HIV Digest	HIV Digest Archive

A novel study, conducted by Ginger Lehrman, involving valproic acid was inspired by two observations. First, HIV eradication has been stymied by the persistence of latent replication-competent virus residing in resting CD4+ cells. Current HIV therapies cannot eliminate virus in these cells. As such, they serve as a pool from which the virus can continue to emerge and infect other target cells. Attempts to "activate" resting CD4+ cells, in combination with intensive antiretroviral therapy, has not led to eradication. In fact, this practice may overwhelm HAART and permit HIV to spread to uninfected cells.

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Second, there are proteins that regulate the expression of HIV in latently infected resting CD4+ cells. Histone deacetylase 1 (HDAC1), for example, represses HIV gene expression and production of virion. Blocking this factor, the authors hypothesize, could lead to an outgrowth of HIV from resting cells without the downsides of activation-- e.g., upregulation of cell surface markers and the cell-to-cell spread of HIV. It turns out that valproic acid, which is a commonly used anticonvulsant, inhibits HDAC1.

To test whether valproic acid can reduce the pool of latently infected cells, four patients who were receiving HAART and had plasma HIV-RNA levels less than 50 copies/mL for at least two years were enrolled and underwent leucopheresis to harvest infected resting CD4+ cells. They then had their HAART intensified with enfuvirtide (T-20, Fuzeon) for four to six weeks, after which 500-750 mg valproic acid was administered twice a day for three months. Leucopheresis was repeated after 16-18 weeks.

During the administration of valproic acid and enfuvirtide, patients' CD4+ cell counts remained stable. Plasma HIV-RNA PCR was undetectable throughout the study for all patients, with the exception of one time point mid-study in a single patient. In that single patient, the viral load increased to 75 copies/mL during an upper respiratory illness and subsequently returned to below 50 copies/mL. A super-sensitive assay to detect a single copy of HIV RNA per mL of plasma was also employed; in three of the four patients, single-digit virus levels were detected. The levels of virus using this assay did not change during the study.

Looking at the resting HIV-infected CD4+ cell population, the investigators found that the frequency of infection of these cells was stable on HAART alone. Following administration of valproic acid and enfuvirtide, three of the four participants experienced a decline of 68% to 84% in their latent- ly infected CD4+ cell pool. The other patient experienced a 29% reduction in infected resting cells, which is with- in the range observed with HAART alone.

This study was performed as a "proof-of-concept" investigation. If the results were negative, it would suggest that the strategy of targeting HDAC1 was unlikely to be a productive approach to eradicating HIV from resting cells; instead of publication in Lancet, the article would likely have been published in the "Journal of Unpublishable Findings." That the study observed declines in the resting cell pool is encouraging, as it supports further study of this agent and other agents that can act in a similar manner.

The authors may have invited public attention (and its handmaiden, criticism) with the last line of their abstract: "This finding, though not definitive, suggests that new approaches will allow the cure of HIV in the future." Critics seizing on the non-definitive nature of the study point out correctly that this is just the first step in what will be a long process and that any talk of a cure is wildly premature. Many also suggest that the independent role of valproic acid, separate from enfuvirtide, remains unclear. Yet, this study also did what it set out to do: test a hypothesis in preparation for future studies. As such, it is valuable and may spark a race to eliminate latently infected CD4+ cells and convince others that HIV eradication is the prize to eye.

Meanwhile, there is no reason at all for patients to start taking valproic acid in the hopes of eliminating their latently infected CD4+ cells. The results here are extremely preliminary and were observed in a small group of patients, one of whom did not experience a meaningful drop in measured latently infected cells.

Editor's Note: from www.thebodypro.com