Hit Viruses

How viruses use a host cell to replicate

1. Invade cell
proteins on the surface of the virus bind to receptors on the host cell. The virus fuses with the cell.

2. Uncoat
Human enzymes dissolve the virus's protein coat, releasing the genes in its core.

3. Multiply
The virus takes over the host cell's machinery to make copies of its genes and proteins

4. Go forth
the genes and the proteins form new viruses, which bud from the cell. and seek new hosts

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hit viruses

To find new target for antiviral drugs, scientists look for genes that human cells don't need but viruses do. One search method is shown here

1. Find unneeded genes
a harmless retrovirus (red) is used to knock out a different gene (green) in each human cell of a colony. If a cell survives, that means the targeted, gene wasn't producing an essential protein.

2. Bring on the enemy
Remaining cells, lacking a gene they don't need, are infected with a virus, such as flu (orange), that would ordinarily kill them all. Yet it fails to kill some.

3. Identify survivors
If a cell survives the virus, that suggests the virus, couldn't reproduce without the protein encoded by the missing gene. A new antiviral drug might target that protein without harming human cells.

4. Break the cycle
A virus's life cycle could be disrupted at different stages by drug that targets a human protein.The only such drug approved so far blocks a receptor that HIV needs to enter human, immune cells.

# Conventional antiviral drugs target the virus itself. For example, Tamiflu blocks a surface protein on the influenza virus that enables it to escape from one cell to infect another.

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hit virus

The key is finding the right target a gene and the protein it encodes, that the human cell doesn't need but the virus does. Human DNA contains more than 20,000 genes, but in any given cell at any given time, many are dormant : some, for instance, are only switched on during embryonic development. With the human genome now fully decoded, investigators can search for target systematically by disabling individual genes in many cells and seeing what happens. Zirus, a company in Buford, Georgia, uses a three step process (see opening illustration): it begin by infecting cells with a harmless retrovirus, which splices itself randomly into human DNA, knocking out any gene it interrupts. Other groups are disabling selected genes with matching bits of RNA. If the cell survives without a particular gene and is now resistant to infection, that gene protein combo is a promising target for a drug.

The first such drug. Pfizer's Maraviroc, is already being used to treat HIV infection ; it blocks a cell surface protein that acts as a receptor for the virus. San diego based nexbio has recently begun clinical trials of a compound called Fludase that inactivates the receptors through which both swine flu and seasonal flu enter respiratory cells. NIAID is vigorously supporting such research, "Over the next 20 to 30 years there will be a paradigm shift in the way we approach infectious diseases," Kurilla says. "I think this will be emblematic of 21st century medicine". -Josie Glausiusz,

to be continued ........

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Hit Viruses

Hit them where they live

Viruses that infect us can't spread without us. Finding their helpers inside human cells may yield drugs that stop pandemics.

Within a few months of the outbreak of swine flu last spring, public health officials reported the first cases resistant to Tamiflu. It was no surprise. The previous winter most cases of seasonal flu had also proved resistant to the drug. Why don't we have antivirals as good as antibiotics are against bacteria? Viruses are willer, they mutate best designed drugs, but researchers are now working on a radical new strategy that just might antiviral equivalent of amoxicillin. The idea is simple : Instead of attacking viruses directly, target the human cells they infect.

Bacteria are organisms that are equipped to reproduce themselves : antibiotics attack that machinery. But a virus is a parasite : It invades a host cell and co-opts the cell's own machinery to make copies of itself thousands of chances to mutate and develop drug resistance. A drug that disables a part of the human cell that helps the virus reproduce, though, could stop it with little risk of resistance. "and if you can identify a host function that HIV, flu and Ebola all require, you can have one drug that is active against all three a board spectrum antiviral," says Michael Kurilla of the National Institute of Allergy and Infectious Diseases (NIAID).

to be continued . . . .

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