In the Western world, the third cause of death for people between 45 and 65 years of age is cirrhosis of the liver. (Heart disease and cancer hold the first two spots.) And the main cause of hepatic cirrhosis is the long-term abuse of alcohol.

Some 170 million men and women worldwide harbor hepatitis C virus infection. Though less lethal than HIV, the AIDS virus, that 170 million body count is four times greater than that caused by HIV infection. Grimly, back in 1989 when virologists distinguished HCV from the A and B varieties of the hepatitis virus, they found large numbers of hemophiliac patients dying of AIDS. Their chronic therapeutic blood transfusions infected them with both blood-borne death sentences. Nowadays, donor blood is screened for both viral impurities. The hepatitis C virus accounts for 80 percent of all liver transplants performed in the U.S., with 8,000 to 10,000 deaths a year.

The liver is an organ famous for its ability to regenerate after injury, but once cirrhosis sets in, that destructive disorder is irreversible. It scars the entire organ and degrades its vital function. It may take years, but eventually cirrhosis is likely to turn into potentially fatal hepatocellular carcinoma.

With a whole body full of target visceral organs to choose from, why or how does such a hep-cat as the hepatitis C virus make an inevitable beeline for the liver? Two teams of scientists, one at Albert Einstein College of Medicine in New York City, the other at Progenics Pharmaceuticals Inc. in Tarrytown, N.Y., may well have taken a giant step toward solving this longstanding riddle of tropism - i.e., attraction to the bull's eye.

Their puzzle-busting report appears in the Proceedings of the National Academy of Sciences (PNAS) released online April 2, 2003, under the title: "L-SIGN (CD209L) is a liver-specific capture receptor for hepatitis C virus." Its co-senior authors are William Olson, vice president of R&D at Progenics and microbiologist Tatjana Dragic, a professor at Einstein.

Viral Attraction To Liver Still A Mystery

"The basic liver-tropism problem with HCV," Dragic told BioWorld Today, "is that as of today we really don't know what it is that determines this virus' attraction for hepatocytes - and lymphocytes," she added, "because those are the two target-cell populations of HCV. Now as for HIV, the AIDS virus that zeroes in on immune cells, it may turn out to be that HCV has parallel fusion receptors or entry receptors that are specific for liver cells and lymphocytes - which would explain tropism.

"But so far that hasn't been discovered," Dragic went on, "so we're left with a problem which is how is it that this hep C virus actually gets targeted to the cells that it infects. For the critical protein L-SIGN, it's actually expressed on the endothelial cells of specialized capillaries, which are in the liver. So it's possible that HCV particles that are captured or trapped by L-SIGN on the surface of the endothelial cells are transcytosed - transferred - across endothelial layers to underlying hepatocytes. And that's how these liver cells would then become infected," Dragic surmised.

"And similarly you could imagine that DC-SIGN, which is expressed by dendritic cells, also captures the virus and then transfers it to lymphocytes in the lymph node. L-SIGN is an idiosyncratic acronym standing for liver-cell-specific ICAM-3-grabbing nonintegrin.' And similarly, DC-SIGN would be dendritic-cell-specific ICAM-3-grabbing nonintegrin.' ICAM is the well-known abbreviation for intercellular adhesion molecule.' Similarly, dendritic cells belong to the immune system."

Reverting to L-SIGN, Dragic explained, "In essence, it would be as if L-SIGN was acting like glue or Velcro that's expressed only in the liver. And by virtue of this entrapment, it would then allow for the viral infection of liver-specific cells, which are hepatocytes."

Co-author Olson pointed out, "Cells that express L-SIGN efficiently bind and capture naturally occurring hepatitis C viral particles. We further demonstrated that L-SIGN binds to a viral protein called E2 that is present on the envelope surface of the HCV particle. L-SIGN is also found on specialized liver cells that form a wall or barrier between the bloodstream and surrounding liver tissue. These cells are the first to contact HCV as it enters the liver via the bloodstream, thereby potentially facilitating rounds of infection."

"And it's a little difficult to explain how HCV has been transmitted so effectively," Dragic observed. "HIV, too, is a blood-borne, sexually transmitted virus. It infects about 30 million people to hepatitis C's 170 million. The mortality rates are not the same. But it still isn't entirely clear how hep C is transmitted. We have a clinic at Albert Einstein that cares for co-infected HCV and HIV patients."

A Cough Can't Spread HCV Infection

"It's person-to-person transmission via the blood," she pointed out. "You can't cough on someone and give them hepatitis C. They have to exchange body fluids or fluid, but it seems to be pretty efficient because it has managed to infect so many people. HCV infection is diagnosed in several ways. When impoverished high-risk populations come into the clinic or hospital, they are systematically tested for some form of acute hepatitis.

"Since submitting our PNAS paper," Dragic said, "there are a couple of things ongoing that we're going to try in terms of these liver nodules. We've shown that they bind the virus very nicely and that their interaction is indeed by E2. What we really want to show now is that once the virus gets captured it can effectively be transmitted to hepatocytes or to lymphocytes. So it can be followed up with real infections.

"Practically speaking, we just now have a first rudimentary entry assay for HCV. So we can take these pseudoparticles, which means that on the inside they have a retroviral particle and on the outside they have hepatitis C glycoproteins. We can then have cells that express L-SIGN and DC-SIGN. Once we get these particles to be captured by those cells we can co-culture them with target cells and see if we actually get transfer, infection or enhanced infection of the target cells.

"Conceptually," Olson predicted, "essential therapies - drug or vaccine - would block or inhibit the binding of HCV to its L-SIGN or DC-SIGN receptor."