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HIV-1 virus production inhibited in the lab

JUNE 4, 2002
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CAMBRIDGE, Mass. -- A form of RNA developed at MIT has inhibited replication of HIV-1 virus in human-derived cell lines, potentially showing a new way to combat AIDS. The in vitro work uses RNA interference (RNAi), a naturally occurring technology used by a variety of organisms to silence genes.

"If many obstacles can be surmounted, this could be a basis for intervention in HIV treatment," said Professor Phillip A. Sharp, director of MIT's McGovern Institute for Brain Research, who shared the Nobel Prize in 1993 for his discovery of the "nonsense" segments of the DNA molecule and RNA splicing.

Those obstacles include finding methods to deliver the short interfering RNAs to cells in animals or humans, and ensuring that the process won’t have negative side effects. The study, published this week online in Nature Medicine, involved four laboratory heads at MIT, Harvard Medical School and the University of Pennsylvania School of Medicine.

The researchers created short interfering RNAs (siRNAs) and demonstrated how these siRNAs can inhibit the growth of HIV through gene silencing. They showed specific examples of regions of the HIV genome and regions of cellular genes that can be targeted to inhibit viral infections.

Carl Novina from the Center for Cancer Research, the lead author of the study, used the analogy of a radio to explain how the RNA interference works to silence genes. "RNA interference acts like a switch, like the volume control on a radio, to turn down the volume of gene expression," he said.

The other lead researcher was Premlata Shankar of the Center for Blood Research and the Department of Pediatrics at Harvard Medical School.

The researchers found two ways of using siRNA technology to potentially inhibit HIV infection. The first is by silencing cellular genes that are essential to HIV infection, thereby making the cells less susceptible to the HIV virus.

The second type of intervention is to use siRNAs to silence the HIV gene itself. Five days after introducing the siRNAs into the cells, virus production was reduced 25-fold, compared to controls.

The work will assist other researchers as they continue to use the siRNA technology in the search for a therapeutic setting, where a drug or gene therapy approach can potentially be used to inhibit HIV and other viral replication.

EXCITING INSIGHT

"RNAi was only discovered a couple of years ago and it is, in my opinion, the most exciting insight in biology in the past decade or two," Sharp said. "The RNAi process occurs naturally in a wide variety of organisms from plants to man. It has been proven that RNAi inhibits viral replication in plants, but as of yet, there is no specific evidence that this occurs in humans or other mammals. What we have done in this research is to direct the RNAi process by adding a synthetic RNA to silence cellular and viral genes."

Sharp worked with laboratory heads Shankar, Judy Lieberman of the Center for Blood Research at Harvard Medical School and Ronald G. Collman of the University of Pennsylvania School of Medicine.

The study was funded by the National Institute of Allergy and Infectious Diseases and the National Cancer Institute. Also contributing from MIT’s Center for Cancer Research were Michael F. Murray and Derek M. Dykxhoorn; from Harvard, Paul J. Beresford and Sang-Kyung Lee; and from the University of Pennsylvania School of Medicine, Jonathan Riess.

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