Can Alcohol Abuse Drug Disulfiram Help Eradicate HIV?

Disulfiram (Antabuse), a medication prescribed to manage alcoholism, can activate resting CD4 cells and flush out latent HIV, a key step towards viral eradication.

Researchers are increasingly exploring a variety of strategies towards a cure for HIV. But eradicating the virus has proven difficult, in part because HIV integrates its genetic material, known as proviral DNA, into human cells.

HIV DNA can remain latent in resting CD4 T-cells for years or decades, where it is safe from current antiretroviral drugs. Eventually, however, these reservoir cells can become activated and start releasing new virus, which is why people with HIV must remain on antiretroviral therapy indefinitely even when their plasma viral load is undetectable.

One strategy for eradicating HIV from the body -- or reducing it to a low enough level that the immune system can control it -- involves forcibly activating resting CD4 cells carrying proviral DNA, in order to flush out the viral reservoir and render the virus susceptible to antiretroviral therapy (ART).

Many compounds can activate resting CD4 cells, but some do so too well: stimulating too many T-cells can lead to life-threatening excessive immune activation known as a cytokine storm. Researchers are therefore looking for more selective activating agents.

Sifei Xing, Robert Siliciano, and colleagues at Johns Hopkins School of Medicine developed a new system for screening large numbers of compounds in a laboratory model of CD4 cells, seeking those that can flush out HIV without toxic side effects. They have tested both novel compounds and existing drugs approved for a variety of indications, mostly cancer chemotherapies.

As described in the June 2011 Journal of Virology, the researchers reported that one widely used compound, disulfiram, appears to reactivate latent HIV without global T-cell activation. Disulfiram is FDA-approved for managing alcohol abuse, as it causes unpleasant symptoms including flushing, nausea, and headache when alcohol is consumed.

These findings led the researchers to conclude, "The extent to which disulfiram reactivates latent HIV-1 in patient cells is unclear, but the drug alone or in combination may be useful in future eradication strategies."

Steven Deeks at the University of California San Francisco and colleagues are conducting a pilot study to evaluate how well disulfiram activates resting CD4 cells and flushes out HIV in patients. Further details about the trial -- which is ongoing but no longer recruiting participants -- are available at http://clinicaltrials.gov/ct2/show/NCT01286259.

Investigator affiliations: Department of Medicine and Department of Pharmacology & Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD; Howard Hughes Medical Institute, Baltimore, MD; Department of Molecular Microbiology and Immunology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD; Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD; University of North Carolina, Chapel Hill, NC.

7/8/11

Reference
S Xing, CK Bullen, NS Shroff, 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 85(12):6060-6064 (abstract). June 2011.