November 5, 2001

Two researchers working at UConn's Center for Excellence in Vaccine Research have discovered a procedure that can overcome virus resistance to the action of interferon. Interferon is a protein produced in response to virus infection and used by the cells of the body to fight infections.

"Although the interferon system can be highly effective as a defense against viruses, it can fail because some viruses have evolved elaborate mechanisms to thwart activation of interferon," say Professors Philip I. Marcus and Margaret J. Sekellick. The two virologists in the Department of Molecular and Cell Biology have been studying how viruses induce cells to make interferon and how that interferon may be used to prevent virus infection.

In a recent publication in the Journal of Interferon and Cytokine Research, and in a report at the annual meeting of the International Society for Interferon and Cytokine Research at the Cleveland Clinic Foundation, Marcus and Sekellick described how interferon action can be enhanced to counter virus resistance. Their technique essentially overwhelms the ability of a virus to block the antiviral action of interferon.

Discovered in 1957, interferon is a naturally occurring protein that can fight off all kinds of viruses. It is the first line of defense used by the body against virus infection. According to Marcus and Sekellick, within minutes after a virus infection takes hold, cells of the body recognize the presence of the virus, because during the course of infection the virus produces a unique molecule known as double-stranded ribonucleic acid (dsRNA) within the cell.

The molecule consists of a twisted coil made up of two strands of RNA. The cell is exquisitely sensitive to the presence of this coil of dsRNA. In earlier studies, Marcus and Sekellick have shown that some cells can detect as little as a single molecule of dsRNA and respond by producing a full yield of interferon.

Once dsRNA is detected by the infected cell, it triggers a series of reactions that lead to the activation of otherwise dormant interferon genes. These cellular genes, stimulated by the presence of virus dsRNA, produce interferons.

Interferons are members of a large family of cellular proteins called cytokines. They are responsible for a wide range of biological effects. It is the antiviral state that interferon can induce in cells, once it is secreted from a virus-infected cell and comes into contact with uninfected cells, that is the focus of research carried out by Marcus and Sekellick.

The attachment of interferon to specific sites on a cell surface will activate more than 100 cellular genes and trigger the development of a dormant antiviral state. This dormant state is activated only by the dsRNA produced during the course of virus infection.

According to Marcus and Sekellick, virus dsRNA plays two roles in the interferon system: it induces the cell to produce interferon, and it activates the antiviral action in interferon-treated cells.

Interferon-treated cells gradually produce less and less virus, until the infection is ultimately eliminated and the host survives. Marcus and Sekellick say one reason the human race has survived many virus infections is because of the rapid response of the interferon system and the protection it affords.

Some viruses, however, are intrinsically resistant to interferon action. Marcus and Sekellick knew that some virus resisted the action of interferon, because they produced proteins that would sponge up the viral dsRNA so that it was not free to activate the dormant state of interferon action.

They reasoned that it might be possible to counter the virus defense mechanism if dsRNA was delivered to the cell in sufficient quantities to overwhelm what the virus could sponge up. Using this technique, they report that when dsRNA is added to interferon-trea ted cells, many different kinds of viruses can no longer resist the action of the interferon.

Marcus and Sekellick say that future research will determine whether the anti-tumor action of interferon may be enhanced using the combined interferon-dsRNA treatment they have reported.

David Bauman