SILVER Topical News

Neglected chikungunya virus emerging threat to world health

Increased travel to and within Brazil and neighbouring countries during the World Championship soccer tournament in the summer of 2014, could conceivably lead to widespread dispersion of the virus throughout the Americas...

The (re)emerging pathogen Chikungunya virus (CHIKV) is transmitted to humans primarily by Aedes aegypti mosquitoes. The name chikungunya, which means “that which bends up,” refers to the symptoms of the disease. CHIKV most frequently causes transient fever with extreme joint pains but in some cases these symptoms may be severely debilitating and persist for months. CHIKV has been known since the 1950s and, prior to the year 2005, had caused occasional small-scale human outbreaks, mainly in African villages close to forests where it circulated relatively harmlessly amongst monkeys and forest-associated mosquitoes. The virus also occasionally caused localized outbreaks in various parts of Asia, where it was presumed to have been introduced from Africa.

CHIKV became “world news” in 2005, when a major epidemic occurred for the first time, on the French island of La Reunion. Almost one third of the population was infected within months and it soon became apparent that the virus was spreading widely and causing outbreaks that affected millions of people, mainly in countries in and around the Indian Ocean. The speed with which this virus continued to disperse, reaching many parts of Asia was alarming. These outbreaks were linked to a mutation in the virus that facilitated its transmission not only by Aedes aegypti but also by an additional mosquito vector, Aedes albopictus, the Asian Tiger mosquito. This invasive mosquito species is no longer only confined to Asia, as over the past decades it has gradually colonized, central Africa, southern Europe and large parts of North and South America.

The significance of the adaptation of CHIKV to Aedes albopictus first became apparent when epidemics of CHIKV fever were recorded in and around Gabon in Africa. It was quickly recognized that Aedes albopictus was effectively displacing Aedes aegypti in urban/suburban regions of Central Africa. The virus also caused a locally-transmitted CHIKV outbreak in a small community in Northern Italy in 2007, which involved almost 300 cases. This was also attributed to the presence of Aedes albopictus in Italy. In this case the outbreak could be traced to an infected human returning to Italy after visiting India where CHIKV was causing widespread epidemics. It seemed only a matter of time before the virus would spread further afield and in December 2013, locally transmitted CHIKV infections were reported from the island of St Martin in the Caribbean, believed to have been introduced by infected humans travelling from Asia. This marked the anticipated introduction of CHIKV into the Americas. CHIKV rapidly spread throughout many islands in the Caribbean and currently is causing explosive outbreaks involving tens of thousands of cases. The virus is expected to disperse further during the rainy season of 2014 and, as it reaches mainland South and North America, it will virtually have achieved global distribution by appearing on all the continents, except Australia and Antarctica. Increased travel to and within Brazil and neighbouring countries during the World Championship soccer tournament in the summer of 2014, could conceivably lead to widespread dispersion of the virus throughout the Americas. Indeed, it is now being predicted that CHIKV-infected travelers may introduce the virus into Europe, when returning from the Americas, thus presenting the threat of outbreaks, particularly in southern Europe where Aedes albopictus is known to have become established.

It is now recognized throughout the world that the quality of life and economic growth are intimately linked and frequently seriously affected by emerging viruses. As indicated above, prior to its unexpected appearance on the world scene in 2005, CHIKV was considered to be a relatively unimportant human pathogen. Currently, there are no available vaccines or antiviral drugs to prevent or treat CHIKV infections. However, with millions of humans already having suffered the painful and debilitating consequences of infection by CHIKV and the prospect of even greater numbers becoming infected during the immediate future, urgent action is required to overcome these gaps in our ability to control and treat CHIKV fever.

Under the European Union Seventh Framework Programme FP7 Project no. 260644, entitled – SILVER – (Small molecule Inhibitor Leads Versus Emerging and neglected RNA viruses) European and Asian virologists, biochemists, medicinal chemists, bioinformaticians and crystallographers are working together to identify the most promising protein targets and to initiate the development of antiviral compounds for the treatment of medically important and neglected RNA viruses. CHIKV was already included in the coordinated research activities by SILVER scientists to develop antiviral lead compounds with the potential to result in chemotherapeutic treatments. These activities are now being further intensified in response to the reemergence and recent global spread of the virus.

In initial studies on CHIKV (under the SILVER initiative) scientists have discovered that “Favipiravir”, a potential antiviral therapeutic agent, currently in Phase 2 clinical trials for the treatment of Influenza virus infection, has significant antiviral activity against CHIKV. Its mechanism of action is now known and it has been demonstrated that Favipiravir can be used to treat CHIKV infection in vivo. The results of these studies were recently published in the Journal of Antimicrobial Chemotherapy.

In further efforts to discover novel inhibitors of CHIKV, SILVER scientists have explored 30,000 chemical molecules for their anti-CHIKV activity. A range of active molecules was then selected for chemical optimization and biological profiling (activity against CHIKV, toxicity, etc.), and at this moment two novel chemical series have been chosen for suitability and efficacy studies in an animal model. For one of these molecules there is good biochemical evidence that it blocks CHIKV replication by a mechanism that is unique in the field of antiviral discovery. The molecule seems to inhibit a viral enzyme that normally protects the viral genome against intracellular degradation. This exciting finding may trigger a new approach to antiviral research that could result in therapeutic treatments for many different viral diseases.

In terms of socio-economic impact and societal implications, the discovery of safe and effective viral inhibitors will contribute to the alleviation of important epidemic outbreaks that in the past have cost the World, billions of Euros/Dollars/Pounds…. In terms of societal impact, viral epidemics cause major human and animal morbidity. Antiviral therapeutic agents have the potential to reduce the impact of such disasters and therefore contribute significantly to the “feel good factor” that is such an important component of successful health policies globally.

Success in this objective would ensure that the impact of the project on scientific discovery, European and global health, European prestige in the global picture, the European economy and the quality of life would be regarded as being of major significance.

Acknowledgements. This SILVER Topical news item was drafted by Martijn van Hemert, Dirk Jochmans, and Ernie Gould, with helpful suggestions from Sandy Gore

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Aedes albopictus female mosquito feeding on a human host.
Author: James Gathany, CDC, 2003
The research leading to these results has received funding from the European Union Seventh Programme (FP7 2007/2013) under grant agreement n°260644-SILVER