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.
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
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
Scroll down to comment on this story.
comments 1 - 15 (of 26 total) next
Ian cordner, Fredericton, CA, 2013-04-14 08:34:46
Undetectable since starting HAART in 1994, how can one be certain that complete eradication has occurred if the HIV virus is undetectable for so long?
Austin e, Avondale, 2013-01-18 20:21:53
Please hurry. I have friends dying as well as myself to this infernal disease..... God speed to those infected the turn around is just around the corner!
mapaseka kheswa, mthatha, 2013-01-10 00:27:15
I'm a female 24 years and iam HIV I JUST tested on the 24 of december 2012 want to findout wherther the is a cure for it (yes/no) plz
Ja, Greenville, 2013-01-05 12:46:01
In this year of our lord 2013 I hope there will be a new developement that will change the way Hiv/AIDS is treated handled etc. its been long enough that the world has suffered from this disease, I really feel that it's time for a change hopefully one of these new experiments will turn out some good news this year as far as destroying Hiv for good, we can only pray and hope to be freed of this illness once and for all, God Bless all and pray for the end of HIV.
brian, pittsburgh, 2012-10-11 21:34:13
hello, to all the negative comments on here about hiv + cures what on earth made you so bitter that you wouldnt want to get rid of the virus instead of bitching about possible cures. Be happy that they are people out there trying to kill off a virus that has effected millions. it may seem hopeless, but in todays technology and medical advances everything is possible. do you think the deadly flu virus had a vacines come out in a year?
Jarlath Healy, Jonestown, TX, 2012-08-29 01:09:23
Speculation, skepticism, conspiracy. What the hell is wrong with us? Be honestly, quiet and listen. Find silence when thinking about your personal skepticism. Look for solace in your speculation. With please in knowing a conspiracy is only something that was made for you to believe. Believe in these gene therapy's, those drug inhibitors and vaccine's. These techniques that outweigh your selfishness and poor activism. Such disrespect for the hundreds of scientists working for you. Such shame.
Marc C. E. Wagner, Pittsburgh, 2012-07-04 21:02:52
Worked done by Dr. Luis J. Montaner at the Wistar Instute has shown that patients treated with Interferon alpha can remain undetected even off HAART for a considerable amount of time; thus lessening the long-term effects of medications. The pieces of the puzzle are beginning to come together. It will take a combination approach to result the cure. Learn more about the biological importance of eATP on facebook at Adenosine Triphosphate in HIV Cure Research. Optimism is always helpful.
John, Minneapolis, 2012-05-05 00:58:31
This strategy for treating HIV seems a bit senseless and futile to me. First, latent HIV is just that, inactive. We all have latent viruses within us-- latent chickenpox, latent flu virus, and so forth. If it is inactive, it is doing no harm so I see no need to mess with latent virus. Second, we are never going to get all the latent virus and thus, trying to eradicate the virus this way seems futile. There seems to be much more promise in the gene therapy treatments.
Y K RAO, INDIA, 2012-05-04 09:20:14
Test 6 patients with developed drug cost 35 Million $ USD
Alex, Rome, 2012-04-11 09:54:40
“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.” = they NEED FUNDING .. I'm sick of all this false claims .. They will not cure this disease, too much money is around
Greg, Dayton, 2012-04-10 11:27:13
Chrissie - You'll see a genuine eradication of the disease when it is no longer profitable. Profit is a double edged sword in medicine. It encourages research and chronic treatment but does not encourage cure.
Marc C. E. Wagner, Pittsburgh, 2012-04-04 21:07:58
I published an article in the journal Current HIV Research describing the use of adenosine triphosphate in combatination with HAART to purge the virus reservoir with the goal of achieving a state of cure. You can learn more about this process by visiting www.marccewagner.com. You can download the full published article from this website or directly from the journal. I welcome feedback on the concept that is presented in this article.
Mark, , 2012-04-01 22:27:46
Interesting, but like many long-termer's, I'd like to finally something conclusive - hopeful but not holding my breath.
Damon A. Bryan, Ocho Rios, 2012-03-31 12:03:33
i most say thank to the many scientists and doctors, and people that put they hard working money. in trying the difference meds, to find a cure soon for us. just to let u all know that jehovah god well help us to find a cure one day. love all to my brothers, sister's
Steve, san francisco, 2012-03-30 16:08:11
comments 1 - 15 (of 26 total) next
Agree with all the comments about the cure being closer than ever, because I think that's a matter of fact now. Another breakthrough announcement was made recently on the cure front, look up 'antibody pgt 128', which is effective at curing 70 percent of hiv strains "Although the antibody does not provide a solution to all HIV infected people around the world, scientists are optimistic about finding a potential lifetime cure because of the success of this research."excerpt from Cornell Daily Sun!
[Go to top]