Rooting Out Dormant HIV

Rooting Out Dormant HIV Researchers believe that the existence of dormant viruses in the immune system is a major obstacle to finding a cure for AIDS. A team of researchers led by scientists at the University of North Carolina at Chapel Hill has shown that the drug vorinostat can be used to unmask hidden HIV virus. Here's a look at the science behind their approach. HIV Infection An HIV infection starts when the viruses attach to specialized white blood cells called CD4+ T cells. The viruses inject their RNA and various enzymes into the cells. HIV virus Viral RNA Cellular DNA Healthy CD4+ T cells The viral RNA turns into DNA, which then integrates itself into the cellular DNA. Viral RNA Viral DNA Integration into cellular DNA In some host cells, histone deacetylase, a class of enzymes that help control DNA expression, silences the infected DNA, and the cells lie dormant instead of replicating the virus. Some of the host cells start producing copies of the virus. Dormant CD4+ T cell Upon maturity, the viruses are released and the host cell dies. Without intervention, the new viruses would infect healthy cells and start the process all over again. Antiretroviral Therapy (ART) ART DO NOT CROSS Antiretroviral therapy fights HIV by protecting the healthy cells. There are more than 20 approved ARTS, targeting different stages of the virus's replication cycle, such as • keeping the virus from attaching to healthy cells, • preventing the injected viral RNA from turning into DNA, • preventing viral DNA from integrating itself into the cellular DNA, and • keeping the replicated virus in infected cells from reaching maturity. The use of ART has increased dramatically in recent years and have contributed to a decrease in HIV-related deaths. Healthy cell protected by ART 7 million 6.65 million People receiving ART People newly infected with HIV AIDS-related deaths 0.3 million SOURCE: World Health Organization 2002 2003 2004 2005 2006 2007 2008 2009 2010 However ... If HIV-infected patients stop receiving ART, the dormant infected cells become active and start producing viruses again. This means patients must remain on ART their entire lives, which could lead to side effects, high financial costs, and the development of resistance. Dormant CD4+ T cells become active. The infected cell starts replicating the virus. The new viruses are released and attack the healthy cells, which are no longer protected in the absence of ATR. Possible Solution UNC researchers and their collaborators showed that by administering vorinostat, a deacetylase inhibitor used to treat some types of lymphoma, to HIV-infected patients who are receiving ART, they were able to activate the dormant cells and make them start replicating viruses. eacetylase inhibitor Suppresses the histone deacetylase that had silenced the infected DNA, thus activating the dormant CD4+ T cells. The infected cell starts replicating the virus. The new viruses have nowhere to go because the healthy cells are protected by ART, which means the viruses cannot replicate. ART DO NOT CROSS ART DO NOT CROSS ART DO NOT CROSS What's Next? The study with vorinostat provided a proof-of-concept to show that the approach is viable. However, vorinostat is associated with a number of serious side effects, so it is likely not an ideal drug for chronic use in HIV patients. Instead, researchers will look for other deacetylase inhibitors that work in a similar manner but are safer and more effective than vorinostat. IL UNC To learn more about the study, whose findings were published in the July 25, 2012, issue of Nature, visit ESHELMAN SCHOOL OF PHARMACY pharmacy.unc.edu/vorinostat2012 GRAPHIC BY JOHN ZHU SOURCES: World Health Organization, avert.org, Wikipedia ART DO NOT CROS ART DO NOT