How AIDS Virus Escapes Cells

UNIVERSITY OF UTAH MEDIA RELEASE

Embargoed by the journal Cell for releaseat 3 p.m. MDT Thursday Oct. 4, 2001

Contacts:-- Wes Sundquist, professor of biochemistry (unavailable Oct. 4-6) - (801) 585-5402, [email protected]

-- Uta von Schwedler, postdoctoral fellow (unavailable Oct. 4-7) - (801) 585-5490, [email protected]

-- Anne Brillinger, public affairs, University of Utah Health Sciences Center - (801) 581-7387, [email protected]

-- Lee Siegel, science news specialist, University of Utah (unavailable Sept. 29-Oct. 2) - (801) 581-8993, [email protected]

-- To reach co-authors of the study at Myriad Genetics, contact Bill Hockett, vice president, corporate communications, Myriad Genetics - (801) 584-3600, [email protected]

STUDY SHOWS HOW AIDS VIRUS ESCAPES CELLSDiscovery Raises Prospect of New Drugs to Control HIV in Infected Patients

Oct. 4, 2001 - Researchers at the University of Utah and Myriad Genetics, Inc., found how the AIDS virus usurps a cell's normal machinery to leave one cell and infect others - a discovery that eventually could lead to new drugs to control the disease in infected people.

In a key part of the new study, the scientists crippled that machinery by "silencing" a gene that normally makes the Tsg101 protein. Without the protein, human immunodeficiency virus (HIV) particles could not escape or "bud" from the cells, leaving them unable to infect nearby cells.

"We showed the virus can't bud without the protein," said Wes Sundquist, a University of Utah biochemistry professor who led the study, published in the Oct. 5 issue of the journal Cell. "Instead, the virus gets stuck at the last stage of leaving the cells."

Researchers at Myriad Genetics identified other proteins within cells that work with Tsg101 to help viruses bud from cells so they can infect other cells, said Kenton Zavitz, a Myriad molecular biologist who helped conduct the study. Many of those proteins "are likely to be good targets" for potential new medicines that would cripple the machinery that helps the virus emerge from cells, he added.

"We do not know if this will lead to new drugs against AIDS, but we hope it will," Sundquist said. "If it does, it will certainly be at least several years away."

Such drugs ideally would help suppress symptoms and control viral "loads" - the amount of HIV - in AIDS patients and in people infected by the virus but who have not yet developed full-fledged AIDS, said Scott Morham, another Myriad molecular biologist involved in the study.

"Current drugs on the market to fight AIDS are resulting in the emergence of drug-resistant mutants of HIV," Zavitz said. "Therefore, it is necessary to identify targets for new drugs that will be the next generation of antiviral medicines."

Tsg101 and the other proteins identified in the new study form the normal cellular machinery that helps target other proteins in cells for destruction or recycling. For example, the proteins help destroy or recycle "growth receptor" proteins when a cell no longer needs to grow, Sundquist said. As part of the process, the proteins make little "vesicles" or particles of membrane material. The proteins that are slated for destruction are put into those particles.

But when HIV infects a white blood cell, the virus commandeers the internal machinery. The cell's normal proteins then are used to produce new HIV particles and help them escape the cell so they can infect other cells.

Sundquist said researchers already knew that a part of the AIDS virus, known as the Gag protein, is essential for HIV to "bud" from one cell and infect another. The new study showed the Tsg101 protein within cells acts as a key link. One part of Tsg101 connects to the HIV Gag protein. Another part of Tsg101 links to other proteins within a cell - proteins the cell normally uses to form the particle-like vesicles.

The researchers used a new technology called "small interfering RNA" to "silence" or block a gene named tsg101 so the Tsg101 protein was not produced. As a result, the AIDS virus could not properly link to the cell's particle-making machinery. So infectious virus particles could not escape the cell. Instead, "clusters of connected HIV particles were stuck at the cell membrane" and could not infect nearby cells, said biologist Uta von Schwedler, a postdoctoral researcher who worked on the study.

Based on the research, Myriad is trying to develop new AIDS drugs that would prevent virus particles from leaving white blood cells and infecting other white blood cells in infected people. The study in Cell found that silencing the Tsg101 gene prevented HIV from budding or emerging from infected cells, said Jennifer Garrus, a biochemistry graduate student who did much of the work under Sundquist's supervision.

Other scientists previously discovered the tsg101 gene and Tsg101 protein. The new study is the first to show their role in helping HIV escape cells so it can spread to other cells.

"We speculate many other viruses may use the same pathway to leave cells" and infect other cells, Sundquist said.

In addition to Sundquist, Garrus and von Schwedler, other University of Utah co-authors of the study were postdoctoral researcher Rebecca Rich, graduate student Owen Pornillos, technicians Kirsten Stray and Melanie Cote, and David Myszka, a research assistant professor of oncological sciences.

At Myriad, Morham and Zavitz helped conduct the study, along with molecular biologists Hubert Wang and Daniel Wettstein.

Morham called the study "a great example of industry collaboration with the university to bring out cutting-edge science."

A copy this news release and downloadable photos of Wes Sundquist and of HIV budding from normal cells and failing to fully bud from mutant cells are available at:http://www.utah.edu/unews/releases/01/oct/aidsbud.html

Wes Sundquist's web site, including animation of HIV "budding" from a cell:http://www.biochem.utah.edu/wes/index.html

University of Utah Public Relations201 S Presidents Circle, Room 308Salt Lake City, Utah 84112-9017(801) 581-6773 fax: 585-3350

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