March 9, 2012
Pathway to a Cure: Cancer Drug Helps Purge HIV From Resting Cells
by Tim Horn
Researchers have shown for the first time that it is possible to target
and interrupt the mechanism by which HIV remains hidden and unreachable
by antiretroviral (ARV) drugs, according to highly anticipated study results
presented Thursday, March 8, at the 19th Conference on Retroviruses and
Opportunistic Infections in Seattle. Though no people living with HIV
participating in the study saw their virus eradicated as result of the
experiment, the findings paint an optimistic picture for scientists in
pursuit of a cure for HIV.
After protease inhibitors were approved in the
mid-1990s, researchers hoped that the advent of combination ARV therapy
would be potent enough to burn out HIV infection over time. It soon
became apparent, however, that no matter how strong the drugs are and
how long a person’s virus level remains undetectable, HIV can still
hide out inside dormant cells and bring the infection flaring back to
life once ARV meds are stopped.
Therapies initially studied to reawaken these cells succeeded in
forcing them to purge their HIV payload, but the therapies caused too
much immune system inflammation. In other words, while they “turned on”
the dormant cells, they also created so many susceptible uninfected CD4
cells that the ARV drugs couldn’t protect them.
What was needed, scientists argued, was a drug that could force out
the HIV hiding within these cells without activating immune system
cells at the same time. One such approach that has gained a lot of
attention in recent years is the inhibition of histone deacetylase
(HDAC), an enzyme believed to play a key role in maintaining HIV inside
long-lived resting cells.
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David Margolis, MD, at his lab at the University of North Carolina School of Medicine in Chapel Hill.
©Charles L Harris for UNC School of Medicine
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An early experiment with an HDAC inhibitor called Depakote (valproic
acid), conducted by David Margolis, MD, of the University of North
Carolina and Chapel Hill and his colleagues, proved promising. But
another round of studies, reported a few years later in 2005, failed to
show that valproic acid significantly affected the recalcitrant
reservoirs of dormant HIV-infected cells.
Margolis and his team then set their eyes on another HDAC inhibitor,
Zolinza (vorinostat), a cancer chemotherapeutic that in 2009 was found
to awaken dormant HIV-infected cells, both in laboratory cell cultures and in blood taken from people on ARV therapy. A year later, Margolis’s group
announced their plans for a clinical trial involving people living with HIV.
The clinical trial enrolled six HIV-positive men averaging 45 years
old. All study volunteers had been on therapy for an average of four
years, had undetectable viral loads and had stable CD4 cell counts in
excess of 500.
The study’s first step was to harvest resting CD4 cells from the
patients, which was needed to test HIV-RNA levels—a marker of viral
activity—inside the cells. From there, the cells were exposed to
Zolinza, which confirmed that the HDAC inhibitor had the ability to
increase HIV-RNA levels.
The second step was to explore whether or not the Zolinza dose
selected for the study—400 milligrams (mg)—had an effect on histone
acetylation, the cellular process needed to turn on HIV expression in
the dormant cells. Margolis reported that there was a more than twofold
increase in this activity within eight hours of receiving a single dose
of Zolinza.
The final step was to check Zolinza’s ability to increase HIV-RNA
levels in the pools of resting CD4 cells obtained after vorinostat,
compared with pre-treatment measurements. Margolis reported that there
was an average 4.8 increase in all six patients, which ranged from a
1.5-fold increase in one patient to a 10-fold increase in another.
The researchers also failed to find a statistically significant
increase in blood-based HIV-RNA levels, suggesting that while Zolinza
succeeded at turning on HIV expression in the cells, it did not have an
unfavorable effect of increasing viral load.
Margolis also noted that any adverse effects reported during the
study were mild and that none appeared to be related to Zolinza
treatment.
“This study provides first proof of concept, demonstrating
disruption of latency, a significant step toward eradication,” Margolis
concluded. “The effort to fully understand the potential of such
approaches to influence both the natural history and clinical
management of HIV infection deserves urgent and accelerated
investigation.”
Search: Zolinza, vorinostat, HDAC, SAHA, Margolis, CROI, cure, eradication, latency, dormant, Seattle
