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The most cancer-causing of the human papillomavirus types create havoc by using proteins called E6 and E7. These proteins neutralize our bodies, safeguards against cancer. E6 binds to a protein called p53, which guards against cancer by arresting cell division. If E6 fails to take out p53, however, the human papillomavirus can still neutralize p53′s protective effects using E7, which binds to a second anticancer sentry stimulated by p53. E6 also interferes with the cell’s self-destruct mechanism, which can protect the rest of the body from pathogens in an infected cell. By these means the papillomavirus is able to keep the cells working in the interest of the virus rather than in the interest of the person.     The lethality of cancer is as devastating to the virus as it is to the person, but the path leading to cancer is a clever solution to a difficult problem. Being sexually transmitted, the human papillomavirus has to deal with the fundamental constraint of sexual transmission: it has to be sufficiently persistent in sufficient numbers to capitalize on future opportunities for transmission. It needs to hide out from a primed and vigilant immune system. The clever solution of the papillomavirus is to keep the cell multiplying and then multiply right along with it. The more the cell divides, the more the virus can replicate itself with little exposure to the surveillance of the immune system.     But how much of the racketeering is too much even for the virus? That depends on the opportunities for transmission. Little exposure to the immune system does not mean no exposure because even a small amount of exposure can make the virus vulnerable to the immune system’s sophisticated virus detection technology. When a virus is clandestinely active within a cell, the cell will post fragments of the virus on its outside walls. It’s like the warning sign posted on the walls of a quarantined house to notify the rest of the community. But the actions taken inside our bodies are not tempered by a liberal mind-set—extremism in defense of the body is no vice. When members of the immune system see the sign, they do not just stay away from the cell; they blow it up. The notice does not read keep out! but rather kill me! By posting this notice of infection, the cell is committing suicide to protect the other cells in the body from infection. For the most cancer-causing of the papillomavirus types, parts of the viruses’ E6 and E7 proteins are posted on the outside of the cell to attract the friendly fire of the immune system. These extreme responses by the body help control the infection in most women before it develops into cervical cancer.     So even a papillomavirus that is clandestinely reproducing as the cells are reproducing may not be clandestine enough. Those viruses programmed for less of this manipulative reproduction may be less likely to attract the immunological attack. By keeping an extremely low profile, such viruses might increase the chances of their being around in the reproductive tract when a new sexual partner is selected. The suppressed activity of the virus translates into a lower probability of infection per instance of sexual contact, but a sexually active person who is not changing sex partners frequently will tend to have more sex with each partner; the sex is just spread out over a long period of time. So the virus’s low profile may still yield a high probability of infection per partner—if the partner is not infected today, then maybe next week, next month, or next year. That strategy is better for us because a virus that keeps a very low profile is a virus that is very unlikely to cause cancer.     On the other hand, if people change partners frequently, then a virus with such self-restraint pays the price of missing transmission opportunities. In a promiscuous society, the papillomaviruses that trigger more rapid reproduction would tend to spread more effectively to new hosts. The more rapid reproduction may make the viruses less cryptic and hence more vulnerable to the immunological defenses of the current host, and more likely to cause a cancerous death or to fall victim to surgical excision, but the reduced tenancy in any single person is offset by the increase in transmission to new people. When opportunities for sexual transmission are high, the virus reaps a high return on its high rate of replication. The dividend is increased representation of the nasty types of papillomavirus in the overall papillomavirus population. When opportunities for sexual transmission abound, human papillomaviruses should evolve toward high virulence.     This is not the kind of statement that can be tested with controlled experimentation. It would be a no-brainer for an NIH ethics committee. But human behavior, being what it is, gives us “natural experiments” that would be unethical had they been planned and executed. One of the most horrific of these situations occurred during the war in what was until recently Yugoslavia. Opportunities for venereal transmission typically increase during wartime, but in that war the opportunities were even greater because rape was used systematically as a weapon. If human papillomaviruses evolve increased harmfulness when the opportunities for transmission increase, they should have done so over the course of the war.     Evidence indicates that they did. Just before the war researchers found that among sexually active women in the region, the most lethal papillomaviruses were less common than the milder types. But by the end of the war these lethal types outnumbered the more benign types by three to one. The vicious viruses increased tenfold over the two years of the war; the benign types remained close to their prewar level. By the third year after the war, the lethal types had begun to recede.     Wartime conditions are extreme. Is there any evidence that the harmfulness of human papillomaviruses depends on sexual behavior in peacetime? Women who have more sexual partners do tend to have more papillomavirus infections. This trend holds from Sweden to Brazil to Colorado. But the risk is not the same for all types of papillomaviruses. The details are still unclear because sufficiently sensitive techniques have been applied only during the past few years, but the current evidence indicates that having more sexual partners increases disproportionately the risk of acquiring the most dangerous papillomaviruses. In Brazil during the mid-1990s, for example, the risks of acquiring the harmful and benign viruses were similar among women who had no more than five sexual partners during their lifetime. Women who had more than five but not more than ten were almost twice as likely to harbor the most dangerous types. Of the women who had more than ten partners, one third were infected with the most dangerous types, three times as many as among the women who had no more than five partners during their lifetime.     The broader implication of these trends is clear: if people start having sex with more people or with less protection, venereal pathogens will not only spread but will evolve to become more harmful. This point makes clear why the threat of disease emergence is largely a homegrown problem. The raw materials for harmful and mild infections are already globally distributed; they are continually being re-seeded by rapid air travel as well as by biological mutations and recombinations, but these processes only provide the raw material. Whether we have a grave problem will depend on whether our local soil—our own behavior—favors the harmful forms over the mild forms.*35\225\2*

Some infections will not peter out on their own even with all the infrastructure money can buy: infections transmitted by sex. But almost all the venereal diseases that are important in one geographic region have already spread globally. This global spread happened long ago because sexually transmitted pathogens tend to have prolonged periods of infectiousness, and people the world over are having sex. People infected with sexually transmitted organisms can carry them across oceans and mountains and around the world, whenever the people themselves can make such voyages.     Could an early warning system work against these truly dangerous globe-trotting pathogens? Some experts imagine massive investments in surveillance and interdiction, but that proposal sounds disturbingly like the efforts directed against drug smuggling. Surely it would be an act of desperation. Surveillance and interdiction might provide an effective barrier against pathogens that pose little threat of spread, such as the Ebola virus, but that would be like building two cages around a dangerous animal when one cage would do. How could such containment work for the more serious threats, such as a new sexually transmitted pathogen, a new AIDS virus? Such pathogens are generally asymptomatic or cryptically symptomatic during much of their infectiousness. Are we going to test each of the millions of international travelers for venereal infection and make them wait with immigration services until the results of their tests are available? The complete failure to control the spread of HIV into new countries during the last decade in spite of the clearest signs of the impending disaster reveals how hopeless such an approach would be.     Experts on AIDS are currently arguing about whether HIV arose naturally through transfer from chimpanzees to humans, or whether medical activities, such as vaccination or reuse of contaminated syringes, played a critical role. If HIV arose naturally, it serves as a warning of the kinds of things that could happen naturally in the future. Yet even if HIV did arise from a chimpanzee virus without any help from medicine, there is a bright side: few new AIDS-like pathogens are likely to invade from some isolated group of humans because there are hardly any isolated groups of humans left on the planet. The recognition of the exaggerated threat from far-off places does come with a few caveats, however. One caveat involves the historical recognition that germs have entered human populations primarily from two sources. The first source is domesticated animals. Unless we start introducing pathogens from domesticated animals in new ways—such as through the transplanting of their organs—the threat from domesticated animals probably holds few new surprises. The second source is other primates. Our biological machinery has diverged evolutionarily from that of other primates more recently than it has from more distantly related species. If a germ enters a human from another primate, especially from another ape, the barriers to setting up shop will be relatively low. At the time of the transfer, the germ’s characteristics will have evolved to take advantage of that other primate; but because that primate is more similar biochemically to humans than, say, lions, we can expect a greater proportion of these transfers to take hold.     The process is much like the differential settlement of North America. Immigrants did not settle the continent randomly but rather settled in places where the climate and topography was similar to their homeland. Scandinavians tended to settle in Minnesota, and Germans in Wisconsin. Those from the British Isles settled more heavily along the Atlantic coast. To some extent these differences depended on what was available, but that cannot be the whole story. Who would be more likely to say that Minnesota winters are not so harsh—an immigrant from England or an immigrant from Norway? Germs, of course, do not have the option of forethought; still, one can ask whether a germ that enters a human from a chimpanzee will find life in humans more harsh than would a germ from a lion. It’s no surprise that although African cats and African primates have retroviruses, we humans have gotten our retroviruses, the HIVs and the HTLVs, from other primates rather than from cats.     It is not just the ability to infect and grow in humans that is important. It is also the ability to get out of a human and into the next human. Many germs have passed the first test but failed the second. The track record indicates that here, too, germs from other primates are more likely to become successfully established in humans. The vector-borne diseases that can perpetuate themselves indefinitely in humans—the malarias, yellow fever, dengue—have come disproportionately from other primates. Other vertebrates have made an occasional contribution—sleeping sickness from ungulates, Chagas’ disease from opossums, plague from rats—but these contributions are vastly less than would be expected if the contributions were proportional to the numbers of these other species. The greatest pool of closely related primates is in Africa, which also has its share of other potential sources, such as ungulates and rodents. We can therefore expect the dribble of germs that will enter and become established in humans to do so in sub-Saharan Africa more often than in other geographic areas.     Rodents do seem to be sending pathogens our way, but many of these rodent pathogens do not persist in humans. Two examples familiar to North Americans are the bacterium that causes Lyme disease and the hantaviruses that cause Four Corners disease. Rodents are probably common sources for such diseases because they live in such close association with us and in such great numbers. Occasionally they cause terrible damage, as occurred with the black plague, but even that disease fizzled out in the human population. That the threat from far-off places is only minor does not mean, however, that we have nothing to fear but fear itself.*33\225\2*