Luring HIV out of its latency may be the secret to developing an effective HIV cure

Contributed by guest blogger: Steven Chan ‘12

The emergence of highly active antiretroviral therapy (HAART) in the treatment of HIV-infected individuals has certainly changed the outlook of an HIV diagnosis today, compared to what such an outlook looked like in the earliest years of the epidemic. Such a treatment regimen, if strictly adhered to, has the potential to suppress the levels of active circulating HIV in the infected individual to a level that is manageable, essentially halting the progression of the disease. It soon became clear however, that these treatments could not effectively clear the body of all HIV particles—the virus manages to stow itself away within the cellular genome of the memory CD4+ T-cells, and remain transcriptionally silent indefinitely. These latent reservoirs of HIV-infected cells prove to be undetectable for these antiretroviral therapies, since antiretroviral drugs can only target HIV-infected cells when they are replicating. And so, memory cells, which replicate infrequently, cannot be effectively targeted, making it impossible to clear HIV-infected bodies of all HIV-particles. “We’re never going to cure anybody unless we go for this latent pool,” says Robert Siliciano, the researcher at Johns Hopkins University that first identified the latent HIV memory-T cells.

A great deal of HIV-therapy research over the past decade has focused on finding a way to coax these infected cells out of their latency to make them detectable by antiretroviral drugs. The problem that has been persistently hounding researchers has been the difficulty in luring these cells out of their latency without triggering the immune system in an inflammation response that would end up doing more harm than good. David Margolis, MD, and his research team at UNC Chapel Hill, who have been working on this problem for a while now, have found success with a set of histone deacetylase inhibitors called Zolinza (vorinostat), a chemotherapeutic cancer drug that has been found to stimulate gene expression within the latent HIV-infected cells without inducing an overwhelming immune response. HDAC inhibitors accomplish this by inhibiting the activity of histone deacetylase, which removes the acetyl groups from the lysine residues in the core histones, resulting in the formation of a condensed and transcriptionally silenced chromatin. By inhibiting this activity, the core histones become less compact, and the chromatin becomes more transcriptionally active. After initial success with in vitro tests in cell cultures and in blood tissues, six HIV-positive men were recruited in a clinical trial pairing this treatment alongside consistent antiretroviral therapy. Each of the study volunteers had already been taking part in a robust antiviral regimen for an average of four years, and displayed undetectable viral loads and stable CD4+ T-cell counts. Post-exposure to Zolinza, HIV-RNA levels—a marker of viral activity—in these patients increased by an average of 4.8 times, ranging from a 1.5-fold increase in one patient to a 10.0-fold increase in another. The drug took effect in as little as 8 hours, inducing a two-fold increase in cellular and chromatin-bound histone acetylation within that time span. Increased expression made these cells susceptible to detection and eradication by the antiretroviral drugs, which proceeds just as efficiently as usual.

Margolis addresses the significance of this advancement, “This study provides first proof of concept, demonstrating disruption of latency, a significant step toward eradication.” Just how effective this drug is in teasing out the latent cells still remains to be seen—with nearly a ten-fold difference in one trial participant compared to the other, the efficacy of such a drug remains questionable. The limited sample size in this initial trial also doesn’t give us too much to go on. There are also concerns that the drug could induce some serious side effects such as blood clots in the legs and lungs, diabetes, fewer platelets and RBC count, as well as dehydration from nausea and vomiting, but at least in this trial, there were only mild adverse effects at worst. Little is known about the potential adverse effects of long-term use of the drug. Margolis et al.’s study design made use of a single dose of Vorinostat, but it is likely that repeated intermittent doses would yield the most optimal effects. “Vorinostat may not be the magic bullet, but this success shows us a new way to test drugs to target latency and suggests that we can build a path that may lead to a cure,” says Margolis. Further studies to assess Vorinostat’s safety and effectiveness, and the way it interacts with other HAART treatments, would certainly be crucial before it can be deployed as a component in future HIV treatment regimen.



Archin N, Liberty A, Kashuba A, Choudhary S, Kuruc J, Hudgens M, Kearney M, Eron J, Hazuda D, and Margolis D. “Administration of Vorinostat Disrupts HIV-1 Latency in Patients on ART,” HIV Persistence, Latency, and Eradication at 19th Conference on Retroviruses and Opportunistic Infections, March 8, 2012,    

Contreras X, Schwenwker M, Chen CS, McCune JM, Deeks SG, Martin J, Peterlin BM. Suberoylanilide Hydroxamic Acid Reactivates HIV from Latently Infected Cells, J. Biol. Chem., January 9, 2009,

Horn T. “Pathway to a Cure: Cancer Drug Helps Purge HIV From Resting Cells,”  AidsMeds, March 9, 2012, cure_1667_22059.shtml

“Lymphoma Drug Wakes Up Dormant HIV,” AidsMeds, March 17, 2009,

Steven Chan is a senior at Vassar College, majoring in Science, Technology, and Society


7 thoughts on “Luring HIV out of its latency may be the secret to developing an effective HIV cure”

  1. Being able to bring HIV out of latent reservoirs would definitely make HAART more effective, as these virus particles would additionally be attacked by the therapy. At the same time, perhaps researching how HIV can become latent in the first place is equally important. Why some HIV viral genomes become incorporated into the host genome and then become silenced is not yet known, and understanding how and why this occurs is of primary importance, as preventing HIV from becoming latent could prove to dramatically increase the effectivity of HAART as well. Additionally, this method would not require inducing a potentially dangerous inflammatory immune response.

  2. The HIV virus like many of my classmates have already mentioned is truly fascinating, favoring not one life cycle over the other (latent or lytic) but instead willing to divide its replication stage between both , a feature which assures it higher levels of survival and allows for it to remain unnoticed in the body of the host for so long, if they are not tested in time. This article I think highlights the importance of research, in discoveries to both the scientific and medical field. While I know that because they are in a latent state the drug cannot be treated by the antiviral drug I am very interested in finding out if it is possible for the scientist to test different CD4 T cells through radioactive isotopes that find HIV antigens and then the scientist can through the use of various chemicals destroy the HIV that is in the latent state, reducing the amount of present HIV in the body.

  3. I think it’s interesting how much dedication there has been among the scientific community to discover a cure for HIV. The virus is characterized by causing significant damage to the immune system, but I think it’s also interesting that scientists don’t want to trigger immunity cells out of latency for fear of the immune system to become to active and create an inflammatory response.

  4. The more I find out about HIV and the different methods of fighting against it, the more I am amazed at how efficiently this virus infects humans and avoids being killed off. Since these groups of CD4+ T-cells that have the virus “hidden” in them are able to be detected, is it possible to just kill off these cells and some how replenish the body with new CD4+ T-cells or would it be extremely harmful to the body to simply destroy these cells?

  5. Does this drug actually slowly eradicate the virus from the system, or simply stabilize viral expression at lower levels? And if that is the case, is it truly possible to build this drug toward a cure, or simply a much more stable presence of the virus in the body? In addition, would the virus not take steps to counter the efficacy of the drug? (That is, it seems that viruses that are more difficult to reach through this particular anti-viral regimen would be selected for, and the drug may eventually cause more harm than good unless the virus could actually be efficiently and relatively quickly eradicated from the system.)

  6. It sounds like vorinostat is a drug that targets epigenetic mechanisms. Does it target specific genes? If so, how does it accomplish this?

  7. Why is the virus able to hide within the CD4 cells if they are a functioning part of the immune system? How does it go undetected there?

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