Study: Key Protein ID'd in AIDS Infection

W A S H I N G T O N, Nov. 21, 2000 -- The AIDS virus uses a protein complex thatdoes housekeeping chores inside cells to spread disease to othercells of the body, researchers say.

Studies published today in the Proceedings of the NationalAcademy of Sciences report that a group of proteins calledproteasomes are used by HIV, the AIDS virus, to assemble new viralparticles and to spread those new particles to uninfected cells.

New Protein Target For Treatment

Ulrich Schubert of the National Institute of Allergy andInfectious Diseases said test tube studies show that blocking theaction of the proteasome proteins can reduce the spread of HIVinfection by about 98 percent.

Schubert, the first author of one study in PNAS, cautioned thatthe research was conducted only in test tubes, and it is not knownwhether the proteasome inhibitors would work against HIV in humans.

“We would never inject this drug into an HIV-infected person,because we do not know what would happen,” Schubert said.

The proteasome inhibitors will be tested in monkeys before anyhuman tests are considered. The animal studies could take months,Schubert said.

Cautious Optimisim

Dr. Jonathan W. Yewdell, an NIAID researcher and co-author ofthe study, said that although inhibiting proteasome shows promiseas a strategy for treating HIV, “It is possible that it may nothave any effect at all.”

He said the proteasome function is essential for healthy cells,and a drug that blocks that function could affect every cell in thebody.

“It is possible that the HIV-infected cells will be moresensitive or that there are effects against the virus before”healthy cells are affected by a proteasome inhibitor drug, saidYewdell.

Yewdell and Schubert said cancer researchers are experimentingwith proteasome inhibitors for the treatment of prostate cancer,and early studies have shown no side effects in cancer patients.

Proteins Destroy Old Proteins

Proteasome’s job inside the cell is to identify and destroy oldor unneeded proteins. Another PNAS study, by researchers atPennsylvania State University, suggests that a molecule calledubiquitin plays a key role in how viruses use the proteasomecomplex in a cell to make new viral particles. Still another PNASstudy, by researchers from the Dana-Farber Cancer Institute,Harvard Medical School and the University of Padua, Italy, alsodemonstrate that ubiquitin plays a role in HIV particle formation.

Yewdell said that one action of the proteasome inhibitor is toblock ubiquitin.

HIV spreads its infection inside the body by forcing white bloodcells, called CD4s, to make new viral particles. These particlesare released from the cells and can then infect other cells,spreading the infection throughout the body.

The final part of this virus-making process is called budding.During budding, a new viral particle wraps itself in a membranefrom the surface of the infected cell and completes itsdevelopment. When the budding process is completed, the virusparticle is released and can then attach to an uninfected CD4 celland continue the infection spread.

Cellular Protein Helps Make Virus

The researchers found that HIV uses the proteasome molecules,particularly ubiquitin, to complete the assembly of a new viralparticle at the cell membrane. When the proteasome action isblocked, HIV particle formation is crippled, they found.

“Inhibiting proteasome causes fewer viruses to detach from thecell and what virus is made is not as good,” said Yewdell.

Proteasome is most active in the budding phase of making a newHIV viral particle. It is different from protease, an enzyme thathelps the HIV virus assemble precursor proteins into activeproteins. Some HIV drugs, called protease inhibitors, work byblocking the action of the protease enzyme.