'Until recently, 2% of mammalian genomes were believed to be important (called “genes” or “coding genome”) and  the remaining 98 % was considered useless. But we are starting to understand that the non-coding part of the genome is critical as well, as it plays a significant role in gene regulation'. Although earlier methods failed to spot them, microRNAs such as those discovered by the ULg researchers in BLV could be identified using deep sequencing techniques.

These small non-coding viral RNAs are non-immunogenic, i.e. they do not induce a response from the infected animal's immune system. 'The virus may thus produce these small molecules while remaining hidden in the host cells. This explains why so far BLV was considered  to be silent in tumours.' explains Van den Broeke.  Although scientists had detected the presence of BLV in these tumours,  there was no evidence of the virus' activity.

Preventing expression of these microRNAs

'We have identified a cluster of ten viral microRNAs and we think they may have an impact on the virus host cells, leading them towards malignancy. These molecules may also play a critical role  in inhibiting the expression of other viral components and as a result may contribute to  virus silencing and escape from the host’s  immune system', indicates Van den Broeke.

In light of these  hypotheses, the researchers have come up with the suggestion that preventing viral microRNA production  may prevent the development of bovine leukaemia. 'If this is the case, a genetically manipulated virus could serve as the basis for a vaccine against this disease and prepare the bovine immune system to react against the infection of a natural virus', she continues.

The next steps in this research will be to study the behaviour of a BLV virus which can no longer produce the small RNAs, and to monitor the disease progression in sheep which are infected by this virus compared to those who carry the  natural strain. 'We will also try to better understand the function of these small molecules in tumor onset and progression ', Van den Broeke adds. 

Where cancerology and animal genomics meet

This work is a good example of interdisciplinary collaboration combining research areas such as cancerology, viral pathogenesis and animal genomics. In terms of the human virus which is equivalent to BLV, the Liège researchers have tried to identify whether it also produces similar microRNAs. 'Preliminary results do not suggest a same mode of action of the human virus at the leukemic stage. However, leukaemia takes several decades to appear after the initial infection in humans’, explains Van den Broeke. 'Non-coding RNA molecules may be produced by the virus  during early stages of infection rather than 20 or 30 years later, when the leukaemia becomes apparent. Obtaining human samples from very early stages is challenging, but that’s  what we will try to verify', concludes Van den Broeke.

The recent discovery of these viral microRNAs in BLV represents a considerable step forward in understanding the mechanisms which underlie its action within host cells and raise a number of new questions. Now that researchers have succeeded in identifying one of the keys to the secret of BLV, they plan on exploring the different hypotheses it raises, with the ultimate goal of one day shedding light upon the mystery surrounding its mode of action.