Gladstone researchers find method to study hidden HIV reservoirs

Scientists are now one step closer to understanding how HIV hides in cells and rears its ugly head once patients stop taking combination drug therapy, which can suppress viral loads to undetectable levels. The phenomenon reflects the existence of hidden populations of latently infected cells. As a result, patients must remain on therapy for life.

Eradication of these cells could lead to a cure for HIV infection. However, researchers have been hampered by their inability to identify them.

Now Gladstone researchers have found a way to identify and study latently infected cells in the laboratory. Their work is published in the April 15 issue of the European Molecular Biology Organization Journal.

“The latent pool is considered to be the barrier to eradication,” said senior author Eric Verdin, MD, senior investigator at the Gladstone Institute of Virology and Immunology and UCSF professor of medicine. “Our work is geared toward finding a way to obliterate this latent pool, which would take us closer to actually finding a cure for AIDS.”

Through genetic engineering, the researchers constructed a recombinant HIV strain carrying a green fluorescent protein. Using this marker, they identified a small fraction of infected cells in which the virus was latent. These cells represented less than one percent of the infected population and had eluded purification until this study.

“Before, the study of latent infection was restricted to the analysis of rare cells circulating in the blood of infected patients. As an experimental model to dissect the molecular basis of latency, these cells were very limiting,” Verdin said. “We now have a laboratory model that we can use to delve deeply into what is going on.”

During infection, the HIV genome integrates into the host cell’s DNA. Transcription of the viral genome leads to production of virus. The Gladstone researchers found that, in latently infected cells, the HIV genome is integrated into transcriptionally inactive regions of DNA called heterochromatin.

Verdin and his colleagues are now trying to identify drugs that can activate latent cells and cause them to produce virus. A preliminary screen identified a number of compounds that can reactivate latent HIV in the laboratory.

“Hopefully, we will be soon in a position to test some of these compounds in an animal model infected with a virus related to HIV. This will allow us to determine whether the “flushing” of latent pools is a viable therapeutic approach in HIV infection,” Verdin said.

The other authors of the study are Albert A. Jordan, PhD, and Dwayne A. Bisgrove, PhD. Both are postdoctoral fellows at Gladstone.

The Gladstone Institute of Virology and Immunology is one of three research institutes at The J. David Gladstone Institutes, a private nonprofit biomedical research institution affiliated with UCSF. The institutes are named for a prominent real estate developer who died in 1971. His will created a testamentary trust that reflected his long-standing interest in medical education and research.