Hit and Run: Eradicating the hidden reservoirs of HIV
HIV infects approximately 35 million people worldwide with the greatest number of infections within sub-Saharan Africa. Current research conducted within the Anti-viral Gene Therapy Research Unit, showcased at the 2014 Research Day and Postgraduate Expo, hosted by the Wits Faculty of Health Sciences, could provide a novel treatment for patients with life-long viral infections, which in the future could improve the health of millions of people in Africa, and globally.
According to Dr Tristan Scott, Postdoctoral Fellow in the Faculty, patients using current antiretroviral treatment (ARV) strategies must be treated their entire lives. “There are complications associated with long-term treatment protocols such as patient non-compliance or treatment failure. The reason for this persistent infection is that HIV can evade ARV therapy, either by hiding in cellular “reservoirs” where the drugs cannot function or by embedding itself into the stable DNA genome of the host immune cells where the virus remains in a dormant state.
“Current ARVs can only manage the active infection, and if treatment is removed, the ‘hidden’ virus will re-emerge and establish infection once again. A therapy that effectively eliminates dormant HIV would increase the wellbeing of patients, who currently have to contend with the difficulties of life-long treatment,” says Scott.
New technologies, however, have been developed in recent years that target specific DNA sequences and can be used to target HIV’s DNA within cellular reservoirs as a new type of treatment approach. The ability to predictably affect HIV can be achieved in two ways. Firstly, by targeting and editing the viral DNA precisely, mutations may be introduced which will effectively disable the virus. Secondly, these technologies can be used to regulate the expression of the virus’ genes.
“The suppression or over-expression of viral genes would deregulate its life cycle and hinder virus propagation. Although therapeutic gene editing is in the very early stages of development, preliminary results suggest it may be able to eradicate dormant virus from cellular reservoirs, opening up the possibility of one day having a “functional cure” for HIV infected patients. Our research aims to develop proof-of-concept research into these technologies to target viral reservoirs,” says Scott.
The technology being explored is the Clustered Regularly Interspaced Palindromic Repeats (CRISPR) with CRISPR associated proteins (Cas), which was recently discovered and has proven to be a game-changer in the field of gene targeting.
“This CRISPR/Cas system has two essential components, 1) A Cas protein, which is the molecular ‘scissor’ that will cut the viral DNA and, 2) a small guide sequence made of RNA that will bind Cas9 and allow the system to specifically recognise HIV’s DNA. The Cas module can be modified to not only cut but also activate or suppress viral genes, which offers a wide range of molecular “tools” that can be used for the therapeutic manipulation of HIV’s DNA.”
This technology has far-reaching applications and is not limited to HIV – it can be used to inactivate many other viruses and rogue genetic elements. “We are also exploring CRISPR/Cas for use against Hepatitis B virus (HBV), which is a virus that chronically infects 350 million people globally, and a large number of patients within sub-Saharan Africa are co-infected with both HIV and HBV. We think the CRISPR/Cas technology is broadly adaptable to multiple viral targets,” Scott concludes.
There are still many hurdles to overcome before CRIPSR/Cas can be used as a possible therapeutic in the clinic, such as controlled delivery to the infected tissue as well as ensuring safety under the most stringent conditions. Nevertheless, this fundamental research will hopefully offer a new therapeutic option for patients living with lifelong viral infections.