Virus Families Are Related

Applied Genetics News,  April, 2002  

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According to Paul Ahlquist of the University of Wisconsin, Madison (500 Lincoln Dr., Madison, WI 53706; Website: www.wisc.edu), broad classes of viruses-including those that harbor the agents that cause such diverse ailments as AIDS, the common cold, and hepatitis-share functional traits that suggest they all evolved from a common ancestor.

The discovery, reported in the journal Molecular Cell, unexpectedly unites half of virology, linking large groups of viruses previously thought to be functionally and evolutionarily distinct.

"Recognition of these links means that principles learned from a variety of virus systems now can be used to illuminate many others, allowing integration and generalization of knowledge across a wide range of important pathogens," says Ahlquist.

All viruses belong to any of six major classifications. Each class differs in important and fundamental ways, and each appears to represent major evolutionary lineages, Ahlquist says. "In each of these classes, there are important pathogens, and in each of these six classes there is lots of different biology."

Working with a positive strand RNA virus called brome mosaic virus (BMV), which they induced to infect yeast, Ahlquist and coauthors Michael Schwartz, Jianbo Chen, Michael Janda, Michael Sullivan, and Johan den Boon, all of the UW-Madison Institute for Molecular Virology, show that key features of replication run parallel in three of the six broad classes of viruses.

Some viruses related by these findings replicate by switching their genes between RNA and DNA, while others store and replicate their genes only as RNAs. However, one commonality among these viruses is that during replication, each passes its genome through an intermediate stage of messenger RNA.

"This viral messenger RNA has two distinct functions," Ahlquist explains. "It is used by normal cellular machinery as a template to synthesize viral proteins, and by virus-induced machinery as a template to replicate the viral genome."

A second common feature found by the Wisconsin team is that this viral genetic template, the messenger RNA, always becomes sequestered within a compartment generated within newly infected cells by the invading virus. "This new virus-induced compartment, in which the virus genome is reserved and copied, shows surprising similarities across these different virus groups."

In studying BMV replication in yeast, Ahlquist and his colleagues examined the function of two proteins, 1a and 2a polymerase, which are important in viral replication. Their electron microscopy of labeled viral components, and additional genetic and biochemical studies, revealed that large numbers of 1a proteins form partially budded spherules containing the viral RNA and 2a polymerase, which is responsible for replicating the viral RNA. These spherules are formed in the membranes of an internal cell structure called the endoplasmic reticulum, which is the site of BMV viral replication.

Their studies also showed that this positive strand RNA replication machinery strongly paralleled that of retroviruses. In retroviruses, a protein called Gag forms a similar budding structure called a capsid that envelops the viral RNA and the Pol enzyme-a reverse transcriptase that copies RNA to DNA. These capsids are formed in a structure called the plasma membrane, where retroviral replication takes place. This replication machinery is triggered by an RNA packaging signal that parallels the action of the signal in BMV.

The three major virus groupings of viruses that showed this surprising affinity are:

* Positive strand RNA viruses, which includes cancer-causing hepatitis C, viruses that cause the common cold and many others.

* Reverse transcribing viruses, which include HIV.

* Double stranded RNA viruses, a grouping that includes rotavirus, a virus that kills approximately one million children a year in developing countries.

These three groupings encompass over half of the world's known virus families. Finding commonalties on such a grand scale bolsters prospects for the development of broad-spectrum antiviral agents.

"These results have added considerably to our understanding of these viruses, and any new basic knowledge is useful in control," Ahlquist says. "If you know the machinery, you know where to throw the wrench to mess it up."

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