Team finds cell gene that helps viruses multiply

April 02, 2000

Working with a virus introduced into a yeast, scientists have found a cellular gene that is commandeered by the virus to help it multiply.

The finding, made by a team of scientists from the Howard Hughes Medical Institute at the University of Wisconsin-Madison's Institute for Molecular Virology, is important because it gives critical insight into the relationship between virus and host cell, and could provide the basis for new genetic strategies to contain RNA virus infections such as those that cause hemorrhagic fever, hepatitis and the common cold.

The discovery was reported this week (April 4) in the Proceedings of the National Academy of Sciences by a Wisconsin team of virologists led by Juana Díez in the laboratory of Paul Ahlquist in the UW-Madison Institute for Molecular Virology.

"This is the first genetic identification of an intracellular host factor that contributes to the ability of the virus to copy its genes," says Ahlquist, an HHMI investigator and a UW-Madison professor of molecular virology. "Loss or mutation of this gene severely inhibits multiplication of the virus."

Finding the gene may help show how viruses manage to selectively amplify their own genes and gather resources at the expense of host cells. Genes similar to the one found in the yeast exist in many other organisms, including humans.

Viruses are resource poor, explains Díez. The typical RNA virus has a half-a-dozen genes, and to succeed in life it needs to commandeer resources from the host cell it infects.

"By using some of the cell's machinery, viruses can copy their genomes and make viral proteins to be assembled into new virus particles which, in turn, go on to infect other cells," Díez says.

Identifying the contributions made by host cells to invading viruses is a critical frontier in virology. Until now, intracellular factors involved in RNA viral infection had not been conclusively identified, despite a number of biochemical and genetic clues. Previously for RNA viruses, the only host factors identified were cell surface proteins that help viruses enter the host cell.

Although the Wisconsin work was done in yeast -- an organism whose entire genome is known to science -- it has implications for understanding how the large family of RNA viruses works in humans, animals and plants. RNA viruses make up about a third of all known viruses and includes hepatitis C, which infects hundreds of millions of people worldwide and leads to progressive liver damage and cancer; polio, encephalitis and hemorrhagic fever.

"All RNA viruses are believed to use some common mechanisms in their multiplication," according to Ahlquist.

A better understanding of how resource-poor RNA viruses use host cells to multiply is essential to developing strategies to ward off viral infections, says Ahlquist. The discovery of a gene that underpins a key step in the chain of viral infection provides important insight into the complicated interplay of virus and host cell.

In addition to identifying a gene that helps the virus subvert the host cell's own reproductive machinery, Díez and Ahlquist says they were able to glean other insights into virus infection by studying the effects on the virus when the relevant gene was removed from the cell: "Loss of this gene had some very specific effects on infection," Ahlquist says. "The results show that the virus uses this cellular gene near the very beginning of the multiplication process to selectively amplify its own genes."

There are significant potential therapeutic advantages to knowing which elements of the cell are involved in viral infection, according to Díez.

It could one day lead to antiviral drugs effective against a broad spectrum of viruses. Moreover, it could negate the viral advantage of high genetic mutation rates, the ability of a virus to change in order to avoid host defenses.

"Such mutation is a significant problem in controlling RNA viruses," says Díez. "Using antiviral drugs to attack the viral multiplication process, which mutates more slowly than some other virus features, is a promising strategy to control RNA virus infections."

In addition to Díez and Ahlquist, co-authors of the PNAS paper include Masayuki Ishikawa, now of Hokkaido University, and Masanori Kaido, now of Kyoto University.

University of Wisconsin-Madison

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