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Researcher teases out secrets from surprisingly ‘intelligent’ viruses

Are viruses alive? After more than 25 years of studying the tiny disease-carrying microbes, Michael Lai thinks so.

“Viruses are very intelligent. They can think. They do things that we do not expect. They adapt to the environment. They change themselves in order to survive,” said Lai, professor of molecular microbiology and immunology and a Howard Hughes Medical Institute Investigator.

The reason why some high school biology teachers might argue with his stance, Lai notes, is that a virus can be crystallized similar to nonliving matter. Plus, viruses depend on other living things to reproduce.

Viruses have ways to enter the human body (through the nasal passages, mouth, skin or via injection). Many have evolved defenses to help them evade the immune system. Viruses that cause infection in humans hold a “key” that allows them to unlock normal molecules (called viral receptors) on a human cell surface and slip inside.

Once in, viruses commandeer the cell’s nucleic acid and protein-making machinery, so that more copies of the virus can be made.

Lai has long probed how these tricky parasites work. He has been especially interested in RNA viruses, which carry their genetic blueprints in what scientists have long considered a relatively flimsy apparatus. Because of the way RNA is copied, it is more prone to mistakes in the genetic code and, unlike DNA, the new copy of RNA is never proofread and corrected.

That’s part of what got Lai interested in studying the coronavirus, which is made up of 31,000 nucleotides and has the longest known viral RNA genome. “Conventional wisdom would say that having such a large RNA genome wouldn’t work, that the virus would become defective. But coronavirus seems to have broken all the rules,” he said.

Lai’s studies of coronavirus have revealed the details of how the virus enters target cells and how it turns on RNA synthesis in the host cell. Coronaviruses cause respiratory illnesses in humans and animals and may cause neurological symptoms similar to those of multiple sclerosis.

Lai is also an expert on the hepatitis D virus, a satellite of hepatitis B virus that can worsen hepatitis infection. In the past few years, hepatitis D infection rates in the U.S. have fallen inexplicably.

Recently, Lai has shifted much of his research efforts to the hepatitis C virus. He counts hepatitis C among the most dangerous infectious diseases in the United States right now. Hepatitis C, an RNA virus that attacks liver cells, spreads from person-to-person mainly through blood products and intimate sexual contact.

Already, four million Americans are believed to be chronic carriers of the virus. About 20 percent of the chronic carriers of the virus will go on to develop more serious liver disease, including cirrhosis and cancer.

The virus was only identified in 1989, and there’s still much that scientists don’t know about it. “Receptors are an important part of the story of how viruses cause infection. But we don’t know what receptor hepatitis C uses to get into the cell,” Lai said.

What’s more, no one knows how to grow hepatitis C in the lab. That means that any research on how the virus replicates in cells is incredibly difficult. But Lai and his research group have managed to study the function of some of the viral genes.

They have discovered that one of the hepatitis C viral proteins binds to a few key players in the human immune system, members of the tumor necrosis factor (TNF) receptor family.

Lai suspects that this may help explain how the virus is able to escape the immune system’s attack and so can develop into a chronic infection in many patients. It may also explain how the virus damages the liver and causes hepatitis.

“This protein is now a potential target for new anti-viral agents,” Lai said.

He hopes his research will lead to new ways to treat people already infected with hepatitis C, so that doctors can stop the virus before it causes serious liver disease.

After all these years, studying viruses’ shifty ways continues to leave Lai with a sense of amazement. Part of this comes from the ability of viruses to shuffle genes with as much deft as some genetic engineers.

“Viruses can pick up pieces of cellular genes or incorporate their genes into the cell’s genome. That means that evolution occurs all the time in viruses. It’s a very dynamic process – that’s why I always feel that the viruses are alive,” he said.

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