Valproic Acid for HIV Infection
Abstract & Commentary
By Dean L. Winslow, MD, Chief, Division of AIDS Medicine, Santa Clara Valley Medical Center, Clinical Professor, Stanford University School of Medicine, Section Editor, HIV, is Associate Editor for Infectious Disease Alert.
Dr. Winslow is a consultant for Bayer Diagnostics and Pfizer/Agouron, and is on the speaker’s bureau for Pfizer/Agouron.
Synopsis: Valproic acid acts as an inhibitor of histone deacetylase 1 (HIDAC1). In a small pilot study valproic acid added to conventional antiretroviral therapy plus enfuvirtide was shown to accelerate clearance of HIV from resting CD4+ T cells in vivo.
Source: Lehrman G, et al. Depletion of Latent HIV-1 Infection In Vivo: A Proof-of-Concept Study. Lancet. 2005;366:549-555.
This proof of concept clinical trial intensively studied 4 patients with HIV infection who had plasma levels of HIV RNA below the lower limit of quantification in a standard viral load assay on standard HAART therapy. The patients initially had their therapy intensified with enfuvirtide (T-20) for 4-6 weeks to prevent spread of HIV infection, followed by the addition of oral valproic acid 500-750 mg twice daily for 3 months. Patients underwent leukopheresis before and after their valproate treatment course, resting CD4+ lymphocytes were isolated. Both replication competent HIV and total integrated proviral DNA were quantified in these resting T-cells. Expressed as infected units per billion cells (IUBP), the 4 patients were observed to have experienced reductions in frequency of infected resting T-cells of 29% to > 84%.
Commentary
While we can now effectively suppress active replication of HIV in patients by use of HAART therapy, once antiretroviral suppression is removed, levels of plasma virus generally rebound rapidly. This is due to the large reservoir of integrated proviral DNA, which largely resides in resting CD4+ T-cells in lymphatic tissue. The holy grail of potentially curative therapy of retroviral infections is the elimination of HIV from this population of resting cells. A number of approaches have been tried, most notably the activation of T-cells using IL-2 in conjunction with HAART to, in theory, drive the latent virus into active replication where it can be inhibited by antiretroviral therapy with the host cells then presumably being eliminated by apoptosis or some other undefined mechanism. Unfortunately, activation of T-cells does not eradicate HIV since, due to the upregulation of HIV transcription which accompanies T-cell activation and the increased number of susceptible uninfected target cells, the net effect is increased HIV replication beyond the threshold which can be contained by antiretroviral therapy.1-3
Histone deacetylation is importnt for quiescence of HIV gene expression in resting CD4+ lymphocytes. Histone deacetylase 1 (HDAC1) mediates chromatin remodeling and represses viral gene expression and virion production.4 The anticonvulsant valproic acid inhibits HDAC, and has been shown to induce HIV expression ex vivo from resting CD4+ cells from aviremic patients treated with HAART, but does not cause upregulation of cell surface markers of activation nor increase susceptibility of cells to HIV infection de novo.5 This small pilot study demonstrated that it is possible to reduce the population of HIV-infected resting CD4+ T-cells in vivo from 29%-84%.
While the results of this small pilot study are intriguing and represent first class laboratory science, the clinical application of these data are still quite a long way from being ready for use in the clinic. Some areas which call for additional experimental data include the observation that a substantial decline of integrated proviral DNA was not observed, although as Lehrman and colleagues point out, this may be less significant than the apparent reduction of infected cells containing potentially replication-competent virus. However, such a modest (less than 1 log10) reduction in infected cells may not be significant in a disease process where the total number of infected cells in the body may number in the hundreds of millions. The experimental design of the study does not allow one to separate the effect of enfuvirtide added to HAART vs the effect of valproic acid in reducing the population of infected resting CD4+ lymphocytes. The effect of this treatment on virus-infected cells of monocyte/macrophage origin and of follicular dendritic cells may be minimal (or considerable) since these cells were not studied. The potential toxicities and drug interactions of valproic acid are considerable. In all, however, this is interesting work and is deserving of additional laboratory and clinical studies.
References
- Chun TW, et al. Effect of Interleukin-2 on the Pool of Latently Infected, Resting CD4+ T Cells in HIV-1 Infected Patients Receiving Highly Active Anti-Retroviral Therapy. Nat Med. 1999;5:651-655.
- Stellbrink HJ, et al. Effects of Interleukin-2 Plus Highly Active Antiretroviral Therapy on HIV-1 Replication and Proviral DNA (COSMIC Trial). AIDS. 2002;6:1479-1487.
- Fraser C, et al. Reduction of the HIV-1-Infected T-Cell Reservoir By Immune Activation Treatment is Dose-Dependent and Restricted By the Potency of Antiretroviral Drugs. AIDS. 2000;14:659-669.
- Romeiro F, et al. Repression of Human Immunodeficiency Virus Type 1 Through the Novel Cooperation of Human Factors YY1 and LSF. J Virol. 1997;71:9375-9382.
- Coull JJ, et al. Targeted Derepression of the Human Immunodeficiency Virus Type 1 Long Terminal Repeat By Pyrrole-Imidazole Polyamides. J Virol. 2002;76:12349-12354.
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