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01 Dec 2020

The search for an HIV cure continues

People can now live healthy lives with HIV treatment, so why is it important to find a cure?

The last 25 years have been revolutionary in the field of HIV. What was a death sentence can now be managed thanks to antiviral therapy.

Not to mention the fact people living with HIV can have a normal life expectancy. A cure remains elusive – but why do we need a cure if treatment is so effective?

“Only 40 per cent of people globally are on antiviral treatment,” says University of Melbourne Professor Sharon Lewin, Director of the Doherty Institute and an infectious diseases physician and basic scientist.

“The contribution needed from the global community to maintain current levels of treatment is about $20 billion a year. The 27,000 people living with HIV in Australia have access to fully subsidised medicines funded by the Commonwealth Government.

“Low and middle income countries have access to generic antiviral drugs which only cost $100 per year but even to fund this, these countries are dependent on contributions from the international community.

“If we were to reach the UNAIDS goals of 95-95-95 – by 2030, 95 per cent of people living with HIV knowing their status, 95 per cent of those diagnosed on treatment and 95 per cent on treatment achieving viral suppression – that figure would be $30 billion. That’s $30 billion each year forever, which is virtually unattainable.”

Professor Lewin has dedicated her career to finding a cure for HIV. She was one of the first investigators in the world to accurately measure very low levels of HIV that can ‘hide’ inside cells in people living with HIV, even while they are on treatment, known as HIV latency – the major barrier to a cure.

Understanding HIV latency and why it persists on treatment is a major objective of her laboratory.

In collaboration with investigators in Perth and San Francisco, Professor Lewin and her team have been able to identify the exact gene where HIV is sitting and why it likes going into some genes more than others.

“This work has led to a very successful collaboration with our close colleagues in San Francisco funded by the US National Institutes of Health where we can look at whether the virus goes into different parts of the DNA when it’s in different cells,” explains Professor Lewin.

Professor Lewin is also known for her pioneering role in investigating the use of immunotherapy, which has revolutionised cancer treatments, as a possible cure for HIV.

“We know the immune system is dysfunctional in cancer, but you can re-educate it to work against the cancer by reversing exhaustion of the immune system,” explains Professor Lewin.

“When cells of the immune system, killer T cells, get worn out they express certain flags or proteins on their surface. One commonly expressed marker is a protein called PD1.

“The real breakthrough in cancer treatments was developing an antibody that blocked the exhaustion markers – immune checkpoint blockers – and allowed the killer T cell to recover function and kill the cancer.”

Professor Lewin and her team are currently trialling these immune checkpoint blockers in both HIV persistence and cancer to see if this approach could be used as a strategy for cure.

“We have shown that these exhaustion markers are important, not just for the immune response. They also allow the virus to go into hiding. If you block these exhaustion markers the virus is lured out of hiding.”

Professor Lewin concedes that while they think it is an important area of research, it’s not straightforward to bring this approach to the clinic in people living with HIV without cancer.

“The side effects of immunotherapy currently are significant, for example, five to 10 per cent of people will get an autoimmune disease.

“In a cancer setting this isn’t a major concern as you have a life-threatening illness, but in HIV, the situation is very different. People can now live normal and healthy lives with HIV, so any intervention for a cure must have very low toxicity.”

Clinical trials to date have only been in people living with HIV who also have cancer, however, they’re currently preparing for the first study in people without cancer thanks to funding through the Melbourne HIV Cure Consortium.

In a separate clinical trial conducted over the last five years, Professor Lewin and her team proved that people living with HIV have very little or no viral replication on treatment. “HIV becomes undetectable, but we know the virus is hiding in certain spots.”

The team was also the first to evaluate drugs that can wake up the virus from its hiding spot. These drugs are called latency reversing agents.

Most recently, in partnership with The Alfred hospital and University of California San Francisco, they demonstrated that a drug called Disulfiram, which is commonly used to treat alcoholism, can also wake up latent HIV virus.

In collaboration with University of Melbourne Professor Damian Purcell’s laboratory and the Walter and Eliza Hall Institute, Professor Lewin’s team have contributed to finding new latency reversing drugs.

“Excitingly, these compounds seem to be quite active on cells we collected from people living with HIV and in particular, are able to synergise with other interesting compounds,” explains Professor Purcell.

“We’re also trying to understand how these compounds work. We think that these latency-reversing drug compounds are interreacting with a molecular switch that can turn the virus on and off.”

This article was first published in the Celebrating Five Years of the Doherty Institute Impact Report.

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