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HIV and Cure: Another Look at the Reservoir, from Melbourne

Romidepsin, a histone deacetylase (HDAC) inhibitor currently used to treat cutsneous T-cell lymphoma, can drive enough concealed HIV out of hiding for the virus to be detected in the blood with standard HIV assays, a first-of-its-kind investigation has shown. "What we saw was a significant release of viral particles from latently infected cells into the plasma of patients, despite treatment with antiretroviral therapy," Ole Søgaard, MD, from Aarhus University in Denmark, said at the 20th International AIDS Conference.

In an earlier study, the same team of researchers was able to measure an increase in HIV viral particles in the blood after treatment with panobinostat, another HDAC inhibitor.

"This is the first work to show that you can wake the virus up and make enough leave the cell, which is quite significant because that means the cell will probably now be visible to an immune response," said Sharon Lewin, MD, cochair of the meeting organizing committee. "It's the first step to get rid of these long-lived sleeping of forms of the virus, and it's actually a big step."

Dr. Søgaard and colleagues recruited, from their outpatient clinic, 6 HIV-positive patients who had well-suppressed viral loads for a median of 9.5 years. Patients received 3 infusions of romidepsin over 14 days in addition to their antiretroviral regimen. This is the first clear evidence that the latent reservoir can be identified and the hidden virus shocked out of its hiding place, said Steven Deeks, MD, from the University of California at San Francisco. "I think this is the single most important advance we've heard of at this meeting, and it's going to have a huge impact in the future."

The concentration of HIV RNA increased 2-4 times after the second infusion of romidepsin. In 5 of the 6 subjects, the undetectable plasma viral load became readily measurable with standard HIV assays — at 46 to 103 copies/mL. "We next went on to see if we could find a significant reduction in the size of the HIV reservoir in these 6 patients," Dr. Søgaard explained.

On the basis of the preliminary analysis, the strategy does not appear to lead to a significant reduction in the size of the reservoir. "Romidepsin in this trial was quite convincing in reversing latency in some cells, although we still don't know how much reactivation you can induce," Dr. Søgaard noted. However, "viral particles were easily detectable with the same viral load assays that we use to monitor treatment response in patients."

Clinical Implications

"It's increasingly clear that early initiation of antiretrovirals most likely reduces the amount of virus that persists in patients on treatment," Dr. Lewin said. "However, most people get treated during chronic established infection," she added, which gives HIV ample time to establish long-lived and undetectable reservoirs that serve as a source of viral rebound as soon as therapy is interrupted.

"One of the strategies we are using to try to reduce the reservoir in chronically infected patients is this kick-and-kill approach, where we attempt to kick cells that have archived HIV within their DNA out of their resting stage and expose the virus on the surface of these cells so that it can be killed and eliminated by the immune system," Dr. Søgaard explained.

Using a reservoir activator, such as romidepsin, to release latent HIV into the blood in combination with a therapeutic vaccine to boost the immune response could lead to more successful eradication of HIV.

In fact, the researchers have launched a study in which well-suppressed HIV-positivepatients will receive both romidepsin and a therapeutic HIV vaccine to see if the dual approach can reduce reservoir size.

"It's the first combination trial to go forward," Dr. Søgaard said.

20th International AIDS Conference. Abstract TUAA0106LB.

Source: Reporting from Melbourne, Australia, for PRN News: Bill Valenti, MD