cattle, it produces blisters around the mouth as in foot and mouth disease - hence the research, and our knowledge of it. Very common in North Pacific marine mammals, this virus entered pigs fed fish offals. Some birds (e.g. fairy terns in Hawaii) carry caliciviruses or antibodies to them. We do not know the host range of the RHD viruses. The tests on kiwis were severely criticised by other virologists and pathologists as unsatisfactory. They are not reliable. There is no knowledge of which native animals could be infected with RHD. Sea birds have not been tested or examined for antibodies. Without such knowledge the direct risks to wildlife are unassessable.
Human health implications are crucial. Acting on reports from independent virologists, the Ministry of Health concluded that it would not support the introduction of the virus. Dr Cherry's appropriate re-interpretation of Australian data on human health impacts disclosed a three-fold increase in gastro-intestinal upsets, flu-like symptoms and rashes in people heavilv exposed to the virus over controls. This cannot be ignored. The search for evidence of impact on people has been minimal. Difficulties in finding suitable control groups, and in interpreting the "background noise" without a massive research effort are inhibitory.
Centro De Biologia Molecular,
"Severo Ochoa"
Cantoblanco, Madrid 28049
Spain
As a virologist having worked with RNA viruses for many years, I feel a deep concern about the evolutionary potential of RCD in the field. The origin of this, as well as of other viruses, is uncertain. Host specificity is not a fixed trait in viruses. Viruses such as RCD mutate continuously and may also undergo recombination with genetic material of cellular and viral RNAs. This may result in changes of host specificity in ways that at present are unpredictable. Vaccines may no longer protect when a change in virulence or host specificity of RCD has occured.
Great Ormond Street Hospital for Children
NHS Trust
London, UK
I am not aware of any incident where a human has sustained a significant exposure to RHDV. In the light of the lack of information, I believe that we should test for antibodies to RHDV in persons who have had contact with infected animals either in the laboratory or the field. It is known for instance that San Miguel Sealion Virus can infect laboratory workers and one can certainly find antibodies to feline calicivirus in humans, suggesting that animal caliciviruses have the potential to infect humans. There is also a calicivirus which was isolated from Herpes like legions in pigmy chimpanzees and another which has caused encephalitis in monkeys that fall within the VESV, SMSLV, genetic cluster. It is probable that viruses that can infect primates would be transmissible to man. I have since learnt that the Australians have screened several hundred people who were likely to have been in contact with RHDV and found no evidence of specific antibodies against RHDV.
There is plenty of evidence that viruses related to VESV/SMSLV and FCV can infect different species. Al Smith has summarised the evidence that VESV/SMSLV can infect many species ranging from fish to primates and possibly man. Smith A W. and Boyt P M. (1990) Caliciviruses of Ocean origin. Journal of Zoo and Wildlife Medicine 21: 3-23. Feline calicivirus strains infect many members of the felidae and also dogs.
As you must be aware RHDV and EBHSV are genetically closely related and probably had a common ancestor but hares and rabbits are quite distinct groups of animals again suggesting the potential for caliciviruses to cross species barriers as a result of mutation. At the recent European Symposium in Reading on Caliciviruses, 15-17th September 1996, evidence was presented that the inner shell of these two viruses are antigenetically very similar and that the differences relate to the outer domains, which suggests that they had a common ancestor. It was also suggested that RHDV has only become virulent in the last 150 years. Dr Al Smith provided convincing evidence that avirulent forms of VESV/SMSLV can become highly virulent after only one passage through a different species.
Departamento de Bioquimicia Y Biologia Molecular,
Universidad de Oviedo,
33006 Oviedo, Spain
You ask if RHDV is a stable virus. Considering the type of genetic material of RHDV, the virions will tend to incorporate more changes in their genomes than other types of viruses (ie. the myxoma virus). Nevertheless not all the genetic changes will confer new properties to the virus (ie changes in virulence or host range). We know the complete genetic information of four independent isolates of RHDV from Germany, France, Italy and Spain, which shows a high level of similarity. Nevertheless, considering that they were all obtained in 1989 this does not allow to say much about its stability and how different they are with respect to the strains circulating now in the continent.
As you might know the initial descriptions of the disease showed that young animals (under two months of age) were not affected by the virus. Also, the virus had the capacity of aglutinating red blood cells, and this property was used to detect and quantify the virus. In the last two years some virus strains no longer aglutinate red blood cells and have gained the capacity to kill young rabbits.These are the types of changes I have mentioned in "60 Minutes". Right now, we are studying these new type of viruses trying to correlate the observed behaviour modifications and the genetic changes we have found. I am afraid this will take some time before we reach to a conclusion. As you see the virus is not totally stable.
You should consider also that RHD was described for the first time in 1984 and we have not previous reports of a pathology of this kind. This is telling us that either RHDV had a non pathogenic ancestor, which suddenly became virulent, or that RHDV jumped from another animal species. Both possibilities are rather intriguing and also point out that RHDV might not be as stable as we wish. Either of these events happened 12 years ago. There are some data supporting the non-pathogenic ancestor hypothesis.
Concerning the RHDV especificity to European Rabbits, I have not seen many published evidences indicating the type of experiments performed to demonstrate this fact. As you say the rabbit calicivirus could infect another species and that would not necessarily mean that it would die or suffer a pathology that we can notice.
When you inject a foreign substance into an animal (i.e. an organ extract containing RHDV) the host immune system normally reacts producing antibodies against it (seroconversion). This fact does not mean that the virus did proliferate in the injected animal. To demonstrate that the virus is able to infect the cells and produce a viral progenie (causing disease or not) you should do something else than measuring the presence or antibodies. The type of techniques to be used are difficult to explain but rely on the capacity of detecting either infective virions or genetic material from the virus in biological samples taken from the animal. To my knowledge nobody has reported the kind of experiments they have used to rule out infection. They just say the virus did not produce disease.
On the other hand if you detect antibodies in an animal that has not been experimentally injected (i.e.a wild animal) it is very difficult to assume seroconversion without infection of the cells and viral replication, unless the animal has been exposed several times to the virus. For instance a fox might develop anti-RHDV antibodies after eating infected rabbits several times. This again will need to be investigated further to see if the fox was in fact infected and not just immuno-stimulated by something in the food.
"The time will come when men such as I will look upon
the murder of animals as they now look upon the murder of men."
--Leonardo da Vinci
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