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Why Not Target Human Genes for Antiviral Drugs? Study Asks

BioWorld Today Correspondent

LONDON — It may be possible to develop drugs to treat viruses as diverse as influenza and HIV by targeting the products of human genes that are involved in allowing an infection to take hold in the body, a study by researchers in Germany suggested.

Scientists from the Max Planck Institute for Infection Biology and their collaborators found 287 human genes that affected replication of influenza A virus.

In two additional experiments, they were able to show that by knocking out the function of selected genes – either chemically or genetically - replication of influenza A virus was substantially reduced in a cell line and in mice.

Thomas F. Meyer, acting director of the Max Planck Institute for Infection Biology in Berlin, told BioWorld Today, "We identified 287 human genes that are involved in viral replication. Not only that, many of these human genes are required for replication of a range of influenza viruses, including sporadic isolates, pandemic isolates such as swine flu and isolates of H5N1 bird flu."

The results indicated, he added, that the targets identified have a broad spectrum of efficacy. "They might be very useful for the development of a novel type of antiviral drug," Meyer said.

An account of the study appeared in the Jan. 17, 2010, issue of Nature in an article titled "Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication".

The Max Planck Institute for Infection Biology has patented the use of the human gene products as targets for antiviral drugs for the treatment of influenza. The group, which has a high through-put screening facility with containment appropriate for the most dangerous pathogens, is open to collaboration with commercial partners or development of spin-offs.

Meyer said the idea of exploring which human genes are important for infection with influenza virus was rooted in the observation that, for an infection to take place, the pathogen must interact with the host cell. Frequently, the pathogen depends on the host cell for growth and replication.

While antibiotics and vaccines target the pathogen, there is no reason why antiviral drugs should not be developed by focusing on gene products of the host that the pathogen needs for its growth, survival or reproduction, he said.

Meyer and his colleagues used the technique of RNA interference to knock down each gene in the human genome in turn, using cells in culture. They had to do multiple experiments for each gene, in fact, using several inhibitors for each gene, because inhibition by a given short interfering RNA (siRNA) inhibitor does not always work.

In all, they used 62,000 siRNA inhibitors to be sure of knocking out all human genes. Not only that, they chose to use a two-step assay to decide whether each gene affected infection by influenza virus.

For the first step, they took cells that lacked each gene in turn, and tried to infect them with influenza; they could tell when infection had taken place because they could stain a viral protein in the cells.

For the second step, they tested whether the infected cells were capable of producing infectious virus: they used the supernatants from each of the infected cell batches to infect fresh cells, each batch of which contained an indicator gene for measuring virus titres. Again, there were 62,000 knockdown batches of the latter.

"This was, of course, a huge task," Meyer said. "We did it using robotic handling and automatic microscopes."

The first round of analysis suggested that hundreds to thousands of genes, when each one was knocked out with a single siRNA, could prevent or reduce infection of the cells with influenza virus. After further rounds of the assay, the scientists were able to reduce the number of human genes involved in viral replication down to 287.

"Existing strategies for dealing with influenza infection have disadvantages," Meyer said. "It can take several months, for example, to develop a vaccine once a new strain of influenza has appeared. The problem with drugs that target influenza is that the virus can mutate so that it becomes resistant and the drug may no longer work. But these human target genes that we have identified are not variable so the virus could not mutate to get around them."

Drugs developed that targeted human genes would therefore be likely to be effective not only against existing drug-resistant influenza strains, but also against unknown variants that may appear in the future, Meyer predicted.

Meyer is aware that his proposed strategy is open to criticism that any drugs that target human gene products could be harmful or have unwanted side effects. "It is true," he said, "that some genes may be essential but others may not be needed all the time – they might only be active during development, for example – or it is possible that we could do without them for short periods."

In addition, he argued, most existing drugs for the treatment of human disease already target human gene products, often with successful results.

"Although, in the past, we have always targeted the pathogen, why shouldn't we use the same strategy that we apply to other diseases, for infectious diseases, too?" he asked.

The team already has further projects under way to probe which human genes are involved in assisting infection with other organisms, including Chlamydia, intracellular pathogens and other viruses.

Published: January 26, 2010