Previously considered as a silent virus, the bovine leukaemia virus (BLV) produces small molecules - microRNAs - invisible to its victim's immune system. The virus may thus produce these small molecules while remaining hidden in the host cell. This explains why so far BLV was considered  to be  silent in tumours. These viral microRNAs may thus be the key to understanding how BLV induces cancerogenesis without triggering an immune response in the organism it is infecting. A study published in PNAS by the Animal Genomics Research Unit of GIGA at the University of Liège, headed by Michel Georges looks into this in more depth.

As its name indicates, the bovine leukaemia virus (BLV) naturally infects cattle and triggers  the development of leukaemia, a cancer of the blood. Although eradicated in Belgium, this disease still affects many countries, particularly in North America and Eastern Europe. 'In the United States and Canada for example, 80% of dairy herds are infected', reports Anne Van den Broeke, Scientific Research Worker  at the FNRS and project leader within the Animal Genomics research unit at the ULg, led by Michel Georges. 'Although it doesn't represent a danger to humans, this disease is a major concern in terms of animal health and causes considerable economic losses to these countries', she continues. Avenues for research may lead to the development of a vaccine  or an early diagnostic test, which are major issues for these countries. Moreover, BLV shares many similarities with a human virus, which is endemic in Japan, the Caribbean and Latin America, and causes leukaemia in humans. 'Clearly, therefore, it is interesting to study BLV as a tool to better understand how the equivalent human virus operates' continues Van den Broeke.

Finally, studying this virus helps unraveling  the fundamental mechanisms which enable viruses to induce anarchic proliferation of cells, i.e. cancer. 'BLV has been studied for a long time and we know that it is capable of coding for oncogenes, cancer-promoting proteins. At the  level of the tumour cell however, these proteins are absent and the previously-documented viral genes are found to be silent'.

Sheep: a uniquemodel

‘Once infected by BLV, it takes about ten years on average for cattle  to develop leukaemia’, continues Van den Broeke. A characteristic which doesn't make it any easier to study the pathogen's mode of action! Fortunately, scientists don't lack the imagination and ingenuity required to overcome this type of obstacle. As an alternative for studying the virus in its natural host, they use sheep as a research model. When sheep are infected with BLV, the disease progresses much more rapidly than in cattle, and leukaemia develops after an average of eighteen months in all infected sheep (while in infected cattle, only a small percentage, about 2 to 5%, develop leukaemia).

In the context of a recent study published in the PNAS (1) journal, Anne Van den Broeke and her team combined observations in this interesting animal model with a cutting edge technology: deep sequencing. 'This technology revealed that BLV produces high levels of a particular class of small non-coding molecules, called microRNAs. These molecules may be one of the keys to understanding how the virus causes cancerogenesis' she reveals. 

When technology pushes the limits

What is deep sequencing? The genetic material of living creatures can be compared to a code made up of four letters, the order of which determines which messages are communicated. 'High-throughput sequencing consists of detecting and decoding these messages without a prior knowledge of the the composition of the genome or transcriptome. It may be compared to the generation of  millions of words or short sentences which bioinformaticians analyse in order to distinguish the words which mean something from those which don’t ', explains Van den Broeke.

(1) Nicolas Rosewick, Mélanie Momont, Keith Durkin, Haruko Takeda, Florian Caiment, Yvette Cleuter, Céline Vernin, Franck Mortreux, Eric Wattel, Arsène Burny, Michel Georges, and Anne Van den Broeke. Deep sequencing reveals abundant noncanonical retroviral microRNAs in B-cell leukemia/lymphoma. Proc Natl Acad Sci U S A 2013 Feb 5;110(6):2306-11. PMID: 23345446.