Purging HIV reservoirs through viral reactivation: hope or delusion?
An interview of Andrea Savarino, Dept. of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy
Alain Lafeuillade: You used to be an optimist regarding HDAC inhibitors to purge the HIV reservoir, where do you stand now?
Andrea Savarino: We have temporarily abandoned that approach. We are currently testing other approaches aimed at 1) intensifying ART in order to suppress the ongoing viral replication and 2) inducing a 'silent killing', that is, the decrease of the half-life of the central memory T-cells harbouring the virus, without activating viral replication.
AL: Are there currently in vivo data supporting -or not- this approach, or is it only a theory?
AS: I presented our preliminary results in monkeys last July at the IAS in Vienna. In my opinion, the results are encouraging. However, I will invite everybody to draw their own conclusions when we publish the data in a scientific Journal.
AL: You have been considered as a promoter of the ‘Shock and Kill' approach, and published a seminal paper on it, is your hope fading now with such strategies?
AS: The data that we obtained with two monkeys treated with an HDACi plus intensified antiretroviral therapy have been disappointing. They showed loss of control of the infection. Also after suspension of the HDACi, the virus went on replicating (see the video). I do not want to say that HDACi drugs, combined with other reactivating strategies, will never find a place in the treatment of HIV/AIDS. However, several issues regarding the anatomical reservoirs where antiretroviral drugs do not penetrate well will have to be solved before treating humans with drugs promoting viral replication. In this regard, an interesting study in monkeys has been published last September (Bourry et al. Retrovirology. 2010 Sep 26;7:78).
AL: In a recent Editorial in AIDS, the group of Janice Clements in Baltimore calls for a pause in eradication trials as they think it could put the brain HIV reservoir beyond control. Is it your opinion that HDACi have currently the potential to do more harm than good?
AS: As these drugs also possess the capacity to enhance ongoing viral replication, I think that Dr. Clements is right. Several colleagues are doing a great job in laying the bases for the future organization of clinical trials for HIV eradication. This job will be of pivotal importance for the testing of future strategies. As they have done so much so far, I ask them to put one more effort, that is, the development of tests to exclude ongoing viral replication. I know this will be an extremely difficult task, but I am sure that they can work it out. This will serve to avoid putting at risk the health of the patients.
AL: Is that also true for clinical trials -which have just been launched- using Interleukin-7 to purge the HIV reservoir? In view of what is currently known on IL-7, do you think that it could work?
AS: The paper of Imamiki et al. to appear in the January issue of AIDS shows that IL-7 induced transient blips in viral RNA that was genetically similar to that observed before IL-7 therapy. The patients then returned to normality with < 50 viral RNA copies/ml. However, they received only one cycle of IL-7, and we cannot predict what would happen following multiple cycles.
AL: Finally, what are, in your opinion, the priorities for this kind of research area?
AS: I think that the controversy on the presence of ongoing viral replication should be solved as soon as possible. This will help a lot the optimization of the strategies that are being pursued.
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Key words: hiv eradication HADC inhibitors, hiv purge, hiv reservoir, hiv reservoirs, hiv reservoirs cure, hiv reservoirs eradication