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HDAC Inhibitors -- Pushing HIV Out of Hiding

March/April 2013

In people who have been taking ART for several years and who have no other co-infections, HIV-infected cells produce very few copies of HIV and appear to infect other cells at a relatively low rate. In many of these cases, HIV can lie dormant (latent) in cells that are resting, until stimulated from time to time. As part of an attempt at curing HIV, it would be important to rid the body of these infected cells. Driving HIV out of hiding in these cells is sometimes called "purging latently infected cells" by researchers.

Several years ago Canadian researchers attempted to cure HIV by giving ART users the anti-seizure drug valproic acid in addition to ART. However, this did not work.


Introducing ...

Valproic acid belongs to a class of drugs called HDAC (histone deacetylase) inhibitors. Since that Canadian trial, researchers have pondered using more potent HDAC inhibitors, such as the following:

  • panobinostat
  • romidepsin
  • vorinostat

Clinical trials with these drugs are underway in Australia, Western Europe and the U.S. in HIV-positive people to assess their impact.


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The Return of Antabuse

The drug Antabuse (disulfiram) is used to treat some people with alcohol addiction, as it causes highly unpleasant reactions when they drink alcohol. In the body, disulfiram is converted into another compound called ditiocarb (Imuthiol, diethyldithiocarbamate). Results of laboratory experiments with cells suggest that this compound has antifungal and anti-parasite and possibly anti-HIV activity. Clinical trials in the late 1980s and early '90s led to mixed results, and the drug was never approved by regulatory authorities for use as an HIV treatment.

At present, researchers are having another look at disulfiram because in laboratory experiments with cells it appears to activate latent HIV.


Bryostatin

An even older drug, bryostatin, was also studied in the 1980s for its impact on HIV-infected cells. In recent years, researchers have found that bryostatin and closely related compounds can have beneficial effects that may make them useful for cure research. In particular, bryostatin appears to be able to coax HIV from latency in different types of cells of the immune system.


For the Future

It is likely that future attempts at curing HIV will require multiple and perhaps novel therapies. Just what those therapies ought to be is still being debated by scientists. In this issue of TreatmentUpdate, we explore several attempts at bringing HIV out of latency in ART users with HDAC inhibitors.


References

  1. Kent SJ, Reece JC, Petravic J, et al. The search for an HIV cure: tackling latent infection. Lancet Infectious Diseases. 2013; in press.
  2. Katlama C, Deeks SG, Autran B, et al. Barriers to a cure for HIV: new ways to target and eradicate HIV-1 reservoirs. Lancet. 2013; in press.
  3. Rasmussen TA, Schmeltz Søgaard O, et al. Comparison of HDAC inhibitors in clinical development: Effect on HIV production in latently infected cells and T-cell activation. Human Vaccines and Immunotherapeutics. 2013 Jan 31;9(5).
  4. Archin NM, Liberty AL, Kashuba AD, et al. Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012 Jul 25;487(7408):482-5.
  5. Deeks SG. HIV: Shock and kill. Nature. 2012 Jul 25;487(7408):439-40.
  6. Gøtzsche PC. Ditiocarb in HIV infection. Lancet. 1988 Oct 29;2(8618):1024.
  7. Doyon G, Zerbato J, Mellors JW, et al. Disulfiram reactivates latent HIV-1 expression through depletion of the phosphatase and tensin homolog. AIDS. 2013 Jan 14;27(2):F7-F11.
  8. Hersh EM, Brewton G, Abrams D, et al. Ditiocarb sodium (diethyldithiocarbamate) therapy in patients with symptomatic HIV infection and AIDS. A randomized, double-blind, placebo-controlled, multicenter study. JAMA. 1991 Mar 27;265(12):1538-44.
  9. HIV87 Study Group. Multicenter, randomized, placebo-controlled study of ditiocarb (Imuthiol) in human immunodeficiency virus-infected asymptomatic and minimally symptomatic patients. AIDS Research and Human Retroviruses. 1993 Jan;9(1):83-9.
  10. Xing S, Bullen CK, Shroff NS, et al. Disulfiram reactivates latent HIV-1 in a Bcl-2-transduced primary CD4+ T cell model without inducing global T cell activation. Journal of Virology. 2011 Jun;85(12):6060-4.
  11. Cillo A, Sobolewski M, Coffin J, et al. Only a small fraction of HIV-1 proviruses in resting CD4+ T cells can be induced to produce virions ex vivo with anti-CD3/CD28 or vorinostat. In: Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections, 3-6 March 2013, Atlanta, U.S. Abstract 371.
  12. Elliott J, Solomon A, Wightman F, et al. The safety and effect of multiple doses of vorinostat on HIV transcription in HIV-positive patients receiving cART. In: Program and abstracts of the 20th Conference on Retroviruses and Opportunistic Infections, 3-6 March 2013, Atlanta, U.S. Abstract 50 LB.
  13. Kinter AL, Poli G, Maury W, et al. Direct and cytokine-mediated activation of protein kinase C induces human immunodeficiency virus expression in chronically infected promonocytic cells. Journal of Virology. 1990 Sep;64(9):4306-12.
  14. DeChristopher BA, Loy BA, Marsden MD, et al. Designed, synthetically accessible bryostatin analogues potently induce activation of latent HIV reservoirs in vitro. Nature Chemistry. 2012 Sep;4(9):705-10.



This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication TreatmentUpdate. Visit CATIE's Web site to find out more about their activities, publications and services.
 

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