4th quarter 2006
The genetic codes of influenza viruses — What they tell us now and how they may help us in the future
As the bird flu virus is endemic in poultry in some parts of the world, sporadic outbreaks of the disease in humans can be expected. Moreover, the continued exposure of humans suggest that the risk of a virus mutating into a more transmissible agent in humans remains high. Until 23 August 2006, 241 laboratory-confirmed H5N1 influenza cases and 141 deaths were reported to the World Health Organization (WHO) from ten countries.
Today, sequencing of very small genomes (all genes of an organism) like those of influenza viruses is a robust and relatively cheap method of getting relevant information about the virus. The "behaviour" of viruses is completely dependent on their genomes. There is no change of virulence, infectivity, transmissibility, etc. without a change in the virus genome. The avian influenza virus genome consists of only eight genes that code for 11 known proteins. Only 13,617 nucleotides (genetic letters) have to be read to understand all the genetic information of these viruses.
Higher mortality in recent outbreaks
In general, the more sequence data created the better. At present, large scale influenza genome sequencing projects are ongoing in the USA. They have discovered, for example, that avian influenza viruses have a particular molecular feature that human influenza viruses do not, which may cause them to be more toxic when infecting human cells. This may well contribute to the higher mortality rates reported in the recent outbreaks as compared to those seen in previous pandemics.
These influenza genome sequencing projects rapidly make sequence information publicly available through GenBank®, an online database everybody has access to. Putting critical genome knowledge in the public domain provides researchers with the infrastructure needed to develop new vaccines, therapies and diagnostics, and improves understanding of the overall molecular evolution of influenza. By 1 August 2006, genome sequences of 1,351 influenza viruses have been made available.
Early detection might slow down global spread
One of the major goals these days is to recognise as soon as possible when mutations have enabled H5N1 to spread from human to human effectively. As this would be the start of a potential pandemic, the earlier it is detected, the higher the chance to contain the infection in the outbreak region or at least slow its global spread. Therefore, it is absolutely necessary to know the sequence of every avian influenza virus that spreads to a human. In addition, the virus from the transmitting animal, from further infected humans and so on should be known. Of special interest are the changes of viral "behaviour" and their genetic correlate (mutation) as they occur during the infection chain. Sequence data can also predict whether drugs like Tamiflu will work effectively. Finally, they are essential for creating a potent vaccine.
Since 1997there have been many avian influenza virus mutations, but only a few human cases. They have affected patterns of virus transmission and spread among birds. However, they have not had any significant impact on the disease in humans, including its modes of transmission. Although mutations in human viruses were found at the receptor-binding site and involved the substitution of more mammalian-like amino acids, their effect on transmissibility is not fully understood. Moreover, these mutations were transient and did not become fixed in the circulating viruses.
Scientists currently do not know what specific mutations are needed to make the H5N1 virus easily and sustainably transmissible among humans. Specific mutations and evolution in influenza viruses cannot be predicted, making it difficult if not impossible to know if or when a virus such as H5N1 might acquire the properties needed to spread effectively among humans.
From the scientific point of few, more human H5N1 infections would improve our understanding of the interaction of the virus with the human organism. This knowledge will of course increase with time and the number of human cases. A pandemic would deliver enough data to answer most of these questions. However, this would probably not greatly benefit patients and the public now. However, should the world be faced with another putative influenza pandemic in some decades, this knowledge might help then.
Cooperation of all stakeholders is decisive
If, however, outbreaks occur in remote villages in developing countries, there might be many problems that could prevent the scientific community from finally getting the sequences of the causal influenza viruses. This was the case in a recent outbreak among eight members of one family in Indonesia. Although the WHO managed to have samples from six patients sequenced, the sequences were not published. The WHO has not formally asked Indonesia to share the sequences, pointing out that its member states own the data and decide whether they want to share it or not. Finally, after some months of protests from virologists, complaining that the withholding of genetic data is hampering the study of the virus, Indonesia agreed to the publication of the virus sequences. This again shows that the fight against the next pandemic will probably be decided in developing countries. The cooperation of all stakeholders (local organisations, the WHO, global scientific community, drug and vaccine industry) appears to be decisive.