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TITLE:  Mice succumb to HIV at last
SOURCE: New Scientists, by Philip Cohen
DATE:   Jun 29, 2003

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Mice succumb to HIV at last

AIDS research could shift into a higher gear thanks to an advance that
for the first time allows HIV to fully replicate inside mouse cells.

Researchers at the University of California, San Francisco added a human
protein called hp32 to mouse cells to help HIV properly assemble its
genome into viral particles. The team is now creating whole mice with the
hp32 gene, and looking for other factors that enhance viral infection.

A genetically-engineered mouse model of HIV infection would vastly
accelerate AIDS research because genetics and immunology are so well
understood in mice. These animals, for instance, would speed the
development and testing of vaccine and drugs.

"Right now chimpanzees are the major models for HIV infection," says UCSF
team member Yong-Hui Zheng. "But those experiments are expensive. Few
labs can keep primates and it's impossible to do the same range of
experiments you can do in mice. So this is very exciting."

But Zheng cautions that even with this advance, a proper mouse model of
HIV could be years away. Researchers have struggled more than a decade to
make mice a suitable host for the virus.

Creating handholds

Mouse cells are naturally resistant to HIV in many ways. Some of these
barriers have been overcome by adding human genes to mouse cells. Two
genes, CD4 and CCR5, create "handholds" on the surface of cells that
allow HIV to invade. Another, CycT1, produces a protein that helps the
virus switch on its genes.

But even with those changes, the virus cannot complete its lifecycle by
packaging its genome into viral particles. Zheng, with Hai-Feng Yu and
Matija Peterlin, discovered this is because mouse cells process the RNA
genome of HIV so quickly into smaller pieces that few full-length copies
of the virus are left.

They discovered that hp32 is responsible for slowing down this process.
When hp32 and the three other human co-factors were added to mouse cells,
HIV was able to invade, switch on its genes and package whole genomes
into infective particles.

"They have overcome a major hurdle towards making a mouse model," says Ed
Berger of the US National Institute of Allergy and Infectious Diseases in
Washington, DC, whose team discovered the role of the HIV cofactor CCR5.

But even though HIV can now live out its life inside the altered mouse
cells, the virus still replicates 50 times more slowly in mouse cells
than human cells. That suggests there must be other human proteins that
boost its replication. "We already have some hints about the identity of
those other molecules," says Zheng.

Journal reference: Nature Cell Biology (vol 5, p 611)


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