A team of scientists from the University of North Carolina at Chapel Hill that includes Professor Angela Kashuba, PharmD, has published pioneering research showing that a drug used to treat certain types of lymphoma could dislodge hidden HIV virus in patients.
The findings, published in the July 25 issue of the leading scientific journal Nature, provide proof of concept for a new approach in the effort to cure AIDS. Researchers believe that a major reason that HIV infection reemerges after patients stop taking their medication is the existence of persistent reservoirs of dormant virus in the immune system that are not attacked by anti-AIDS drugs. Disrupting and clearing these reservoirs are critical to finding a cure for AIDS.
“This work provides compelling evidence for a new strategy to directly attack and eradicate latent HIV infection,” says David Margolis, MD, a professor at the UNC School of Medicine who led the study.
“Long-term, widespread use of antiretrovirals has personal and public health consequences, including side effects, financial costs, and community resistance. We must seek other ways to end the epidemic, and this research provides new hope for a strategy to eradicate HIV completely from the body.”
Researchers at UNC, in collaboration with scientists from the Harvard School of Public Health, National Cancer Institute, Merck, and the University of California at San Diego, conducted a series of experiments to evaluate the potential of the drug vorinostat to activate and disrupt the dormant virus. Vorinostat is a deacetylase inhibitor used to treat some types of lymphoma.
Initial laboratory experiments showed that vorinostat unmasked the hidden virus in CD4+ T cells, specialized white blood cells that the virus uses to replicate. Researchers then administered vorinostat to eight HIV-infected men who were medically stable on antiretroviral therapy. The levels of active HIV virus were then measured and compared to the levels before administration.
The patients receiving vorinostat showed an average 4.5-fold increase in the levels of HIV RNA in CD4+ T cells, evidence that the virus was being unmasked. This is the first published study to show the potential for deacetylase inhibitors to attack latency within dormant virus pools in a translational clinical study.
Kashuba, a professor in the School’s Division of Pharmacotherapy and Experimental Therapeutics, says the results pave the way for researchers to look for other deacetylase inhibitors that work in a similar fashion but are safer and more effective.
“Vorinostat is associated with a number of serious side effects, so it may not be an ideal drug to use chronically in HIV-infected patients,” says Kashuba, whose lab conducted pharmacokinetic monitoring on the study volunteers to ensure they received safe and effective doses and to pinpoint the optimal time to collect their blood cells.
“However, vorinostat provides us with a starting point in understanding the relationship between drug exposure in the body and how virus is released in the cells. We now know that this is a viable target in people, and we can search for more potent and safer drugs to move into clinical studies.”
Funding for the research was provided by the National Institutes of Health, Merck & Co., and the James B. Pendleton Charitable Trust. Early results of this study were first presented and reported in March 2012 at the Conference on Retroviruses and Opportunistic Infections in Seattle, Washington.
The research conducted is part of a UNC-led consortium, the Collaboratory of AIDS Researchers for Eradication, funded by the National Institute of Allergy and Infectious Diseases. The consortium is administered by the North Carolina Translational and Clinical Sciences Institute at UNC, one of sixty medical research institutions in the United States working to improve biomedical research through the NIH Clinical and Translational Science Awards program.
