Prospects of Using Histone Deacetylase Inhibitors (HDACi) for an HIV Cure
There is now a concerted effort from scientists, clinicians and funding agencies to identify ways to achieve an HIV cure, either functional or sterilizing. Multiple strategies are currently being investigated, including the use of HDACi.
A recent review of the topic has just been published by the Australian group of Sharon Lewin and is summarized below. For more information, please refer to the original paper (1).
HDACi have been tested in vitro during the last few years using 3 different kinds of cell models:
-Latently infected cell lines:
They have several limitations. First, they represent clonal populations in which a single integration site is present. This is in contrast with latently infected CD4+ T cells from patients where integration is largely random throughout the whole genome. Then, these cells are rapidly dividing, whereas latently infected CD4+ T cells found in vivo are resting. Finally, in latently infecetd cell lines, integration usually occurs at sites of heterochromatin, whereas in resting CD4+ T cells from patients, HIV integrates into sites of active gene expression.
-Latently infected primary CD4+ T cells:
They have recently been described. These models are more difficult to generate in vitro but likely represent more accurate models of patients derived cells. They remain, however, technically demanding.
-Resting CD4+ T cells from HIV-infeceted patients on ART:
They are the gold standard but need time, large quantities of blood and are only semiquantitatives. Because there is only 1 latently infecetd cell in a million in the blood of these patients, it is not feasible to use them only to test drugs activating latent HIV.
There are several classes of HDAC. Class I HDAC include HDAC1, 2, 3 and 8. HDAC1, HDAC2, HDAC3 and histone 3 may have a role in maintaining latency, and the mechanism may differ in different cell types.
A large list of products has now been established that act, as HDACi, on HIV latency.
Vorinostat has activity against both class I and II HDACs. It is able to induce HIV production from latently-infected cell lines, monocytic cell lines, models of latently infected primary CD4+ T cells and CD4+ T cells from patients.
In latently infected cell lines, the dose required to reactivate HIV is between 0.25 and 100 micro Mol. In resting CD4+ T cells from patients, it is 0.25 to 0.50 micro Mol. This dose is able to induce the production of HIV from 67-85% of patients on suppressive ART in vitro, according to studies.
Other interesting HDACi are Givinostat, which acts at therapeutically relevant concentrations on HIV and has limited cell toxicities, and Entinostat, which shows enhanced activity and specificity against HDAC1 and 3 and has a toxicity similar to vorinostat.
There is also a panel of compounds tested by Merck.
Combinations approaches have already been studies in vitro, and will probably be of great interest. In particular, HDACi act synergistically with Bryostatin or methylation inhibitors for activating latent HIV.
HDACi also exhibit other relevant activities:
-They induce apoptosis. This may potentially be a highly desirable feature, HDACi inducing both virus production and cell death in the same cells.
-They reduce coreceptors expression. Givinostat has been demonstrated to reduce by 50% the expression of CXCR4 on CD4+ T cells and CCR5 on monocytes.
-They have immunomodulatory effects and anti-inflammatory activities.
Vorinostat is currently tested in 2 clinical trials.
The first trial at the University of North Carolina concerns HIV-infecetd patients on suppressive ART who receive a single 200 mg dose of vorinostat, followed by escalating doses up to 600 mg at 2 to 4 week intervals. The primary end point is a change in expression of HIV RNA in resting CD4+ T cells from blood.
The second trial is conducted at the Alfred Hospital in Melbourne and examines the effect of vorinostat at 400 mg per day for 14 days. The primary end-point is a change in cell-associated unspliced RNA in CD4+ T cells from blood and rectal tissue.
There are obviously concerns about the potential toxicities of these drugs in patients showing an excellent quality of life on ART. However, given that the onset of gene activation and suppression is extremely rapid with HDACi, it is possible that only a short course of these drugs may be required for reversing HIV latency and this would reduce the possibility of adverse events. However, even if HDACi are unable to promote viral production from latently infected astrocytes, any enhanced activity of the LTR can induce tat, which is independently neurotoxic. Monitoring of potential CNS toxicities is therefore important during such trials.
Wightman F, Ellenberg P, Churchill M, Lewin SR. HDAC inhibitors in HIV. Immunol Cell Biol. 2011 Nov 15. doi: 10.1038/icb.2011.95. [Epub ahead of print]
Key words: HDAC, HDAC inhibitors, HDACi, HIV cure, HIV eradication, HIV reservoirs, Histone Deacetylase Inhibitors