New HCV Host Cell Receptor Identified

By Liz Highleyman

Understanding how the hepatitis C virus (HCV) enters human host cells is an important step in the development of new therapeutic agents.

It is known that HCV entry requires the CD81 co-receptor on the surface of host cells, and other cellular molecules have also been implicated, but to date, at least one critical factor has been missing.

Now, as reported in the February 25, 2007 advance online edition of Nature, researchers from Rockefeller University and the Aaron Diamond AIDS Research Center have identified another protein that plays an essential role in HCV cell entry.

Using an iterative expression cloning approach, the investigators identified claudin-1, a tight junction component that is highly expressed in the liver. They found that claudin-1 is required for HCV infection of human hepatoma cell lines, and is the first factor to confer susceptibility to HCV in non-hepatic cells.

Discrete residues within the first extracellular loop of claudin-1 are critical for HCV entry, the researchers reported. Moreover, antibodies directed against an epitope inserted into the claudin-1 first extracellular loop were able to block HCV infection. In fact, the researchers did not observe HCV entry into any cells that did not express claudin-1.

The kinetics of this inhibition indicate that claudin-1 acts late in the entry process, after viral binding and interaction with the HCV co-receptor CD81, the researchers wrote. They concluded that claudin-1 represents a “novel key factor for HCV entry and a new target for antiviral drug development.”

However, they noted that even more co-receptors may be required for efficient HCV entry, since HCV does not enter mouse cells or certain human cells that express CD81, claudin-1, and another suspected co-receptor, SR-B1.

Several investigational anti-HCV agents act directly against the virus -- unlike interferon, which stimulates the body’s immune response.

“Anti-HCV drugs currently under development are directed against viral enzymes required for viral replication, to which the virus can readily evolve resistance,” said lead author Matthew Evans. “HCV may be less able to develop resistance to drugs targeting receptors on the host cell.”

In the future, hepatitis C treatment is expected to increasingly resemble antiretroviral therapy for HIV, using combinations of drugs that inhibit multiple stages of the viral lifecycle.