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AIDS Cure Quest Advances as Cancer Drug Finds Hidden HIV
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Download the PDF here
Download the PDF here
Nature study publication & commentary below, pdfs attached
By Robert Langreth and Shannon Pettypiece - Jul 25, 2012 4:41 PM ET Bloomberg news
LINK:
AIDS Cure Quest Advances as Cancer Drug Finds Hidden HIV
25 Jul 2012
A Merck & Co. (MRK) drug for a rare type of cancer flushed out hidden deposits of HIV ... The Foster City, California- based company, which makes the HIV treatments Atripla
A Merck & Co. (MRK) drug for a rare type of cancer flushed out hidden deposits of HIV in a study, according to researchers who say the results provide a hint that curing AIDS may someday be possible.
The finding on Merck's Zolinza, reported today in the journal Nature, comes as researchers at the International AIDS Conference in Washington this week express optimism a cure is on the horizon. While current treatments hold the disease at bay, stopping the drugs can be a death sentence since it allows infected cells that remain hidden within the immune system to re-emerge, spreading the virus anew.
A single dose of Zolinza reactivated the hidden cells in eight infected patients, a first step toward finding and eliminating all virus traces from the body, according to investigators at the University of North Carolina at Chapel Hill and Whitehouse Station, New Jersey-based Merck who undertook the research.
"If we ever have a cure for AIDS, a big part of it will be this type of strategy," said Steven Deeks, a professor of medicine at the University of California, San Francisco, who wasn't involved in the study. "It's all about getting the virus out of the hiding place and coming up with a way to kill it."
Over the last few years, drugmakers including Gilead Sciences Inc. (GILD), Merck, and Johnson & Johnson (JNJ) have been quietly building up teams of researchers focused on developing ways to wipe out hidden reservoirs of the virus, said Romas Geleziunas, director of clinical virology at Gilead, in an interview at the conference.
'Hottest Topic'
While the research remains years away from large-scale human testing, curing AIDS "is one of the hottest topics right now in biomedical research because there are finally ideas," he said. "Pharma now is really behind this."
Gilead has been working on AIDS cure research for three years, according to Geleziunas. The Foster City, California- based company, which makes the HIV treatments Atripla and Viread, has two approaches in laboratory testing.
In one, Gilead scientists are working with academic researchers to test a lymphoma drug called Istodax from Celgene Corp. (CELG) in a small HIV patient trial that could begin next year, said Geleziunas. If the trial shows promise, Gilead would then try to come up with an improved version. Celgene isn't pursuing its own testing of the drug for HIV, spokesman Brian Gill said in an e-mail.
A record 34.2 million people worldwide are living with HIV, the virus that causes AIDS, according to UNAIDS, the United Nation's division devoted to treating and preventing the disease. It remains a killer disease globally, with about 4,000 deaths a day attributed to it last year alone, the data shows.
Chronic Disease
Today's drug cocktails have transformed AIDS into a chronic disease by preventing the virus from replicating. Yet they can't cure the disease because the current medicines don't kill HIV-infected cells. If a patient stops taking the drugs, the virus will eventually come roaring back, thanks to hidden deposits inside rare dormant blood cells.
In each patient, there are about a million of these infected cells, Geleziunas said. Finding a way to wake them up so they can be spotted and eliminated is a main goal of researchers sleuthing for a cure, he said.
"It is going to be a step by step slow battle, but we can see a way forward," said David Margolis of the University of North Carolina at Chapel Hill, who led the Nature study and has been working for 18 years on ways to eliminate the hidden HIV virus deposits.
Early Trials
There are now roughly 12 patient trials in early stages testing various approaches to curing the disease, said Sharon Lewin, a professor at Monash University in Melbourne, Australia, in an interview. At the AIDS meeting, she said she met with representatives from about 15 drug companies interested in cure research.
"There is quite a bit of research and I think that is new," said Lewin, who is also conducting a patient trial of the Merck lymphoma drug in HIV patients.
At J&J, the world's biggest maker of health care products, 15 researchers in Belgium are focused full-time on developing drugs that could lead to a cure, said Marie-Pierre de Bethune, a vice president in infectious diseases with J&J.
The researchers have taken 35,000 compounds from J&J's library of experimental drugs and tested them against the virus in the lab to see which activate the dormant virus and make it reveal itself to the immune system, de Bethune said in an interview at the AIDS meeting.
Drug Combinations
Researchers will likely have to combine several medications to kill off the hidden virus deposits -- one group to wake up the hidden cells and another that would then prompt the immune system to kill them.
"One drug isn't going to do the trick to cure the disease and many approaches will be needed," de Bethune said.
So far, there is only one person who has ever been cured of HIV, Timothy Ray Brown -- the so-called Berlin Patient. His HIV was wiped out after getting a bone marrow transplant in 2007 for cancer. The donor had a rare gene mutation that made the new white blood cells resistant to infection with the AIDS virus.
"I am cleared of the AIDS virus," Brown said at a news briefing on July 24 in conjunction with the International AIDS Conference. "It is my hope that my life and my story will inspire others to follow a path to a cure that will help everybody."
Zolinza Study
While a bone marrow transplant isn't a practical solution for curing HIV for the masses, Brown "showed that scientifically it was possible" to cure a patient, said Margolis, senior author of the study on Merck's Zolinza.
"Four years ago there was virtually nobody talking about eradication research publically," Margolis said in an interview. Now "a lot of people are jumping in."
When Margolis started working on hidden HIV reservoirs back in 1994, researchers weren't even sure they existed. His first grant proposal on the subject was rejected, he said.
Margolis's new study shows that Zolinza, a type of cancer drug called an HDAC inhibitor, can turn on the dormant immune system cells infected with the AIDS virus.
All eight patients were controlled on existing drugs, and remained on their regular therapy. They received one dose of Zolinza, and then had blood cells removed during a procedure called leukapheresis.
Laboratory tests of the cells found that the average virus expression in the dormant cells increased five-fold, indicating at least some of the virus was being driven out of its hiding places, the researchers wrote. Initial results of the Margolis study were presented at a conference in March.
'Step Forward'
What isn't clear from the study is whether the hidden HIV- infected cells were killed, Margolis said. They also don't know what fraction of the hidden virus was activated.
Nonetheless, "this is an important step forward," said Daniel Kuritzkes, chief of infectious diseases at Brigham & Women's Hospital in Boston. "This is the first compelling evidence we have that we can induce virus expression from latently infected cells."
Kuritzkes is studying additional bone marrow transplant patients infected with HIV to see if the transplants can sometimes wipe out virus reservoirs even if they aren't from donors with cells resistant to HIV, like the cured patient Timothy Ray Brown. Initial results from this study are slated to be presented at the AIDS conference.
Prototype Drug
Merck's head of infectious disease research, Daria Hazuda, said she doubts Zolinza itself would be a drug that eradicates HIV. The strategy behind the trials is to use Zolinza as a prototype that could pave the way for more potent compounds that are better at flushing the HIV out.
The company has "dozens" of scientists working in the early stages of research on the problem, Hazuda said.
The goal is to come up with a combination therapy, much like current treatments for hepatitis C, that can cure a significant fraction of HIV patients over a treatment course that might last a month to a year, she said.
One factor driving the resurgence of interest in cure research is the failure to come up with an AIDS vaccine, according to Hazuda. In September 2007, a promising Merck AIDS vaccine failed in large-scale trials.
"It was a real jolt to the entire field," when an experimental Merck AIDS vaccine failed in large patient trials in 2007, Hazuda said. "I think that woke people up with respect to thinking more serious about eradication and thinking more broadly about prevention research."
Basic Research
Research toward a cure "is still in the very primitive early basic science stages," said Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases.
He said it was important to pursue the studies aggressively even though the odds of success aren't clear. The Bethesda, Maryland-based NIH has spent $122 million on HIV eradication research in 2010 and 2011, the agency said.
Other scientists are openly optimistic.
"Right now is probably the most hopeful and optimistic that we have ever been feeling about the possibility of a cure for HIV," said Rowena Johnston, director of research for amfAR, The Foundation for AIDS Research.
"The chances are pretty good we will have a cure that will be applied widely in the next couple of decades," UCSF's Deeks said.
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HIV: Shock and kill - Commentary by Steve Deeks in Nature
Nature (26 July 2012)
HIV therapeutics is about to enter a new phase. Over the past 25 years, the focus has been almost entirely on developing and optimizing drugs aimed at inhibiting active HIV replication. Although this strategy has resulted in dramatic benefits for those with access to therapy, it has its limitations. Patients must take the drugs daily for life, and subtle toxicities accumulate over decades. Inflammation and immune dysfunction - which seem to have detrimental clinical consequences - persist even when viral replication is suppressed. Finally, and most importantly, the global resources necessary to deliver complex drug regimens, for many decades, to everyone in need are lacking. We require a therapeutic strategy in which a permanent disease-free state can be achieved after a more limited intervention. In other words, we need an effective cure for HIV infection1, 2. On page 482 of this issue, Archin et al.3 report a proof-of-concept study that provides the first evidence that such a cure might one day be feasible.
HIV persists during effective therapy in part because its genome becomes stably integrated in certain white blood cells known as resting memory CD4+ T cells4. These latently infected cells do not express viral proteins and hence remain invisible to the immune system. If activated, however, they can ignite new rounds of viral replication - a risk that forces patients to remain on therapy indefinitely. Theoretically, drugs that reverse latency might lead sequentially to HIV RNA synthesis, viral protein production, release of HIV particles and (hopefully) killing of the infected cell by the virus or by the patient's immune system. Therefore, a cure might be possible if the latent virus in all infected cells can be forced out of its hiding place, leading ultimately to the death of the cells and to the elimination of the viral reservoir. Such a potential therapeutic approach is known as 'shock and kill' (Fig. 1).
Latency is maintained in part by the activity of histone deacetylase (HDAC), an enzyme that removes acetyl groups from DNA-bound histone proteins and, in so doing, affects gene expression. Although some HDAC inhibitors can induce mutations (at least in vitro), they might be able to reverse latency5, 6.
Archin et al. set out to test the anti-latency activity of vorinostat, an HDAC inhibitor approved for the management of certain cancers. Given safety concerns, the researchers first screened patients to ensure that they had an HIV reservoir that was responsive to the drug. To do this, the authors extracted white blood cells from the patients (by a procedure known as leukapheresis), purified resting memory CD4+ T cells and then exposed such cells to the inhibitor. Of the 16 subjects screened, 11 exhibited a statistically significant vorinostat-mediated increase in HIV RNA expression and, of these, 8 patients eventually participated in the study.
The researchers administered a low dose of the drug (200 mg) to these eight subjects to ascertain tolerability. A few weeks later, a higher dose (400 mg) was given to determine anti-latency activity. Within six hours of this dose, the authors extracted resting memory CD4+ T cells from the patients to measure the concentration of cell-associated HIV RNA. In the eight subjects, levels of HIV RNA in resting CD4+ T cells increased in response to vorinostat, with the mean increase being 4.8-fold and the range 1.5-10.
As is common in such first-in-person clinical trials, this provocative study raises more questions than it answers. First, how should the field balance the ethical concerns about administering potentially toxic drugs to HIV-infected people who are otherwise healthy? The ideal population for these studies are those who have been doing well on long-term therapy, but this just happens to be the group with the lowest apparent need for a cure. Second, will future studies of anti-latency drugs require a costly and inconvenient leukapheresis before and after drug exposure? In San Francisco, the cost for such a procedure is over US$2,500. Therefore, a sensitive and high-throughput measure of viral latency is clearly needed.
Third, how much of the viral reservoir might be eliminated by HDAC inhibition? In the current study, the cells isolated from 5 of the 16 tested subjects failed to show any response to vorinostat and therefore these patients were not eligible for the clinical trial. Although those who eventually received the drug exhibited an increase in HIV RNA production, the overall clinical effect was probably marginal, as the concentration of viral particles in plasma did not increase and there was no apparent decrease in the size of the HIV reservoir.
Fourth, which assays will we use in the future to screen potential drug candidates for anti-latency activity? Vorinostat has demonstrated activity in most tests5, 6, but not all7. Finally, what is the fate of the virus-producing cells after HDAC inhibition? Although many investigators have assumed that either the virus or the host immune system would destroy such cells and would therefore clear the virus, recent data suggest that this might not be true8. If the ultimate goal is to shock and kill infected cells, then more work is needed on how to eliminate them9, 10.
Despite these uncertainties, the importance of Archin and colleagues' study cannot be overstated, as it provides a rationale for an entirely new approach to the management of HIV infection. In many ways, their results are comparable to the initial finding that the anti-HIV drug zidovudine (also known as AZT) reduced viral replication in people. Even though zidovudine proved to have limited benefit on its own, the result showed that HIV could be inhibited, and the drug eventually became the basis for the first generation of drug combination regimens. I hope that HDAC inhibitors could ultimately become part of a combination approach to curing HIV infection.
Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy
Nature (26 July 2012)
N. M. Archin1, A. L. Liberty1, A. D. Kashuba1, S. K. Choudhary1, J. D. Kuruc1, A. M. Crooks1, D. C. Parker1, E. M. Anderson2,
M. F. Kearney2, M. C. Strain3, D. D. Richman3, M. G.Hudgens1, R. J. Bosch4, J. M. Coffin2, J. J. Eron1, D. J.Hazuda5&D. M. Margolis1
Despite antiretroviral therapy, proviral latency of human immunodeficiency virus type 1 (HIV-1) remains a principal obstacle to curing the infection1. Inducing the expression of latent genomes within resting CD4+ T cells is the primary strategy to clear this reservoir2, 3. Although histone deacetylase inhibitors such as suberoylanilide hydroxamic acid (also known as vorinostat, VOR) can disrupt HIV-1 latency in vitro4, 5, 6, the utility of this approach has never been directly proven in a translational clinical study of HIV-infected patients. Here we isolated the circulating resting CD4+ T cells of patients in whom viraemia was fully suppressed by antiretroviral therapy, and directly studied the effect of VOR on this latent reservoir. In each of eight patients, a single dose of VOR increased both biomarkers of cellular acetylation, and simultaneously induced an increase in HIV RNA expression in resting CD4+ cells (mean increase, 4.8-fold). This demonstrates that a molecular mechanism known to enforce HIV latency can be therapeutically targeted in humans, provides proof-of-concept for histone deacetylase inhibitors as a therapeutic class, and defines a precise approach to test novel strategies to attack and eradicate latent HIV infection directly.
Among the many important aims of future HIV research is the development of therapies of finite duration capable of eradicating HIV infection. The persistence of quiescent HIV infection within a small population of long-lived CD4+ T cells is currently a major obstacle to this goal1. Histone deacetylases (HDACs) are recruited to the HIV long terminal repeat (LTR) promoter, establishing one of several restrictions that can limit LTR expression and maintain viral latency2, 3. Deacetylated LTR chromatin seems to play a key contributory role in regulating HIV expression, and especially in maintaining proviral quiescence and latency. In vitro, HDAC inhibitors have been shown to disrupt latent proviral HIV infection in both cell culture models and ex vivo assays using cells from HIV-1-infected patients. Although disrupting latency has been proposed as part of a strategy to eradicate HIV infection, previous studies using the weak HDAC inhibitor valproic acid did not consistently demonstrate a marked depletion of resting cell infection7, 8, 9, 10, 11 in patients on antiretroviral therapy (ART). However, the effects measured in these studies are significantly downstream of the molecular site of action of HDAC inhibitors, and thus the proximal pharmacodynamic measures of HDAC inhibitor activity and HIV-1 expression were not evaluated. Here we show that HDAC inhibitors disrupt the latency of proviral genomes within resting CD4+ T cells, establishing the first (to our knowledge) class of drugs that could lead to the eradication of HIV infection.
VOR is a potent HDAC inhibitor used to treat human malignancies. At clinically relevant concentrations, VOR inhibits the class I HDACs most important for repression of HIV expression4, 12; it also induces LTR expression and virus production in vitro from the resting CD4+ T cells of HIV-positive patients on ART with levels of plasma HIV RNA below the detection limit (BDL)5, 6, 13. As the most proximal measure of effect on latent infection is expression of HIV-1 RNA, we developed a sensitive assay to enable a direct measurement of unspliced gag HIV RNA within the resting CD4+ T cells of HIV-infected patients. The assay has a limit of detection of 1 copy per million resting CD4+ T cells, and a limit of quantification of 10 copies per million resting CD4+ T cells.
To evaluate the effect of VOR on latent infection in vivo, HIV-infected patients receiving stable ART with plasma HIV-1 RNA <50 copies per ml for at least 6 months and a CD4 count >300 μl-1 were enrolled following informed consent. To demonstrate that it was ethical to expose patients to an experimental agent with potential risk in a study with no proven clinical benefit for the individual, we validated the ability of this assay of HIV RNA within resting CD4+ T cells to measure HIV expression at baseline, and to detect up-regulation of HIV expression in resting cells from each patient after physiological exposure to VOR.
Patients maintained suppressive ART, and purified populations of resting CD4+ T cells were obtained by continuous-flow leukapheresis and negative selection in an immunomagnetic column7. To establish a baseline, we measured the mean quantity of HIV-1 gag RNA in pools of 1 million resting CD4+ T cells immediately after their isolation from patients. To measure validated biomarkers of VOR effect in peripheral blood mononuclear cells (PBMCs) of patients, we performed parallel assays of total cellular histone acetylation and measured histone acetylation by chromatin immunoprecipitation (ChIP) at the human p21 gene promoter, a gene known to upregulate chromatin acetylation after VOR exposure14. Then to model the effect of a clinical dose of VOR, multiple replicate pools of 1 million resting CD4+ T cells were incubated in complete media alone, with 335 nM VOR, or with 3 μg phytohaemagglutinin (PHA) and 60 U interleukin-2 (IL-2) for 6 h. VOR conditions were selected to mimic the unbound drug exposure expected after a single 400 mg dose of VOR in vivo5.
Validation assays were performed in resting CD4+ T cells isolated by leukapheresis from 16 patients with plasma HIV RNA BDL (Fig. 1a). In each patient a total of 48-72 million highly purified resting CD4+ T cells were studied; that is, 12-48 million cells in each condition, depending on cell availability. In 9 patients following 6 h of culture of 16-24 million cells without stimulation in media alone, HIV gag RNA was quantifiable at a mean level of 52 ± 32 copies per million cells. However, in the other 7 patients in whom 12-24 million cells were studied (Fig. 1a), HIV RNA was not quantifiable at a limit of 10 copies per million cells, although in all but 2 of these patients RNA was detected but not quantifiable (>0 but <10 copies per million cells).
Following in vitro exposure to 335 nM VOR for 6 h, HIV RNA expression was significantly upregulated in 8 of 9 patients in whom resting CD4+ T cell HIV RNA was quantifiable without HDAC inhibitor exposure, and also in 3 of 7 patients in whom cell-associated HIV RNA was <10 copies per million cells before HDAC inhibitor exposure. In all 11 patients in whom expression was induced by VOR, HIV RNA expression was also induced after 6 h of exposure to PHA. Levels of HIV RNA induction were similar after 6 h of exposure to PHA or VOR, although in other experiments (data not shown) levels of HIV RNA plateaued after 6 h of exposure to VOR, but continued to increase when PHA exposure was extended for up to 16 h.
Of the 11 eligible patients in whom an induction of HIV RNA expression following in vitro exposure to VOR could be measured, eight patients (Fig. 1b; CD4 count 432-1,147 μl-1, mean 713 μl-1) continued their long-term ART (tenofovir, emtricitabine and efavirenz in all) and agreed to receive a single dose of VOR at 200 mg to ascertain tolerability. Global cellular histone acetylation in PBMCs was unchanged up to 24 h after dosing, and histone acetylation at the human p21 gene promoter was modestly increased in only two patients (data not shown).
Two to four weeks later the safety and tolerability of a 400 mg dose of VOR was assessed, including acetylation measurements, and VOR plasma concentrations measured serially up to 24 h after dosing (Fig. 2). Maximum VOR concentrations of 244 ng ml-1 (median, range 153-301) occurred a median of two hours (range 0.5-4) after dosing. VOR pharmacokinetics were similar to those reported in other populations15, 16. This exposure resulted in a significant increase (P < 0.01) in acetylation of total cellular histone H3 (median 1.6-fold) in all eight patients, and trend towards increased acetylation of histones at the human p21 gene as measured by ChIP in patients 2, 3, 4, 5, and 7 for whom sufficient cells were available (Fig. 2).
Four to five weeks later, a second dose of 400 mg of VOR was administered and resting CD4+ T cells collected 4-7 h later, after the previously measured peak VOR level. We measured HIV RNA in multiple pools of resting CD4+ T cells within this window of time, when cellular biomarkers of increased acetylation had been previously documented, and induction of HIV LTR expression mediated by HDAC inhibitor activity would be possible. During exposure to VOR, an increase of 1.5- to 10.0-fold (mean 4.8) in expression of unspliced HIV-1 gag RNA within resting CD4+ T cells was measured in all eight patients (Fig. 3). Expression following the 400 mg dose was significantly increased (P < 0.01) when compared to baseline levels of RNA expression for all patients. Patients 1 and 2 underwent leukapheresis 3 to 4 months after dosing and protocol completion to provide cells for other research, and in both cases a statistically significant decline in HIV RNA expression per million resting CD4+ T cells after VOR dosing was observed (patient 1: after VOR 290 copies, off-protocol 70 copies per million cells, P < 0.001; patient 2: after VOR 186 copies, off-protocol 105 copies per million cells, P = 0.003). These observations support the conclusion that the increase in HIV RNA expression was causally related to VOR exposure. This conclusion assumes that the isolation of RNA from resting CD4+ T cells largely excludes actively infected cells, and reflects RNA expression in cells that are functionally defined as latently infected17.
Throughout this limited exposure, VOR was well tolerated, with no adverse events greater than grade I; none of these effects were attributable to VOR. Additionally, we measured single-copy assay viraemia18 on occasions before VOR exposure, and at 8 and 24 h after doses of 200, 400 and 400 mg of VOR (10 assays in total). Despite the upregulation of HIV RNA expression measured in circulating resting CD4+ T cells, no significant change of low-level viraemia was observed. Median plasma HIV RNA (in copies per ml) by single-copy assay in these 8 patients was 13 (range 3 to 23), <1.0 (range <1 to 3), 2 (range <1 to 3), <1 (range <1 to 1), 3 (range 1 to 6), <1 (range <1 to 5), <1 (range <1 to 1.2), and <1 in all assays, with no consistent trend towards an increase in plasma HIV RNA after VOR exposure.
This study demonstrates that the quiescence of latent, integrated HIV provirus within resting CD4+ T cells, a significant barrier to the eradication of HIV infection, can be disrupted by an achievable and tolerable exposure to an HDAC inhibitor. A single, clinically tolerable dose of VOR induces the expected biological effect-histone acetylation-consistent with HDAC inhibitor exposure within the PBMCs of HIV-infected, ART-treated patients. These effects are temporally associated with increased levels of HIV RNA expression detected within resting CD4+ T cells, demonstrating that, at least for a period of time in some infected cells, all of the restrictions that limit the expression of latent proviral genomes have been overcome. Nevertheless, although histone deacetylation is associated with HIV RNA expression, the precise molecular mechanisms through which VOR mediates this effect remain to be fully explained.
HIV RNA induction in vivo often appeared to be of greater magnitude than that seen in vitro, perhaps due to an underestimation in the modelling of physiological exposure in vitro, or other phenomena induced by drug exposure in vivo. Further testing will be required to determine if the in vitro assay presented here is predictive of a subset of patients who do not respond to VOR, or if such pre-screening is unnecessary. Nevertheless, assays of HIV RNA associated with resting CD4+ T cells may be useful in the pre-clinical and clinical testing of new and combination approaches to disrupt HIV latency.
Precise studies will be required to determine which dosing regimens of VOR or other HDAC inhibitors are safe and result in sustained disruption of HIV latency. We did not observe an alteration of low-level viraemia. This may be due to the very low levels of plasma viraemia present in these patients at baseline, that our sampling missed the brief effect of a single exposure to VOR, or that stable, low-level viraemia reflects virion production from sources other than resting CD4+ T cells. Further, a limited evaluation did not reveal a substantial reduction in the frequency of replication-competent HIV within resting CD4+ T cells (data not shown). This is not surprising, as such an effect is likely to require more than a single dose of VOR, or additional interventions to clear infected cells. These are important goals for future studies.
VOR, like the HDAC inhibitor in wide clinical use, valproic acid, is deemed a mutagen as predicted by the Ames test in bacteria, although DNA damage induced by VOR is known to be repaired in normal human cells19, 20. Mutations in normal cells are not observed following long-term growth in the presence of VOR (P. A. Marks, personal communication). Nevertheless, the risks and benefits of attempts to eradicate HIV infection will have to be carefully weighed. Whereas it remains to be seen if the use of VOR in combination with suppressive ART is sufficient to result in the depletion of latently infected resting CD4+ T cells, or whether additional interventions are required, these findings demonstrate that therapy targeted at persistent, latent infection within resting CD4+ T cells is feasible, and open the way for the development of HDAC inhibitors with improved specificity, potency and safety profiles for the selective targeting of latent proviral genomes.
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