As Hiv persists in latently infected T cells in patients on long term antiretroviral therapy (Art), one strategy to flush out this residual Hiv disease is to activate and "purge" the Hiv reservoir.
In vitro support
Hiv Antiretroviral Drugs
Several experiments in cell lines models of Hiv latency have in case,granted information on the mechanisms involved in the maintenance of Hiv latency. One of the most studied mechanism is histone deacetylation. Several compounds called Histone Deacetylase Inhibitors (Hdaci) have been shown capable to wake up Hiv in vitro from its latent state. The strategy is, therefore, to use such compounds in aggregate with Art, in order to safe uninfected cells, and activate latently infected cells and let them die of this productive infection.
Initial Disappointment
The first attempts at activating residual Hiv disease from its latent forms were unsuccessful. Use of cytokines, like Interleukin-2, or Okt3 antibodies, led to a broad activation of the immune system, like a cytokine storm, which was toxic for the patient with no convincing proof of any Hiv stockroom decline. Valproic acid is an agent used against epilepsy that has Hdaci activity. Combined to Art and a fusion inhibitor, T-20, it was initially shown to be able to cut the Hiv reservoir. However, subsequent studied were unable to confirm these preliminary results. It was then demonstrated that this Hdaci was weak and, in particular, not exact of the type of Histone Deacetylase involved in Hiv latency.
New Drugs on the Horizon
With a great characterization of the Histone Deacetylase sub-types, Several compounds have been screened with promising activity. One of then is vorinostat, or Saha, which is already on the shop for a rare kind of hematopoietic malignancy. However, other issues are slowing testing of this drug to purge the Hiv reservoirs, which are more ethical than scientific. The dilemma is to use potentially toxic drugs in patients on long term Art which are well and live general lives...
There are other molecules able to reactivate Hiv in vitro that act via other pathways than histone deacetylation. Such a aggregate is Prostratin. Although its improvement was initially impaired by the fact that it was extracted from a rare plant, its chemical synthesis has been thriving and will allow clinical testing in protocols.
How to Move Forward?
The next urgent step is to test these potentially "purging" drugs in animal models of Hiv infection. Several macaque models are available, which reflect both the establishment of Hiv reservoirs and anatomic compartments. There is some concern that these purging approaches would be too potent in sanctuaries like the brain where Art diffusion is impaired.
Once animal models will have validated the approach, small pilot studies in humans will be mandatory.
There is a possibility that Several agents will have to be combined or sequenced to reactivate the Hiv reservoir, as some molecules will act on some cells and others in other subsets of the reservoir.
A large international plan is needed to coordinate this research.
Hiv Reservoirs Part 5: Purging the Hiv reservoirThanks To : hiv antiretroviral drugs
