502865223

HIV drug could thwart virus’ ability to resist

Scientists have announced a new anti-HIV drug that they say could stop the virus’ tendency to become resistant to treatment.

The research will be presented at a meeting of the American Chemical Society on Monday.

Treatment has been revolutionised by through drug “cocktails” that transformed infection from an almost-certain death sentence into a manageable condition. But the virus’ ability to develop resistance to drugs has meant the regimen need constant tweaking to stay effective.

“This disease has gone on for over three decades,” says Dennis Liotta, from Emory University. “We’ve got to try to find new solutions. Even with the 30 approved drugs that we have, and even when you completely suppress viral replication, we still see disease progression.”

Liotta’s research team at Emory University decided to tackle the resistance problem.

To replicate HIV fuses with human immune cells by interacting with key proteins. Its genetic contents subsequently spill inside the immune cells, and the viral proteins then hijack the cellular machinery to make copies of themselves.

One drug company (Pfizer) has developed a compound that blocks HIV’s interaction with one of those proteins, a co-receptor called CCR5. But the virus can also use a second co-receptor, CXCR4, to enter cells. If a drug targets just CCR5, a more virulent strain that favors CXCR4 could emerge over time, says Liotta.
In theory, drugs targeting CXCR4 would be an effective addition to the arsenal against HIV. But interfering with that protein, which regulates several of the body’s inflammatory responses, could lead to serious side effects.

Liotta’s team decided to search for compounds that might be able to bind both CCR5 and CXCR4 at the same time, while avoiding serious side effects.

“Essentially, we took a step back and said instead of creating yet another cocktail of multiple drugs to stop the different mechanisms of HIV, we thought we could design one that hit multiple targets at once,” says Anthony Prosser, a graduate student in Liotta’s lab. If a new drug could block HIV entry by interfering with CCR5 and CXCR4, it could be paired with a traditional cocktail targeting other stages of the virus lifecycle for an even more robust treatment.

Prosser came up with a method to synthesize compounds that likely would bind both co-receptors. Lab tests identified the most effective ones, and the group’s partners at pharmaceutical company Bristol-Myers Squibb found that the compounds also blocked HIV reverse transcriptase, an enzyme that’s key to the virus’s ability to copy itself.

“The agents were active against CCR5, CXCR4 and HIV reverse transcriptase,” Liotta says. “That was unprecedented. Also, they don’t perturb any of the CXCR4 signaling pathways that lead to inflammation.”

“We’ve got a long way to go, but this is a very exciting finding,” Liotta says.