The Fear of the Known
Publishing the genetic sequence of a transmissible influenza virus might be scary, but harder decisions are yet to come
The Evolving Viral Cloud
The evolutionary success of the influenza virus rests on two clever strategies: pack light and venture far. The influenza genome is a minimalist masterpiece, containing the sparest of genetic information: At 13,800 nucleotides long, its genome is roughly 100,000th the size of our own and is divided into eight RNA segments that encode 11 proteins. Like all viruses, influenza cannot replicate on its own. The information in the viral genome ensures that the virus can enter the cells of the host and, once inside, co-opt part of the machinery of the host cell for its own ends.
That light luggage is coupled with a mechanism for copying genetic information that has evolved to be remarkably … inaccurate. When influenza replicates its genetic information, it makes roughly one mistake in every 100,000 nucleotides it copies; under certain circumstances, it may make as many as one mistake for every 5,000 nucleotides. In contrast, our own replication machinery makes no more than one mistake for every 50,000,000 nucleotides copied.
The reduced fidelity of viral replication is no coincidence. Instead, it is a strategy evolved to cope with the myriad challenges facing the influenza virus, from the deadly scrutiny of the host immune system to the complex challenge of adapting to a new environment—or host. Inaccurate replication is shape-shifting at its best. As new sequences for the surface proteins of the virus result from this constant rain of mutations, these proteins take on new shapes, enabling them to evade—if only temporarily—the vigilant scrutiny of the host immune system. On occasion, two different strains meeting in the same host will take advantage of the segmented character of the influenza genome to swap entire fragments, once again giving the virus a temporary edge over the immune system.
The characteristically high mutation rate of influenza viruses has profound implications for the reports of increased transmissibility. In retrospect, the mutation rate helps explain why, after only a few rounds of selection using the ferret model system, airborne transmission evolved. The low fidelity of viral replication ensures that these mutations, and billions of other combinations of new mutations, have been—and are constantly being—generated as part of the natural history of influenza. The mutations seen in the ferret experiments are not new. They are only new to us. We had simply never seen them before in a characterized strain—possibly because in the much harsher viral world outside of the laboratory, these particular strains would not stand a chance.
Combinations of mutations that increase transmission, infectivity or virulence arise constantly. We, the human hosts, are saved by the fact that the viral lifestyle involves a set of competing claims: Mutations that increase transmissibility may inadvertently reduce the virus’s ability to enter host cells. Seen in this light, the influenza genome represents a compromise solution to a set of sometimes contradictory challenges. We are also helped by the virus’s complete dependence on its host. Influenza viruses cannot simply invade our bodies and promptly kill us off in an orgy of viral replication—that would be suicide. Instead, viruses must manage their hosts. A less transmissible strain that keeps its host alive, mobile and capable of interacting with other naive hosts may well outcompete a virus that is highly transmissible, aggressively infective and fulminating in its consequences.
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