#cas9-activators

HZhang, Y., Yin, C., Zhang, T., Li, F., Yang, W., Kaminski, R., et al. (2015). CRISPR/gRNA-directed synergistic activation mediator (SAM) induces specific, persistent and robust reactivation of the HIV-1 latent reservoirs. Scientific Reports epress. http://doi.org/10.1038/srep16277

When it comes to HIV/AIDS treatment, we live in a combination best-of-times/worst-of-times. In many parts of the world, HIV/AIDS remains a catastrophic issue. Yet for people with access to treatment, there now exist many highly effective ways to treat HIV and live a long, healthy life. There are many classes of HIV drugs, each of which functions by blocking a specific step of viral replication or maturation. When taken continuously, these treatments can reduce one’s viral load to undetectable levels, and can effectively make a person incapable of transmitting the virus. This is a truly amazing state of affairs, and we at Sick Papes stand in awe of the activists and scientists who fought for decades to bring us this day. (We also spit on the grave of the homophobic shit-head Presidential Administration who actively made the crisis worse.) (We also salute the brave people like rapper Mykki Blanco who are fighting the enduring stigma of HIV.)  

However! There is a major issue for all existing treatment regimens: they must be taken continually for one’s entire life, and even a short lapse can cause the virus to come roaring back. This is because there are reservoirs of cells in your body that house “silent” copies of the HIV virus that do not replicate at all, and are invisible to the current replication-blocking treatments; whenever a person stops taking their drugs, these silent reservoirs flare up. The forefront of research on HIV treatment is therefore to find ways to target and destroy these silent reservoirs of HIV positive cells in the body, the source of perpetual risk.

Today’s Sick Pape presents a proof-of-principal for a technique to kill these silent pockets of HIV+ cells in an otherwise healthy person. To do so, the authors take advantage of a bangin’ new technique for activating any gene-of-interest in the genome. This technique, which was invented independently by several labs, involves the perpetually press-shy Cas9 protein…but with a naughty twist. Whereas Cas9 typically cuts DNA (at a genomic location controlled by a 20-bp “guide RNA”), Cas9 can be made unable to cut DNA by mutating specific amino acids in the catalytic core of the enzyme. This catalytically dead Cas9 (”dCas9″) can be fused to transcriptional activator domain, and guided to a gene’s promoter, thus transcriptionally activating that gene [insert DJ airhorn sound]. What’s more, dCas9 can also be fused to a repressor domain, or any other functional domain. In other words, we can now turn on or off any gene in the genome at will: it’s lit. 

Wenfei Hu’s lab, located in downtown Philadelphia, took advantage of this technique to activate the HIV genome in the reservoir cells where the virus hides. Once HIV has been activated, these cells can be killed by the immune system and/or existing drugs. This is obviously dope - but do keep in mind that all of this work is done in cell culture, where it is trivial to deliver dCas9 and guide RNAs to the cells. To make this technique work in humans will take some doing, but man I think someone’s gonna figure out that pretty soon. After all, Cas9 was only discovered like an hour and a half ago, and already a whole army of TED-talking Equity bros are frothing at the mouth to get rich off drugs.