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Today, there is only one class of antiviral medicines against herpesviruses - a family of viruses that cause mononucleosis, herpes, shingles, and meningitis among other illnesses - meaning options for treating these infections are limited. In a search for new drugs to treat viral infections, scientists at the University of Utah School of Medicine found that a medicine routinely used to treat heart failure, spironolactone, has an unexpected ability to block infection by Epstein-Barr virus (EBV), a herpesvirus that causes mono and is associated with several human cancers. Importantly, spironolactone’s ability to block viral infection appears to be independent from its ability to treat heart failure. But because all herpesviruses depend on SM-like proteins to spread infection, the work also has broader implications. How grid computing helps scientists to discover new diseases, by identifying new viruses from previously unknown genetic sequences.
Identifying as many viruses as possible improves the chances of correct diagnostics and helps to determine the best treatment for patients. Lia van der Hoek and colleagues from the Virus Discovery Unit, at the Academic Medical Centre of the University of Amsterdam (AMC), has been working on VIDISCA – a method to spot new viruses from previously unidentified genetic sequences.
Respiratory infections such as croup (that can cause a narrowed trachea, shown by an arrow) are a major child health problem, but many are caused by still unknown viruses.
The hunt for new viruses starts at the hospitals, with the collection of nose and throat swabs from affected patients. Success first came in 2004, when the team reported the discovery of the coronavirus NL63, which is implicated in croup – a disease that causes throat swelling and coughing in children under six-years old. The genome of the coronavirus NL63 was sequenced and the analysis showed that the virus was a new species with distinctive features. Over the past six years Lia’s work on the VIDISCA method has benefitted from developments in the so-called next generation sequencing techniques. The National Centre for Biotechnology Information (NCBI) has created the BLAST tool to compare given sequences with databases via the web.

Looking for a solution, Lia contacted Antoine van Kampen, head of the AMC bioinformatics department, who assigned Barbera van Schaik to the problem. The workflows and databases were made available to the Virus Discovery Unit via the e-BioInfra platform developed and operated by the e-bioscience group of Silvia Olabarriaga. With these tools at hand, Lia’s team is able to analyse a VIDISCA-454 experiment within 24 hours compared to weeks of intensive manual work. Lia's team is able to analyse a VIDISCA-454 experiment within 24 hours, compared to weeks of intensive manual work. This case study was prepared with the help of Lia van der Hoek, Silvia Olabarriaga and Barbera van Schaik. If viruses become resistant to these frontline treatments, a growing problem particularly in clinical settings, there are no alternative drugs to serve as backup.
They find that the drug’s antiviral properties stem from its ability to block a key step in viral infection that is common to all herpesviruses. Currently available drugs block a middle step of the viral infection cycle by inhibiting virus’ ability to replicate DNA. Previous studies showed that the drug treats heart failure through a different, metabolic mechanism. Spironolactone could be developed as a new medicine against EBV, a common and dangerous infection among transplant and other immunocompromised patients.
Spironolactone could be a template for a new class of drug directed against all herpesviruses. However, in up to 40% of the cases it’s not possible to define the exact cause of the disease and this means that there are viruses still unknown to science. Knowing which virus is responsible for which disease is also very important to detect potential epidemics or to assess the seriousness of viral infections.

Back at the lab, the first step of the VIDISCA method is to remove residual cells and other biologic material, to enrich the sample’s viral genetic material. The virus was spotted in samples taken from a 7-month old baby, admitted to a Dutch hospital with symptoms of acute respiratory infection. But uploading data from VIDISCA-454 to this portal proved to be virtually impossible, given that the average experiment produces approximately 400.000 sequences. A test with 1444 samples produced 4,783,684 sequences and showed that the analysis can be repeated within 14 hours, compared to 17 days if it would run sequentially on a local server. Lia now hopes to find new viruses linked to respiratory infections, diarrhoea, meningitis, encephalitis and other serious diseases. Spironolactone’s target is distinct from that of existing drugs, revealing that it could be developed into a new class of anti-herpesvirus drug. They found that like these drugs, spironolactone can block EBV replication in cells, but it does so by targeting the so-called SM protein, required for a late step in the infection cycle.
This study demonstrates that a drug similar to spironolactone shares its ability to treat heart failure but not its antiviral properties. The genetic sequences in the sample are then amplified with standard laboratory techniques. One way of solving the conundrum is to compare the mystery sequences to known viruses catalogued in massive reference databases, such as GenBank.

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