A couple of years ago, during the height of the worldwide bull market, some playful stock brokers in London turned a 10-year-old kid loose to invest at will. It was rumored that the little child out-competed the fund managers over a two-week period, making more money than they did.

This possibly fictitious tall tale was recounted to BioWorld Today by mathematical geneticist Michael Stumpf at University College in London. He is first author of a paper in the Proceedings of the National Academy of Sciences (PNAS), released online Oct. 22, 2002. Its title: "Herpes viruses hedge their bets." The article's senior author is mathematical biologist Vincent Jansen, associate professor, also called a reader, at Royal Holloway University of London.

"We said in our paper," Stumpf noted, "that investment fund managers, like viruses, operate in very unpredictable environments. For them, it might seem a smart strategy guided in the end by a simple random-number generator."

To which Jansen added, "It works in many cases about as well as a very clever fund-managing strategy." It does so also for herpes viruses, which are pathogens notorious for infecting people with chickenpox and shingles, then hibernating for long periods of latency elsewhere in the human body.

"The reason for this viral behavior," Jansen explained, "is that a latent virus is hedging its bets. Varicella zoster virus [VZV], which causes chickenpox and shingles, can infect an awful lot of susceptible humans. That would be great for the virus. There might also be good reason to believe there would be only a few because the virus is going around the population, and many people for natural means are getting immunized against its infection."

Looking At Latency From Virus Viewpoint

"So from the virus' viewpoint," Jansen continued, "a very useful thing to do is hold back some of your infectivity and try to get in at a later time, when you might be lucky. There may be a lot of susceptibles around then. And that is the simple explanation for evolution of latency.

"Shingles marks the second round of infectivity," Jansen went on. "In chickenpox you have a primary infection. Your child falls ill and itchy, starts shedding the VZV virus. After that the immune system suppresses the virus. So back in the body you pass from these few sites of latency, like certain neurons. Much later - 20 or 40 years later - the virus can then reactivate and cause shingles. That's a second opportunity to infect, and means hedging your bets. Either you infect a lot during the time the virus caused chickenpox, or you come back out of hibernation, and some infections later, it causes shingles.

"What triggers shingles is a question that has been argued by many others, who look for molecular mechanisms," Jansen pointed out. "What we're suggesting is that this might be something completely unrelated to what scientists are looking for in the host person. It could be almost anything. Hopefully, that bit of insight might help in finding how emergence from latency - reactivation of infectivity - actually works. It need not be like stress, as many people propose. It could be any trigger that would delay reactivation a long enough time. It might not relate at all to the condition of the host. That's the main finding of our PNAS paper."

More broadly, Jansen said, "Viruses need a certain minimal population size in order to survive. And if we go back to an early stage of human evolution - the susceptible non-immune groups in which people dwelt - the population would be a lot smaller. So it was thought that many viruses could not emerge until much later. In our mathematical model," he recounted, "we don't look at one viral strain. We compare a number of strains that differ in their latency periods. We let them loose in the math population to see how well they do there. And what we find is that the ones that have a longer latency period do well whenever the number of susceptibles in the human populations are very unpredictable."

"Hedging appears," Stumpf said, "because if the virus is going to replicate into an initial infective round, it wouldn't reproduce but would go through the population pretty quickly. The whole population would be immune for life. That was the initial argument that people brought up in the 1960s or so - that you have to have a minimum population size of 50,000 to 100,000 to allow enough children to be born who are not immune to chickenpox, so can be expected to carry on the disease."

Here's Where Herpes Hedging Comes In

"VZV infects at a little bit older age when the expected population size becomes smaller than that minimum size we needed to sustain the childhood chickenpox. So VZV has to wait a little bit in latency, and take some of the infectious material to inflict shingles after 20 or 40 years or whatever. So that's how the hedging comes in. If all the virus had was spent on the primary infection, the chickenpox stage, then it wouldn't have anything left to infect the next generation. The whole population would have been immune following that initial infection."

Neither Stumpf nor Jansen see any immediate utility or medical application for their viral evolutionary mathematical analysis. "Evolution of herpes virus is so slow compared to hepatitis C or HIV that I think this doesn't really help medical research," Stumpf observed. "It just shows that applications from ideas of ecology and evolution of medicine might give insights into certain disease mechanisms like latency." The team is now "looking into other biological systems, such as seed germination." The team is investigating when plants germinate and when they stay inert.

"What we want to do next," Stumpf said, taking a lead from the viral latency book, "is explore how much strategy it takes in a simple toy model of the stock market. For example, if you know that the market fluctuates a little bit, knowing the average fluctuation, how much of your money should you invest in stock for a given time," he concluded, "and how much should you keep on the safe side in liquid cash?"

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