Journal Club: HIV/AIDS
Presentation: “Coaxing Out the Enemy: Using HDAC inhibitors to purge HIV-1 from Latent Viral Reservoirs”
Presenter: Mark Jeng (2nd year BMS student)
Paper: Archin, N.M., et al. Administration of Vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy. Nature. 2012 Jul 25;487(7408):482-5.
In a nutshell:
Thanks to the development of antiviral therapy in the past couple of decades, HIV/AIDS has been transformed from a fatal disease into a chronic yet manageable illness. Nevertheless, there is still no cure.
One of the biggest challenges facing researchers is the problem of completely eliminating latent reservoirs of the virus from the body. Current therapies target actively replicating viruses, but HIV can down-regulate replication of its genes and evade the drugs, only to become active later. A lot of ongoing research efforts aim to target these latent reservoirs. The idea is that if we can get all the viruses to replicate, it may be possible to eliminate them once and for all.
One method of activating latent HIV-1, as explored by the authors of this paper, is to target histone deacetylases (HDACs), a class of proteins that help regulate gene expression. Cells have a substantial amount of DNA to allow for all the genes that may be expressed, and this DNA needs to be highly compressed (in the form of chromatin around histone proteins).
When genes are expressed, the chromatin opens up more to allow for replication, and when genes are silenced, the chromatin remains compressed. HDACs negatively regulate gene expression by promoting the compression of the chromatin. In the context of latent HIV, HDACs suppress viral gene expression. Therefore, inhibiting HDACs may reverse latency and increase HIV expression.
The authors of this paper specifically test the HDAC inhibitor vorinostat in a clinical trial with HIV-positive patients. They find that use of this drug correlates with increased HIV gene expression and reduces the histone deacetylation associated with HDACs, suggesting that HDAC inhibition may be a promising therapeutic strategy for eliminating latent HIV.