By David N. Leff

Like cat burglars, viruses use a variety of tools - and accomplices - to break and enter target cells in the human body. Just as some thieves specialize in robbing banks, and others concentrate on ripping off private homes, some viruses infect the lungs and air passages, to cause the common cold, or less common pneumonia. Others, like HIV, go for the cells of the immune system.

Poliovirus lies low in the intestines, but attacks and destroys the muscle-controlling neurons of the central nervous system (CNS). To be sure, in advanced industrial societies - thanks to blanket vaccination - poliomyelitis has dwindled in the past half century from a seasonal paralyzing epidemic to a near-curiosity. But the infection is still endemic in many countries, and the World Health Organization (WHO) has a network of 130 regional laboratories to track cases of sudden juvenile paralysis, and confirm the identity of the virus.

Just as WHO wiped out smallpox in the 1970s, it has now launched a campaign to certifiably eradicate poliomyelitis worldwide within the next five years. Besides UNICEF and the governments of Australia, Canada, Denmark, Germany, Japan, the U.S. and UK, a number of business corporations (among them, Microsoft) are buying in to this initiative.

Scientists know a lot about the disease and its viral perpetrator, but they still have a lot to learn.

"When poliovirus produces disease," observed virologist/crystallographer Michael Rossmann, "it enters and infects neurons in the CNS. But mostly the virus exists attached to cells in the intestinal tract. It lives in the gut, more or less like a carrier, and most of the time when you get infected with poliovirus, you don't have any negative effects. But how the virus actually migrates from the intestinal wall to neurons of the nervous system is not clear."

Rossmann occupies an endowed chair of biological sciences at Purdue University in West Lafayette, Ind. He is senior author of a paper in the current Proceedings of the National Academy of Sciences (PNAS), dated Jan. 4, 2000. It is titled: "Interaction of the poliovirus receptor with poliovirus." A similar but independent paper, back-to-back in the same issue of PNAS, by co-authors at the National Institute of Arthritis, Musculoskeletal and Skin Diseases in Bethesda, Md., bears the title: "Three-dimensional structure of poliovirus receptor bound to poliovirus."

Deep Canyon Hideout Foils Immunity Police

"Our purpose," Rossmann told BioWorld Today, was to find out how the virus recognizes specific target cells, and then enters them. We found out that the poliovirus receptor on the target cell, which was known already, binds into what we call 'the canyon' on the viral particle."

This topographical feature is a deep, narrow depression found on the surface of many picornaviruses, of which poliovirus is a member. Virologists hypothesize that this canyon provides a snug hiding place for the cell's long, thin receptor molecule, whereby its now-tightly clasped virus can escape detection by the body's immune defenses.

"We established how it binds," Rossmann went on, "the orientation of the receptor molecule relative to the virus, and therefore confirmed what I had predicted back in '85 - that receptors tend to bind into the canyon. We also found that the poliovirus tends to bind at essentially the same site as where the rhinovirus receptor binds - also into a canyon."

Rhinoviruses cause nothing worse than the common cold, but served the Purdue co-authors as a sort of seeing-eye dog for tracking the poliovirus' infectious pathway by comparison.

"Rhinoviruses and polioviruses are rather similar," Rossmann explained, "but not the same. They identify and bind to different receptor molecules on their target cells. But although they are different viruses, infecting different cells, binding to different receptor molecules, the place rhinovirus binds to is similar. On the other hand, the poliovirus receptor binds to the same site, but lies more on the surface of the virus."

He made the added point, "The important thing - the site of binding - is probably the trigger involved in the initial stages of uncoating the virus - that is, removing its protein coat to release the viral nucleic acid genome into the cell for further synthesis of new viruses. Polioviruses are spherical icosahedrons in shape, composed of 20 equilateral triangles, with 60 identical binding sites on each viral particle. The receptor molecules are recruited from the target cells to this site of initial attachment, like fingers wrapping themselves around and pulling the viruses into the cell. And that can be done because of the long molecule."

Specificity Is Lock-And-Key Key

"The receptor," Rossmann observed, "is a component of the target cells, in which there are transmembrane molecules. And the poliovirus has learned to use these receptor molecules on the cell, which we call CD155, in order to enter and infect it. They become receptors for the viruses."

What this accomplice receptor, CD155, does in normal life remains a mystery. "All we know about it," Rossmann said, "is that the poliovirus uses this molecule as a receptor. We don't know what its normal function is.

"Specificity," he noted, "is key to allowing the virus to enter a target cell. A virus and its receptor must be perfect complements, like a lock and a key, in order for infection to occur. Our findings provide new insights on what differentiates one virus from another, and they may suggest ways for developing drugs that prevent illnesses caused by viral pathogens.

"For polio," he observed," we have at present good vaccines, but in general, in terms of clinical applications, I think this is the first time we are really learning about how the virus recognizes and enters cells. We know the receptor molecules used by many viruses, but we don't know how the virus interacts with them - except now for poliovirus, and previously for rhinovirus. That doesn't mean we have an immediate application," Rossmann concluded, "but first we need to know more about how things work, how a virus enters its target cell."