Research Profile – An Inside-out Approach to Halting HIV

A young Canadian researcher has identified two genes that could hold the key to preventing HIV from replicating.

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Dr. Stephen Barr

Dr. Stephen Barr believes the secret to shutting down the Human Immunodeficiency Virus (HIV) resides within us.

He sees a day when Health Canada and the U.S. Food and Drug Administration approve drugs that will either "mimic or mobilize" the human immune system's innate ability to stop viral cells from replicating.

"It's doable, absolutely," says Western University's Dr. Barr. "With advances in sequencing the human genome, we're gaining more insight into our immune system and how it combats infections. We are learning that we possess multiple genes that can potently inhibit HIV replication."

Attempts to stop the spread of HIV, which has claimed the lives of more than 25 million people since its emergence in the early 1980s, have largely focused on finding a vaccine that can block the virus before infection takes hold. Unfortunately, despite a massive global effort, no such vaccine has yet been found to defeat the insidious and extremely complex virus.

But Dr. Barr and other researchers around the world believe there is another way: unleashing the power of genetically programmed cellular restriction factors, which, essentially, are naturally occurring proteins that can inhibit HIV's life cycle. "Typically, vaccines approach the virus outside of the cell," he says. "We feel there is huge potential on the inside, using innate immunity."

With the help of funding from the Canadian Institutes of Health Research, Dr. Barr has identified two gene candidates –TRIM22 and HERC5 – that, when expressed in cells, restrict the replication of viruses such as HIV.

"Both are novel antiviral genes that target the assembly of HIV," says Dr. Barr. "They can hit four different steps of the HIV life cycle with the ultimate end goal of trapping the virus in the cell. We haven't found an HIV protein that can counteract TRIM22 and HERC5."

But if these are naturally occurring proteins expressed by genes, why aren't they already restricting the replication of HIV in cells? It could be that the genes are simply overwhelmed by the invasion of the HIV virus. Or they have mutated in some way, or somehow been switched off.

The next step is to fully investigate how TRIM22 and HERC5 work, how they express themselves, and why they do not work in most infected individuals. "We're trying to gather information on the molecular mechanisms that underlie these activities. Our goal is to develop novel therapeutics, such as antiviral inhibitors or gene therapy vectors (vehicles to carry genetic material to target cells), that mimic or mobilize this function in humans."

Tweaking the body's innate immune defences to fight viruses is not new, says Dr. David Evans, Director of the Alberta Institute for Viral Immunology, pointing to the use of interferon – proteins that cells manufacture to repel pathogens – as the best-known example.

"Interferon therapy is the current standard of care for treating hepatitis C infections. So, we know that these systems can be tweaked to treat infections or, ideally, prevent them. What people like Stephen are doing is trying to figure out the internal sensors, the burglar alarms that cells use to sense they are being infected by a virus or, if they have been infected, prevent it from getting out."

While he is optimistic, Dr. Barr is also realistic. He doubts any single drug can defeat the disease. "HIV is very mutagenic -- it changes every time it replicates. Any drug we throw at it technically can be averted by the virus eventually. But our hope is to come up with an additional drug that can be used in combination with others to shut down the virus."

"Typically, vaccines approach the virus outside of the cell. We feel there is huge potential on the inside, using innate immunity."
– Dr. Stephen Barr, Western University
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