Study Questions Role of HDAC Inhibitors in HIV Cure Research

March 30, 2012

The Keystone Symposia conference "Frontiers in HIV Pathogenesis, Therapy and Eradication" is taking place this week in Whistler, Canada. A poster presentation at the meeting by Jana Blazkova (click here and scroll down to see the abstract) from the laboratory of Anthony Fauci at the National Institute for Allergy and Infectious Diseases (NIAID) seems likely to place a proverbial cat among the pigeons when it comes to the use of HDAC inhibitors as a strategy to reverse latent HIV infection. HDAC inhibitors are a class of drugs that target cellular components involved in the repression of gene activity, and many studies have reported that they can cause expression of HIV proteins by latently infected, resting CD4 T cells. At the HIV Persistence Workshop in December 2011 and at CROI earlier this month, preliminary results from a small phase I clinical trial of the HDAC inhibitor vorinostat (also known as SAHA) in people with HIV on antiretroviral therapy (ART) were reported by researcher David Margolis. Analysis of cell-associated HIV RNA expression from large pools of resting CD4 T cells sampled from six participants indicated that a single 400mg dose of vorinostat led to a significant, roughly 5-fold increase compared to baseline measures, with the effect being relatively consistent (ranging from 1.5 to 10-fold). The results generated considerable press coverage due to being widely viewed as a first step toward disrupting HIV latency and perhaps curing the infection.

Jana Blazkova's poster presentation offers data that suggests that the impact of HDAC inhibitors may be far more limited than has been hoped. Blazkova and colleagues -- including latency expert Tae-Wook Chun from NIAID -- sampled resting CD4 T cells from 27 individuals with suppressed viral loads on long term ART, and then tested the ability of different compounds to induce expression of HIV RNA by latently infected cells in the laboratory. Three HDAC inhibitors were included: vorinostat, valproic acid and oxamflatin. A pan-stimulator of T cells, anti-CD3 antibody, was used as a control along with prostratin, a compound which activates latent HIV via a different mechanism than HDAC inhibitors. The study found that, after exposure to the HDAC inhibitors, the amount of virion-associated HIV RNA in culture supernatants (the fluid in the culture outside of the CD4 T cells) was not significantly different from that seen when no treatments were added. In contrast, there was the expected significant increase in the amount of HIV RNA in the supernatants after addition of anti-CD3 and prostratin.

Additional analyses showed that there was no correlation between the amount of HIV RNA detected after exposure to HDAC inhibitors and the frequency of resting CD4 T cells containing HIV DNA. For both anti-CD3 and prostratin, the correlation between these two measures was statistically significant. Comparison of the envelope gene sequences between the HIV RNA and HIV DNA also showed that the RNA detected after HDAC inhibitors appeared to be inducing a very limited subset of the diverse sequences that were detectable in the latent HIV DNA.

Tae-Wook Chun included a description of the findings in a talk at the conference on Wednesday evening but, surprisingly, the data did not prompt any questions from Margolis or any of the other scientists in attendance who are studying HDAC inhibitors as potential reversers of HIV latency. Chun took pains to cite the importance of Margolis's work in placing the goal of purging the HIV reservoir back onto the research agenda, and stated his hope that perhaps the in vivo results will trump the observations of his laboratory. In the absence of a discussion, the explanation for the divergent findings is unclear, although one difference is that Margolis is measuring cell-associated HIV RNA in his trial whereas Blazkova et al looked at virion-associated HIV RNA in culture supernatants; perhaps it is possible the bulk of the RNA induced by the HDAC inhibitors did not exit the infected cells. If the primary goal is to make the latently infected cells visible to the immune system, as was suggested by studies presented at CROI, it might not matter so much if the cells do not produce many virions because intracellular production of HIV proteins should be sufficient to cause presentation of HIV antigens to CD8 T cells. However, in the absence of effective immune responses against the latent HIV reservoir displaying any viral antigens, it appears unlikely that HDAC inhibitors could cause sufficient virion production to trigger HIV-induced cytopathic effects and thus kill infected resting CD4 T cells. This conclusion is supported by the findings reported by Robert Siciliano's laboratory at CROI (covered in a prior blog post), which showed that functional CD8 T cell responses are needed to eliminate latently infected resting CD4 T cells after exposure to vorinostat. Although it may be possible to address this issue by bolstering CD8 T cell responses, if HDAC inhibitors only awaken HIV in a small subset of latently infected cells -- the other main finding of this new work -- that will be a much thornier problem to solve.

Blazkova's study is in press at the Journal of Infectious Diseases and it is likely that there will be further discussion of the data once it is published.

Richard Jefferys is the coordinator of the Michael Palm HIV Basic Science, Vaccines & Prevention Project Weblog at the Treatment Action Group (TAG). The original blog post may be viewed here.

This article was provided by Treatment Action Group. It is a part of the publication Michael Palm HIV Basic Science, Vaccines & Cure Project.
See Also
No Proof of New HIV Cure, Despite Headlines -- Here's What We Know
The Only Cases of HIV Cure or Remission
Beyond the Berlin Patient: How Researchers Are Now Trying to Cure More HIV-Positive People (Video)
What Would an HIV Cure Mean for You?

No comments have been made.

Add Your Comment:
(Please note: Your name and comment will be public, and may even show up in
Internet search results. Be careful when providing personal information! Before
adding your comment, please read's Comment Policy.)

Your Name:

Your Location:

(ex: San Francisco, CA)

Your Comment:

Characters remaining:


The content on this page is free of advertiser influence and was produced by our editorial team. See our content and advertising policies.