Human viruses harbor ancient kill code

Deep in the genetic material of pathogenic human viruses such as HIV-1, hepatitis B and assorted herpes viruses, lies an ancient kill code that is at least 800 million years old, reports new Northwestern Medicine research.

“We believe these viruses can kill their host cells using the kill code,” said lead study author Marcus Peter, a professor of medicine at Northwestern University Feinberg School of Medicine. “Understanding how viruses affect cell survival, particularly, how they kill their host cells, could provide a novel way to attack virus-infected cells and eliminate them.”

The findings may open the way to eliminate all HIV-1 infected cells to cure patients of AIDS, Peter said. “This might be feasible because the virus only infects a very small percentage of its host's immune cells,” he said.

Peter is currently studying whether certain viruses -- specifically HIV-1 -- actually use the code sequences to kill.

The study was published in iScience Dec. 11, 2019.

In research published in 2018 in Nature Communications, Peter and his team discovered sequences in the human genome that, when converted into small double-stranded RNA molecules, trigger what they believe to be an ancient kill switch in cells to prevent cancer.

“Human viruses must have coevolved with a mechanism that old,” said Peter, the Tom D. Spies Professor of Cancer Metabolism and leader of the translational research in solid tumors program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University. “Viruses during evolution act like mirrors of our cellular functions.” 

RNA is best known for its role in facilitating the translation of genes into proteins which regulate all cellular functions. However, there are many very small RNAs (microRNAs) that do not code for proteins and rather suppress gene expression.

In his new paper, Peter and colleagues show the kill code can be found across all microRNAs in 17 human disease-causing viruses. These new data suggest many of these viruses can kill cells by activating the code.

A screen in this new work included microRNAs from viruses that cause disease by killing cells. The scientists first showed that a viral microRNA with known anticancer activity in human Kaposi's sarcoma-associated herpes virus uses the kill code. Then toxic microRNAs also were found in HIV-1, which kills certain types of immune cells, and in the hepatitis B virus that causes disease by killing liver cells.

“This provides a new view on how viruses cause tissue destruction and may open a path to develop novel antiviral therapies,” said first author Andrea Murmann, research associate professor of medicine at Feinberg.

Currently, 38 million people worldwide are infected with the AIDS virus HIV-1 with no cure in sight. An even greater number of patients -- 250 million people worldwide -- suffer from hepatitis B.

“Understanding how viruses affect cell survival, particularly how they kill their host cells, could provide a novel way to attack virus-infected cells and eliminate these cells without affecting uninfected tissues,” Peter said.

The discovery that microRNAs of many human disease-causing viruses contain the kill code validates the concept of the kill code itself.

“In my view it confirms that we are dealing with an ancient mechanism that emerged during evolution and got hijacked by viruses,” Peter said.

Next, Peter’s lab will test whether HIV-infected T cells (a type of immune cell) can be killed by treating them with artificial microRNAs that carry a strong kill code without killing uninfected immune cells. If scientists observe a selective death of HIV-infected cells, then this could be a viable strategy to attack only HIV-infected cells after driving the virus out of hiding in the genome of the infected cells.

Other Northwestern authors include Elizabeth T. Bartom, Matthew J. Schipma and Jacob Vilker. 

The research was supported by grant R35CA197450 from the National Cancer Institute of the National Institutes of Health.