Getting HIV Out of its Hiding Places – Reports from CROI 2012

 NATAP/CROI: HIV Eradication Study by DMargolis with Cancer Drug

Here is link to webcast of the oral session at CROI called HIV Persistence, Latency, and Eradication where Dr David Margolis presented the results of the study he conducted which is discussed below:

from Jules Levin: The drug Zolinza used in this study appears to have been able to “disrupt HIV latency, a signifucant step in eradication”, flush out HIV RNA from latently infected resting CD4 cells, which is considered perhaps the major HIV reservoir that remains after successful HAART reduces & sustains HIV viral load to below 50 copies. This study has been a while in the making, years in fact, previously another drug was tried but unsuccessfully, and this drug & experiment appears to be successful, at least at first blush. It remains to be seen what the ultimate success will be in controlling HIV with this approach as well as with other approaches. So this appears to be a hopeful & successful step, but with more steps to go.

Zolinza May Help Reduce Latent HIV Reservoirs In People With HIV (CROI 2012)
Published: Mar 9, 2012 7:14 pm
Results from a recent small study indicate that Zolinza, a drug currently approved to treat a certain type of lymphoma, may successfully reduce the size of the latent HIV reservoir in HIV-positive adults taking antiretrovirals.
“This is a proof of concept demonstrating that latency can be targeted. This is a significant step towards eradication of HIV infection,” said Dr. David Margolis, a professor of medicine at the University of North Carolina at Chapel Hill and lead author of the study.
“The ability of this drug to deplete latent infection remains to be established and would be the next immediate goal of our work,” he added.
Dr. Margolis urged more research into the ability of Zolinza and other drugs to eliminate or reduce the latent HIV reservoir as a regular part of HIV infection management.
The results were presented yesterday at the 19th Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.
Latent HIV is HIV that is not actively replicating. Instead, it lies dormant, often in immune system cells with long lifespans, such as memory cells (cells that “remember” bacteria and viruses from past infections so they can be effectively fought again). Since antiretroviral drugs usually work by blocking replication, they do not work on latent HIV.
Eradicating latent HIV is a top priority for scientists attempting to cure HIV, and several drugs are currently being tested for their ability to reduce or eliminate this hidden reserve of the virus.
Zolinza (vorinostat) is a histone deacetylase (HDAC) inhibitor, a type of drug currently used as mood stabilizers and anti-epileptic treatments. More recently, HDAC inhibitors have been investigated as anti-cancer agents, and Zolinza is approved to treat a type of lymphoma.
Research has shown that Zolinza successfully activates latent HIV in infected cells in the laboratory. Once latent HIV is activated and begins replicating, scientists hope it will become susceptible to elimination with antiretroviral therapy (see related AIDS Beacon news).
In this study, researchers investigated whether the drug is capable of activating latent HIV in adults whose HIV is well-controlled with antiretroviral therapy.
The study included six HIV-positive participants, each of whom received a single dose of 400 mg Zolinza. All participants had undetectable amounts of HIV in the blood.
Researchers measured the amount of HIV RNA, a marker of latent HIV, in resting CD4 (white blood) cells, a type of immune cell that is targeted by HIV and is thought to be a major source of latent HIV. The researchers measured the HIV RNA both before and within eight hours after giving the participants Zolinza.
Results showed that the amount of HIV RNA measured in participants’ resting CD4 cells increased an average of five-fold after they took Zolinza. According to the study authors, this indicates that Zolinza successfully reactivated the latent HIV in these cells.
There was no increase in the amount of HIV in participants’ blood due to the treatment.
Participants reported no serious side effects, and none of the side effects were attributed to taking Zolinza.

Administration of Vorinostat Disrupts HIV-1 Latency in Patients on ART
N Archin1, A Liberty1, A Kashuba1, S Choudhary1, J Kuruc1, M Hudgens1, M Kearney2, J Eron1, D Hazuda3, and David Margolis*1
1Univ of North Carolina at Chapel Hill, US; 2HIV Drug Resistance Prgm, NCI-Frederick, MD, US; and 3Merck Res Labs, West Point, PA, US

Background:  Despite ART, proviral latency of HIV-1 remains a principal obstacle to curing the infection. Inducing the expression of latent genomes within resting CD4+ T cells is a primary strategy to clear this reservoir. While histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA or vorinostat [VOR]) can disrupt HIV-1 latency in vitro, the utility of this approach has never been directly proven in a study of HIV-infected patients.
Methods:  HIV+ participants on ART, stably <50 copies/mL, maintained ART, and resting CD4+ T cells are obtained via leukapheresis. If an increase in the frequency of HIV RNA expression was observed following ex vivo exposure of resting CD4+ T cells to VOR, patients received 400 mg VOR at separate visits. First, VOR pharmacokinetics were measured. Then biomarker measures of HDAC inhibition in peripheral blood mononuclear cells (PBMC), and measurements of unspliced HIV gag RNA in pools of 1 million resting CD4+ T cells were quantified during VOR exposure.
Results:  Five men have been studied (medians: age 45; CD4 count 562 cells/µL; 4 years of ART). VOR has been well tolerated with no adverse events greater than Grade I, and no adverse events attributable to VOR. Measures of PBMC cellular histone acetylation, and chromatin-bound histone acetylation at the human p21 gene promoter increased more than 2-fold within 8 hours of VOR dosing. VOR PK was comparable to oncology studies with Cmax 263 ng/mL (range 204 to 301) and Tmax 2 hours (range 1 to 4). In each participant, HIV RNA levels increased significantly in pools of resting CD4+ cells obtained after VOR dosing compared to baseline measurements (mean 5-fold, range 3- to 10-fold).
Conclusions:  We measured HIV RNA expression directly within circulating resting CD4+ T cells of patients in whom viremia was fully suppressed by ART. In all patients studied thus far, a single dose of VOR rapidly increased both biomarkers of cellular acetylation, and simultaneously induced up to a 10-fold increase in HIV RNA expression in resting CD4+cells. This is the first demonstration that a molecular mechanism known to enforce HIV latency can be specifically and successfully targeted in man, resulting in readily measureable HIV RNA expression in highly purified, resting CD4+ T cells. Our study provides proof-of-concept for HDAC inhibitors as a therapeutic class to directly attack and potentially eradicate latent HIV infection, and defines a precise approach for evaluating such strategies.

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