Trailblazer: a gene therapy pathway to a cure for HIV

Professor Sharon Lewin is an infectious diseases physician internationally renowned for her research into all aspects of HIV disease – specifically in strategies to achieve an HIV cure. She is the recipient of the NHMRC Elizabeth Blackburn Investigator Grant Awards – Clinical Medicine and Science (Leadership). Research Excellence Awards are awarded annually to the top-ranked researchers and teams following peer review of applications to NHMRC’s highly competitive grant schemes.

It was in 1981 that the world heard the first descriptions of unexplained illnesses in gay men in New York and Los Angeles – which happened to be the year I started medicine. In 1983 came the discovery that AIDS is caused by a virus called HIV. Then it took until 1985 for tests to be developed to diagnose someone.

At the time it felt that the science of HIV was moving at a very rapid rate –in retrospect, compared to COVID, it wasn’t fast at all. But we were solving things, understanding how the virus replicates, what cells it replicates in.

I became aware of HIV in 1984, during my first year at the Alfred Hospital in Melbourne, Victoria, studying pathology. At that time, we thought that this was an issue for the gay community, still quite rare, and heavily stigmatised.

But when I spent a year working in Kenya in 1989, in a small rural hospital in the middle of nowhere, I became aware of the scale of HIV and what it was doing to devastate communities across Africa. I was already interested in infectious diseases and realised then that I wanted to do something that had a big impact on a major global problem, and that this was going to be through research.

Read more: HIV and gene editing

I’d always been very interested in the physical sciences in high school. I always liked the precision of maths and physics, where things have a single answer with no uncertainty. I thought I might become an engineer or an astronaut, but my parents convinced me to do medicine.

For the first two years of study I kept thinking about switching to engineering, but I began to realise that I loved the people side of medicine. I became very humbled by the fact that through medicine you are given this precious gift of helping people at the most vulnerable times of their lives.

It’s a very privileged position, and I began to find it immensely interesting applying my scientific knowledge to solve problems for people in the clinic.

HIV taught us so much about both viruses and the immune system. There has been an explosion of better treatments. Anti-virals were developed in the mid 1990s that very powerfully got rid of virus from the circulation, allowing people’s immune systems to recover – people literally got off their dead beds and returned to work.

It was an amazing time.

Now people with HIV can have just one antiviral tablet a day, or even an injection every two months. But keeping all these people on treatment for the rest of their lives costs a lot of money – and we’re seeing this all crumble before our eyes, with the change in US policies on supporting global health.

I’ve worked on many viruses, both chronic and acute: HIV, hepatitis B, and then COVID of course. But my long-standing interest has been in HIV latency.

In contrast to a virus like COVID, HIV can establish what we call a silent or latent form, because it becomes part of a person’s own genome, their own DNA. Once inside the DNA, it can effectively go to sleep, but the virus is always there. Antivirals stop the virus from replicating, but they can’t get rid of these cells that carry a latent or silent form of HIV. And if that cell gets activated, the virus pops out again.

So we can treat HIV, but we haven’t been able to cure it – until about 15 years ago.

Timothy Brown was an American living in Berlin at the time who received a bone marrow transplant from a donor who was naturally resistant to HIV – one percent of Caucasians lack the receptor that HIV needs to enter their cells. And his clever doctor gave him a transplant from a donor that had carried that mutation. And so Timothy Brown was the first of seven or eight cases cured following bone marrow transplant.

That really opened our eyes to the potential of gene therapy to provide a pathway to an HIV cure. Gene therapy has gone through some dramatic changes in the last 15 years, largely driven by technological advances such as CRISPR, and then more recently through mRNA – the potential to deliver gene therapy directly into people, rather than taking cells out, modifying them, and putting them back in.

At the moment, gene therapies are very expensive because we take blood out of the body, modify the gene, then put back the modified genetic material. But if we could just inject the gene scissors directly into a person, then suddenly that becomes a scalable strategy. When we talk about a cure for HIV, it will most likely be quite a high-tech intervention like this. I’m very excited about the potential.

Back in 2020, my lab started looking at mRNA to deliver CRISPR as a gene-editing strategy for COVID, not for HIV. But over the last five years, we’ve built this whole new program of work, finding new particles that can target where HIV hides, and delivering gene-intervention technologies and gene editing tools to get rid of the persistent virus. My work has changed dramatically.

I’ve also always kept an eye on what’s going on in cancer, because the cancer challenge is very analogous to HIV. That’s because small amounts of cancer can survive in the body for a long time and then relapse. This is very similar to what happens with HIV – small amounts of virus persist in what we call the HIV reservoir, and then suddenly in a person off treatment, the virus is activated.

Over the past 15 years or so, we’ve tested different cancer-type treatments to knock out the HIV reservoir and also boost the immune system, because the fundamentals are very similar. So our work has a lot of relevance to diseases outside of HIV.

Science needs all kinds of people working together and all kinds of personalities – all they need to have in common is that they are aiming for excellence and the truth. And as you tackle bigger problems, you need bigger teams. Teams do well when they’re made up of diverse people. It sounds a cliché, but it’s true.

I’ve always been a people-person. One of the most enjoyable aspects of my scientific career has been the people who I have met and worked with – the various clinicians and researchers across Melbourne and Australia, and the whole global scientific community, as well as the people with HIV whom I have cared for and have participated in our clinical trials. All amazing people. You all share the same passion and a common bond, which is really quite extraordinary. That’s what science is all about.

Professor Sharon Lewin is an infectious diseases physician internationally renowned for her research into all aspects of HIV disease – specifically in strategies to achieve an HIV cure. She is the inaugural Director of the Doherty Institute; a Laureate Professor of Medicine at The University of Melbourne; and the immediate Past President of the International AIDS Society.

As told to Graem Sims