Study: Key Protein ID'd in AIDS Infection

The AIDS virus uses a protein complex that does housekeeping chores inside cells to spread disease to other cells of the body, researchers say.

Studies published today in the Proceedings of the National Academy of Sciences report that a group of proteins called proteasomes are used by HIV, the AIDS virus, to assemble new viral particles and to spread those new particles to uninfected cells.

New Protein Target For Treatment

Ulrich Schubert of the National Institute of Allergy and Infectious Diseases said test tube studies show that blocking the action of the proteasome proteins can reduce the spread of HIV infection by about 98 percent.

Schubert, the first author of one study in PNAS, cautioned that the research was conducted only in test tubes, and it is not known whether 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 any human tests are considered. The animal studies could take months, Schubert said.

Cautious Optimisim

Dr. Jonathan W. Yewdell, an NIAID researcher and co-author of the study, said that although inhibiting proteasome shows promise as a strategy for treating HIV, “It is possible that it may not have 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 the body.

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

Yewdell and Schubert said cancer researchers are experimenting with 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 old or unneeded proteins. Another PNAS study, by researchers at Pennsylvania State University, suggests that a molecule called ubiquitin plays a key role in how viruses use the proteasome complex in a cell to make new viral particles. Still another PNAS study, by researchers from the Dana-Farber Cancer Institute, Harvard Medical School and the University of Padua, Italy, also demonstrate that ubiquitin plays a role in HIV particle formation.

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

HIV spreads its infection inside the body by forcing white blood cells, called CD4s, to make new viral particles. These particles are 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 membrane from the surface of the infected cell and completes its development. When the budding process is completed, the virus particle is released and can then attach to an uninfected CD4 cell and 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 viral particle at the cell membrane. When the proteasome action is blocked, HIV particle formation is crippled, they found.

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

Proteasome is most active in the budding phase of making a new HIV viral particle. It is different from protease, an enzyme that helps the HIV virus assemble precursor proteins into active proteins. Some HIV drugs, called protease inhibitors, work by blocking the action of the protease enzyme.