School of Medicine finds promising treatment possibility for AIDS

By Marissa Meredyth

Researchers in Pitt’s School of Medicine think they might have found a new way to treat… Researchers in Pitt’s School of Medicine think they might have found a new way to treat HIV/AIDS.

While studying an HIV protein that plays an essential role in the progression of AIDS, researchers have discovered compounds that show promise in a new possible treatment for the disease.

Professor Thomas E. Smithgall said drugs currently used to treat AIDS work by blocking the proteins that HIV needs to function, thus preventing the virus from replicating.

But “mutant viruses can emerge that are no longer responsive to the drugs, and there is no vaccine, continuing a need for new and different AIDS drugs,” Smithgall said.

He said it’s been difficult for researchers to develop medicines to treat HIV because they’ve had difficulty finding compounds that can interact with Nef, a protein that plays an essential role in the progression of AIDS.

Nef, an HIV protein, is important for boosting HIV replication and for the transition from a state of HIV infection to one of AIDS, Smithgall said.

“If a compound could be found that interfered with Nef function,” he said, “then it might be useful in preventing AIDS.”

There is evidence that people infected with HIV and who have mutations in the Nef gene take longer to develop disease symptoms, or AIDS.

Smithgall said researchers have been able to delay or prevent disease symptoms from occurring in animals by disrupting Nef production.

But “research on Nef has been difficult or [has] failed in the past because Nef lacks biochemical activity that can be directly measured, making it difficult to target with drug-like compounds,” he said.

Smithgall and a team of biologists, pharmacologists, chemists, geneticists and virologists sought to find a way to measure Nef function indirectly by coupling it to another protein, called Hck.

Nef activates Hck in HIV-infected cells, and it’s activity can be measured easily.

Smithgall said that because of this, the researchers were able to use Hck as a reporter for Nef activity in a screening process that looked for compounds that might influence Nef-induced activation of Hck.

With the help of the Pitt’s Drug Discovery Institute, Smithgall and his colleagues screened a library of 10,000 chemical compounds against the coupled Nef-Hck protein.

They found three compounds that inhibited the activity of Nef-Hck and interfered with HIV replication. One compound suppressed HIV replication to undetectable levels, Smithgall said.

“Our work is in a very early stage,” he said. “What we have is an important proof of concept. Whether this ever translates into a new therapy will require a lot more work.”

The next step is to move these compounds into animals for testing.

Smithgall said this is where a lot of development takes place because of extensive studies that test to make sure the compounds don’t have dangerous side effects, like causing cancer.

If the animal models show promise, Smithgall said, he and his colleagues hope to license the compounds to a drug company that would be interested in human trials.

But more importantly, Smithgall said the group’s work establishes the concept “that HIV Nef is a rational target for antiretroviral therapy.”

He said this research was part of a team effort that included collaborators in the Drug Discovery Institute, pharmaceutical sciences and virologists in his department.

It took a lot of hard work by a lot of people over a long period of time, he said.

Quoting Thomas Edison, Smithgall said, “Success is one percent inspiration and 99 percent perspiration.”

“Well,” he added, “if you asked the people in my lab group who worked on this over the years, they might say that is a rosy view.”