Published online 30 March 2009 | Nature | doi:10.1038/news.2009.208

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One greenhouse could produce a million doses of virus-blocking chemical.

The protein, produced in N. benthamiana , could be the basis of a new HIV microbicide. Wikepedia

Researchers have used plants to make large amounts of a protein that could help prevent the transmission of HIV.

The study brings the prospect of a commercial protein-based microbicide for HIV a step closer, the researchers say. Such microbicides have so far proved too expensive to mass-produce.

Using a modified form of the tobacco mosaic virus, the scientists, based in the United States and the United Kingdom, introduced genes into Nicotiana benthamiana — a member of the tobacco family — so that it produces a protein made by red algae called griffithsin (GRFT).

Previous studies on human cells growing in the lab have shown that GRFT is effective against HIV. It's thought the protein binds to the virus' surface and stops it from infecting healthy cells.

To date, clinical trials with non-protein microbicides against HIV have been disappointing. Carraguard, a chemical that inactivates HIV by damaging proteins on the virus' surface, was the first anti-HIV microbicide to make it to the end of phase III clinical trials. But in late 2007 it was found to be ineffective against the virus (see Anti-HIV gel trial fails). Scientists hope that protein-based microbicides will fare better.

Protein promise

"Proteins have been shown to provide some of the most effective protection against HIV, and GRFT is perhaps one of the most potent inhibitors yet described," says Kenneth Palmer, a virologist at the University of Louisville, Kentucky, who led one of the teams. Palmer also works for Intrucept Biomedicine, an Owensboro, Kentucky-based biotechnology company that is commercializing the microbicide.

The expensive equipment traditionally needed to make recombinant proteins has hampered efforts to produce protein-based microbicides cheaply. "Microbicides have to be cost-competitive with condoms if they are to be accessible to women in developing countries," says Palmer.

Scientists have tried modifying plants before to express the desired proteins in an attempt to bring down costs. But until now, the plants have failed to make enough of the proteins.

"The best candidates for microbicides are either protein-based or made from small molecule drugs. But recently, the appetite for protein microbicides has waned because people could not see a way of producing them at quantity or [low] cost," says Julian Ma, a molecular immunologist at St George's Hospital, at the University of London, UK.

"This is a landmark study because it shows for the first time that proteins can be produced in large quantities, so it brings back the possibility of producing protein microbicides," adds Ma, who also researches the production of protein drugs in plants.

Trials and tribulations

The team harvested more than 60 grams of GRFT from N. benthamiana plants in a greenhouse with an area of 460 square metres. Palmer says the group chose the plant because it is very susceptible to viral genetic modification, and because it can be grown at high densities in greenhouses. Their work is published today in the Proceedings of the National Academy of Sciences USA.

Palmer estimates that this amount of GRFT could produce roughly one million doses of microbicide, administered as a gel. "This is the first realistic manufacturing process for producing proteins in plants," he says.

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There are currently no plant-made pharmaceuticals on the market, although a handful are in clinical trials, including a treatment made in carrot cells for Gaucher's disease, a metabolic disorder. Palmer hopes to begin clinical trials in the next few years.

One worry is that the algal protein could trigger an immune response in humans, Palmer says. But preliminary tests of the protein's effectiveness against HIV, its safety and toxicity, carried out in human cervical cells and in a rabbit model, are promising.

"It looks very exciting. But will it work in a monkey model?" asks Ian McGowan, co-principle investigator of the Microbicide Trials Network, an international collaboration researching anti-HIV microbicides. "It will be fascinating to see what concentration of the protein will be needed, as when you move from the test tube to animals and then humans, you often need to scale up concentration significantly," he adds.