Volume 14, Number 2—February 2008
Christophe Mérieux Conference, Trends in Virology
The first Christophe Mérieux Conference, titled Trends in Virology, was held in Les Pensières, Annecy, France, from June 24 to June 26, 2007, under the sponsorship of Fondation Mérieux. This event was initiated by Dr Christophe Mérieux, who was deeply committed to the global fight against infectious diseases, and it was dedicated to his memory. The objective was to draw general lessons from recent emerging infectious diseases involving viruses and to improve the preparedness of the health community through better surveillance and response to viral spread and epidemics. This conference was the first of a series on virology and emerging infectious disease that will be held every 2 years. (The program is available from www.fondation-merieux.org/en/knowledge/conferences/meetings.php.)
The inaugural address from A.D.M.E. Osterhaus noted that over the past 6 decades, viral emerging infectious diseases in humans and animals have dramatically increased worldwide. Emergence or reemergence of viral diseases has been caused by major changes in the social environment, in medical and agricultural technologies, and in ecosystems, which have created new niches for viruses to cross species boundaries and adapt to a new species. Serious investments in virology research disciplines will be cost-effective and save animal and human lives. However, collaboration and coordination between all public health professionals must be improved to establish early warning systems and effective preparedness plans.
Virus entry and replication strategies are potential targets for antiviral drug treatments. Several examples of the role of viral glycoproteins, their ligands, and cellular proteins of the signaling pathways have been described. Structural modifications of vesicle stomatitis virus (VSV) and severe acute respiratory syndrome-associated coronavirus (SARS-CoV) viral glycoproteins allow membrane fusion and virus entry. Binding of viral proteins to their ligands activates signaling pathways—focal adhesion kinase for human herpesvirus 8, JAK1, tyk2 and STAT1/2 for West Nile virus (WNV), I κ B-kinase, and nuclear transcription factor κ B (NF-κB) for influenza virus—resulting in virus entry, DNA delivery to nucleus, and modulation of protein expression that stimulate or inhibit virus replication. As an example of application, a new drug, SC75741, which blocks the NF-κB pathway without affecting the interferon (IFN)-γ pathway, may suppress the cytokine storm observed during influenza A virus (H5N1) infection.
Several presentations addressed the issue of new drug candidates. Results obtained with chemicals or small interfering RNA (siRNA) are encouraging; some of them are active against several viruses. Viral proteases (HCV and SARS-CoV) and viral RNA–dependent RNA polymerases (Lassa virus, HCV, WNV) are major targets, but treatments targeting viral enzymes often induce the rapid emergence of drug-resistant viruses. Epidemiologic data from New Zealand suggest the recent emergence of a single influenza virus lineage resistant to adamantane by a reassortment event. This lineage has spread in countries where adamantane is not widely used because of linkage to advantageous mutations in genes other than M2. Oseltamivir remains a treatment option in influenza infections, including those caused by the H5N1 subtype, because of the low frequency of resistance and because resistant strains remain susceptible to zanamivir. Better strategies for hepatitis B virus (HBV) treatments are needed to prevent drug resistance. The options of early add-on strategies and de novo combination therapy (highly potent drugs with a high genetic barrier of resistance and complementary cross-resistance profiles) and immunotherapy (cytokines/vaccine therapy/cellular therapy) combined with antiviral agents should be evaluated.
A session was dedicated to new preventive or therapeutic vaccine approaches. The importance of vector choice for synthetic vaccines and the selection of efficient animal models are critical. Recent clinical studies have confirmed the efficacy of L1-based human papillomavirus (HPV) vaccine in preventing or eradicating viral infection and thus preventing dysplasia. New approaches that use attenuated vaccines against tick-borne encephalitis virus and WNV in which large deletions have been introduced seem to be promising and have also been tested for the prevention of dengue. Regarding hantavirus vaccination, interesting results have been obtained in People's Republic of China, where 20 million people have been vaccinated with an average preventive rate of 90%.
Therapeutic vaccines act at the level of cellular immunity. HBV- and HCV-infected patients are characterized by impaired specific immune responses, which may render particularly challenging the implementation of therapeutic vaccination as a stand-alone approach. An important question to answer is whether vaccination must be conducted before antiviral drug therapy or in combination with such therapy. For HBV, the goal is to strengthen the T-cell response, to redirect the immune response to a TH1 phenotype, and to increase innate immunity and activity of natural killer (NK) cells. An HCV vaccine that uses modified vaccinia virus Ankara as vector can induce effector T cells to migrate in the liver where they induce cross-reactive T cells. Patients with advanced cervical cancer have been vaccinated with E6 and E7 peptides from HPV16 and could mount a specific T-cell response able to lyse cancer cells in vitro. However, several phase I or phase I/II studies that use peptides, recombinant proteins, or vaccinia-based vaccines have shown only limited benefits.
Vector genetic determinants have a strong impact in arbovirus epidemiology, and RNA interference (RNAi) could limit the persistence of viruses in mosquitoes. Also, the introduction of RNAi-based transgenic resistance, a possible future direction in prevention, is being currently explored in the case of dengue.
Surveillance is critical to controlling emerging infectious diseases. Predicting the next emerging infectious disease is not possible. Socioeconomic drivers and environmental and ecologic conditions are major determinants, with population density being the more important predictor. The frequency of all emerging infectious disease events has substantially increased since 1940, reaching a peak in 1980–1990; 61.4% were zoonoses. However, the distribution of socioeconomic drivers explains the concentration of emerging infectious disease events at higher latitudes and in industrialized countries, particularly the resistance to treatments.
Many viruses affecting humans are likely to be transmitted by bats: Hendra virus, Australian fruit bat lyssavirus, Menangle virus, Nipah virus, SARS-like CoV, Ebola virus. Some of them are transmitted from bats to pigs and then to human on small pig farms; ecologic events like forest fires may explain the spillover of viruses such as Nipah virus in Malaysia. An active surveillance of migratory birds and the analysis of reported imports and exports of poultry and wild birds between countries are mandatory to monitor influenza pandemic emergence.
The spreading of Nipah virus and Japanese encephalitis virus (JEV) in Asia is a major concern. Nipah virus infections have occurred in Bangladesh, India, and Cambodia. Approximately 45,000 JEV cases are reported annually in Asia, and this number, probably underestimated, may increase in the future, in relation to the vector epidemiology. Measles reemerged recently in People's Republic of China and is now carefully monitored by a network of laboratories that have developed the capacity to conduct molecular epidemiology.
New laboratory tools that combine performance, ease-of-use, and throughput are now available. Equipment required to conduct field surveillance (immunoassays and molecular assays) is now available but its performance still needs to be improved.
Early warning and response to epidemics are also critical. ProMED-mail uses the Internet and Short Message Service to alert health authorities and populations in an infectious emergency. ProMED reaches 40,000 subscribers and has played a critical role during the SARS and anthrax crises. The World Health Organization Alert and Response Department is the operational arm of the new International Health Regulation, which will better support outbreak control at several levels: coordination, epidemiology, social mobilization, vector and environment, laboratory, case management, ecologic studies, media, logistics, and security.
Suggested citation for this article: Vernet C, Zoulim F. Christophe Mérieux conference, trends in virology. Emerg Infect Dis [serial on the Internet]. 2008 Feb [date cited]. http://dx.doi.org/10.3201/eid1402.071317
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