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.
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.
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