BioEd Online

A 'safe' version of Ebola has been developed by researchers hoping to broaden opportunities to study the deadly virus. If approved by national regulatory authorities, the non-infectious virus could be studied in a broader variety of labs, removing a major roadblock to finding a cure.

Current work on Ebola viruses (EBOVs), which cause deadly haemorrhagic fever, is conducted in a small number of laboratories rated at biosafety level-4 (BSL-4) — the highest level there is. "The lack of sufficient BSL-4 space and trained personnel and the rigors of working in BSL-4 laboratories have severely hampered basic research with EBOVs," Peter Halfmann, of the University of Wisconsin, Madison, and his colleagues write in a paper describing the new Ebola virus in Proceedings of the National Academy of Sciences¹. This, they say, is slowing down the development of vaccines and antiviral compounds.

Current knowledge of Ebola is "still too limited" because of a lack of facilities, agrees Jens Kuhn, a virologist and biosafety expert at Harvard Medical School who was not involved with the research.

"Halfmann’s system could be a breakthrough," says Kuhn. "It could give many researchers in BSL-3 or even BSL-2 facilities access to authentic filoviruses [Ebola and Marburg], without putting them at risk of lethal infection."

But there are still some safety concerns, researchers say, as anyone wanting to change the virus back into a lethal form might be able to do so.

Problems with proxies

Other researchers have attempted to get around the lack of biosecure laboratory space by instead working with proxies: viruses that have similar behaviours to Ebola, or individual Ebola proteins. But results from this method don't always apply to real Ebola.

Instead, Halfmann and his group took a wild virus and knocked out one of its seven genes — a gene for a protein called VP30, which is crucial for the virus's replication — and replaced it with a marker gene.

Modified in this way, Ebola can only be kept going inside cells genetically altered to express VP30 — monkey kidney cells in this case. These Ebola viruses resemble wild Ebola in terms of their life cycle, structure and growth. But they cannot thrive outside these specially designed cells, so are non-infectious.

The researchers tested this by incubating the new virus in normal human cells — the virus did not replicate or make viral proteins. Nor could the virus pick up the gene for producing VP30 from its host monkey cells.

Safe system

"It’s a very nice system because it is safe," says Elke Mühlberger, an Ebola expert at the Phillips University of Marburg in Germany. "If this protein is not there the virus is just dead."

In fact, it is so safe it has limitations: it can't be used in animal models, for example, because it cannot infect a live animal. It should be very useful, says Mühlberger, for studying the virus and testing antiviral compounds. VP30-less Ebola also has potential as a vaccine, although this hasn't been explored.

"The idea of making a biologically contained virus is not necessarily new," says Heinz Feldmann, chief of the Special Pathogens Program at Canada’s National Microbiology Laboratory in Winnipeg, who worked on the new Ebola. "But it is the first time that this has been achieved with Ebola."

Safety concerns

There are still some potential problems, however.

Ebola is an RNA virus, meaning that to modify it in the way Halfmann did one first has to make a DNA version, modify this, and then convert it back to an RNA virus. "If you have only the [RNA] virus and the cell line, it is safe," says Mühlberger. But the DNA version has more dangerous potential, she adds.

"Having this system at hand would make it relatively easy to convert the 'contained' virus into a real, infectious and lethal virus again," says Kuhn. "Are we prepared for many researchers and graduate students to have access to this system? Or will work with it remain confined to a few facilities, thereby not accelerating filovirus research after all?"