By David N. Leff

When infectious hepatitis incapacitated some 200,000 U.S. troops in Italy during World War II, diagnosis of the disease was straightforward: "For the first two days, you're afraid you're going to die. For the next two days, you're afraid you're not going to die."

In those days, that non-lethal liver inflammation was the only hepatitis game in town. Now, there are half a dozen known hepatitis viruses, labeled A, B, C, D, E and G, with no end in sight. Two of them, B and C, can be fatal.

Until a decade ago, hepatitis C virus (HCV) was known only as "non-A, non-B," because virologists couldn't identify it. In 1987, scientists at Chiron Corp., in Emeryville, Calif., pulled off that trick.

Worldwide, HCV strikes 60 million people. The only treatment is injections of recombinant interferon-gamma (INF-*), which the virus shrugs off in 80 percent of cases treated. How the pathogen accomplishes this resistance to interferon was its closely held secret, until publication this week of a paper in Virology (Academic Press), dated April 14, 1997. Its title: "Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein."

Microbiologist Michael Katze, the article's principal author, from the University of Washington, in Seattle, said that, against interferon antiviral therapy, "Viruses are not stupid; they fight back."

How Interferon Fights Back Against HCV

"Interferon is a natural substance, part of the body's immune defenses," Katze explained, "produced in response to a viral infection. It exerts its antiviral effects by inducing the synthesis of probably over 50 genes. One of those genes is called PKR. It's a protein kinase, which has been shown and studied for the last 15 or 20 years to be a strong component of the antiviral strategies induced by interferon."

Katze and his team theorized that the hepatitis C virion might generate resistance to INF-* by deploying one of its own nonstructural proteins, known as 5A. "And by a variety of molecular techniques, including biochemical, transfection and yeast genetics analysis," he said, "we demonstrated that that is exactly what happens."

Nonstructural 5A (NS5A) is not a part of the virion's bodily make-up. Rather, it's encoded by one of the genes in the HCV genome when the virus starts replicating inside a cell it has infected.

"The nonstructural 5A protein," Katze said, "up until our discovery, was a complete mystery as to what it might do. In conjunction with earlier epidemiological studies by the Japanese, our work suggests that NS5A is intimately involved in providing the ability of the virus to resist INF-*.

"Furthermore," he added, "when this NS5A protein is defective, the virus succumbs to the antiviral effects of the interferon."

Katze then asked rhetorically: "So does this mean we have a cure around the corner? Definitely not. But for the first time we have a clue as to why interferon is only 20 percent effective against HCV. And we believe that a drug that may block the interaction of NS5A with PKR, in combination, perhaps, with interferon therapy, could reduce the HCV infection to the point that the body's immune system might then clear the virus, and patients will respond to treatment with the combination therapy."

Such an inhibitory drug already is under active development at RiboGene Inc., in Hayward, Calif. Katze is a scientific advisor to the company, which has licensed his anti-HCV technology from the university.

RiboGene's president and CEO, Charles Casamento, said: "We are developing a screen to assay more than 100,000 compounds for the NS5A protein. Our vision is to administer such an NS5A-blocking drug, in order to make interferon far, far more effective among the 80 percent of patients in which it now fails."

Casamento added: "We estimate that in 24 to 36 months, we will put such drugs into humans."

What's The 40-Percent Solution?

Casamento made the point: "We know HCV can be transmitted by blood-to-blood contact from transfusions, by surgery, dialysis, IV drug use, tattooing, acupuncture, vaccination. Mother-to-child is apparently very rare.

"But in 40 percent of the cases," he emphasized, "we're not really sure how it is transmitted. That, to me, is a real problem, because we're not sure what we need to protect against."

Casamento said RiboGene has raised some $30 million to date and that the company is "just closing another financing."

He added that the company may also look to collaborate on a drug's development. "If you look at the millions of people in Asia who have HCV * very high incidence there * it would be logical for us, as a strategy, to collaborate with an Asian pharmaceutical company. *