Download Article PDF/SlidesDr. Margolis began his October 2005 lecture with a crucial question. Two decades into the HIV/AIDS epidemic, what is to be done in the next decade? The answer, it seems, couldn’t be clearer: the evaluation of novel methods to prevent infection; the ongoing establishment of concrete treatment modalities to prevent disease in the infected; and, of particular interest to Dr. Margolis, continued momentum toward the eradication of infection.
The discussion of eradication is certainly not new to the pages of The PRN Notebook. Early treatment, intensified treatment regimens, and immune-based therapies to achieve this goal have all been pursued—with limited success—and discussed in detail over the past ten years. Just as it seemed as if the possibility of eradicating HIV was nothing more than a pipe dream, exciting new research has emerged—utilizing a truly novel approach and exploiting a very common compound—bringing the possibility of a cure to the forefront once again.
The compound in question is valproic acid, best known as Depakote, a tried and true treatment for bipolar disorder and epilepsy. The property of valproic acid exploited in the current approach is its known ability to inhibit histone deacetylases, enzymes that evidently maintain the integrated and latent HIV quiescent in the host genome. Although still in its infancy, the early work of Dr. Margolis and his colleagues has opened an exciting new avenue of research for the potential eradication of HIV. PRN was pleased to host Dr. Margolis at its October meeting to explain the theory behind, and the data supporting, continued evaluation of this approach.
| I. The Eradication Hypothesis Reborn | Top of page |
In 1995, experiments conducted at the Aaron Diamond AIDS Research Center (ADARC) and the University of Alabama independently established that HIV infection is a highly dynamic process, with a potential to produce more than 10 billion virions daily, even during the asymptomatic stage of disease (Ho, 1995; Wei, 1995). Employing antiretroviral therapy, these teams demonstrated that levels of HIV-RNA in plasma dropped by half approximately every 48 hours, signifying that enormous numbers of virions are produced by infected cells with relatively short life spans. Subsequent experiments documented the existence of a second, much slower phase of HIV clearance in plasma during therapy; this second phase was associated with the suppression of viral replication in long-lived cells in tissue. Simple mathematical modeling suggested that all cells harboring the virus would die off within about three years of maximally suppressive therapy, thereby raising the possibility of complete eradication of HIV from the human host.
The successful realization of this model with the currently available therapies depended on two key assumptions. First, the model presumed that all of the identified cellular populations had relatively the same short half-lives. And second, the estimate presumed that the suppression of viral replication achieved using combination antiretroviral therapy was, in fact, complete and total suppression of all HIV replication.
By November 1997, however, three research reports had laid to rest the first of these assumptions. The reports—representing a series of studies conducted at Johns Hopkins University School of Medicine, the University of California at San Diego, and the National Institutes of Health—confirmed the persistence of a viral reservoir consisting of latently infected, dormant memory CD4+ cells with integrated proviral DNA (Finzi, 1997; Chun, 1997; Wong, 1997). Given the estimated half-lives of the memory CD4+ cells range from six to 44 months, eradication would require anywhere from 10 to 60 years of chronic antiretroviral therapy.
Even this more sophisticated and biologically plausible reservoir-based hypothesis is dependent on the same key variable or fallacy—that of unconditional and total halt of viral replication with current antiretroviral therapy. Complete and absolute suppression is required in order to thoroughly snuff out latently infected cell populations and to prevent the reseeding of other long-lived cells. Studies completed over the past six years have unfortunately demonstrated that HIV replication does, in fact, persist even in those patients who consistently maintain undetectable viral loads with effective antiretroviral treatment (Zhang, 1999; Ramratnam, 2000). For eradication to be achieved, it is now clear that approaches to target and deplete latent infection within resting CD4+ cells are necessary.
One attempted approach has been the combination of intensive antiretroviral therapy with immune-based therapies—such as interleukin-2—to activate resting CD4+ cells. Forcibly activating these cells, the hypothesis held, would precipitate their death. And with the use of antiretroviral therapy, any released virus would be prevented from spreading and infecting adjacent cells.
While preliminary data from studies—see “Studies of HIV Latency: Implications for Treatment and Virus Eradication,” an article based on a presentation by Tae-Wook Chun, PhD, in the June 1999 issue of The PRN Notebook—were encouraging, final results (Chun, 1999) and additional research failed to demonstrate that this approach achieved viral eradication. A likely explanation for this, as was suggested in a paper published in 2000, is the fact that activation not only induces viral replication, it can increase the number of susceptible uninfected cells beyond the threshold that can be protected by antiretroviral therapy (Fraser, 2000).
What is needed, it seems, is an agent capable of inducing the expression of quiescent HIV, while simultaneously limiting any activation of CD4+ cells. One such approach being investigated by Dr. Margolis and his colleagues is the inhibition of histone deacetylase 1, an enzyme that appears to maintain latency of integrated HIV.
| Conclusion | Top of page |
In concluding his talk, Dr. Margolis reviewed some of the tasks ahead. “To move this field forward, we really need better assays than the terribly labor-intensive leukopheresis assay,” he said. “Ideally, a model system for latency or eradication should be developed.” He also mentioned that there are other HDAC inhibitors being explored—not necessarily for HIV infection—including several being evaluated in cancer trials. “Would these other HDAC inhibitors be too potent and toxic? Or would they be better than valproic acid? We don’t know.”
Dr. Margolis also noted that there are approaches other than targeting HDAC that might facilitate this same mechanism. “Critical is the characterization of persistent replication and finding out why it’s happening, where it’s happening, and how to avoid it,” he commented. “We want to be able to test new antiretrovirals, as well as vaccines, because all of these patients that have suppressed viremia have lost anti-HIV immune responses. If we are to clear this chronic infection, we will likely need the help of the immune system. Ideally, in the future, we will have strategies that turn on a viral expression program, and perhaps even a cell expression program, that results in low-level virus production or no virus production, along with death of the infected cell without too many toxic effects on the human host.”
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