Traits link array of viruses

Digging deep into their reproductive machinery, scientists have found startling evidence that 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 long thought to be functionally and evolutionarily distinct. The finding could well speed the search for vaccines and treatments for a wide range of virus-related ailments that plague both people and animals.

“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 Paul Ahlquist of the Howard Hughes Medical Institute at UW–Madison.

Ahlquist, the UW–Madison Kaesberg Professor of Molecular Virology and an author of the study, says the new results show that the viruses that cause ailments as distinct as the common cold, West Nile, hepatitis C, foot and mouth disease, and many others are functionally and, likely, evolutionarily related to HIV, the virus that causes AIDS.

The finding is a surprise because many of the viruses responsible for these illnesses were thought to reproduce in ways so different from one another biologically that they were long believed to be unrelated.

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 much-explored model virus, Ahlquist and co-authors 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. It turns out, says Ahlquist, that while the viruses in these three groups build different structures to move between host cells, basic mechanisms in their replication seem to be the same.

This chart illustrates how 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, says molecular virologist Paul Ahlquist. Graphic: Courtesy Howard Hughes Medical Institute

Although diverse, viruses as a rule are relatively simple organisms composed of genetic material — RNA or DNA — packed inside a protein coat. Their goal is to reproduce and pass along their genes using the reproductive machinery of the cells they invade to make virions, infectious particles that act like seeds to infect other cells.

The parallel features discovered by the Wisconsin team involve the mechanisms by which viruses replicate their genetic information after they commandeer the cells of the hosts they infect.

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 newfound commonality among these viruses is that during replication, each passes its genome through an intermediate stage of a particular kind of RNA — 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.”

On the surface, the reproductive workings of viruses are extremely complicated as, over time, they have evolved subtle and intricate ways to camouflage themselves or otherwise circumvent the immune defenses of their hosts. Finding common threads, says Ahlquist, means it is possible to generalize knowledge across broad classes of viruses.

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, the virus that causes AIDS.
• Double stranded RNA viruses, a grouping that includes rotavirus, a virus that kills about 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.”