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Scientific Method / Science & Exploration

Compounds coax HIV out of hiding so it can be eliminated

New compounds easier to make, not toxic, and work at lower concentrations.

HIV "buds" out of immune cells, like this T cell.

Chemists have built molecules that flush out human immunodeficiency virus (HIV) hiding inside immune cells. While these compounds do not cure the virus that causes AIDS, they could be a powerful addition to current treatments, which cannot eradicate these dormant viruses.

Current HIV treatment requires a cocktail of drugs to kill viruses replicating in T cells, and patients must regularly take their medicine to keep the virus at bay. HIV can hibernate in these cells and reemerge to infect patients if they stop treatment.

Another approach to treating HIV aims to reactivate these dormant viruses, thereby allowing the immune system (or the virus itself) to kill the cells where they are hidden. In conjunction with cocktail therapies that keep HIV under control, this approach has the potential to completely purge the virus from a patient.

Once such potential drug, called prostratin, binds to a protein (protein kinase C) that helps reactivate hibernating viruses. Chemist Paul Wender, of Stanford University, first synthesized prostratin in the lab in 2008, and the compound is being considered for clinical trials.

Bryostatin 1, a compound produced by a marine organism, might be a useful HIV treatment, too, because it binds to protein kinase C better than prostratin. But there are several concerns about using it as a potential medicine. Bryostatin is hard to come by, both in nature and in the lab. And, perhaps most worrisome, bryostatin can cause negative side effects in humans.

Now Wender and his colleagues have built seven molecules related to bryostatin, two of which are about 1,000 times more effective at reactivating dormant HIV than prostratin. These molecules appear non-toxic in early cell tests.

These “bryologs” retain chemical groups important to the potency of bryostatin, yet their synthesis is streamlined enough that the scientists can make the bryologs on a large scale. The researchers build and connect molecular fragments to form an entire bryolog. That means they can potentially change reactive groups on the fragments to enhance each compound’s effectiveness while reducing negative side effects.

The scientists treated cells that model a latent HIV infection with each new bryolog. The new compounds reactivated dormant HIV at concentrations 25 to 1000 times less than current preclinical compound, prostratin.

The researchers are currently testing the bryologs in animals. They hope these new compounds could be used as part of a treatment that eliminates all HIV currently in someone's body, whether the virus is active or not. That could be one way to completely eradicate the virus, they add.

Nature Chemistry , 2012. DOI: 10.1038/NCHEM.1395 (About DOIs).

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