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Is an End to AIDS in Sight?

HIV virus attacking a cell. martynowi_cz/iStockphoto

HIV virus attacking a cell. martynowi_cz/iStockphoto

By David Harrich & Kirsten MacGregor

Gene therapy is showing promise as a way to turn HIV against itself and cure AIDS.

Los Angeles, 1986. A new virus is taking hold. It has only had a name for 3 years but its symptoms are already disturbingly familiar at emergency rooms across the USA. Young people are being struck down and fear – hysteria even – is growing in the community alongside misinformation. When I meet people and tell them where I work, they refuse to shake my hand for fear of catching the virus.

I am an enthusiastic 26-year-old research assistant in the HIV laboratory at the University of California (UCLA). I am simply grateful to put my science degree to use after several years in the job wilderness. I have no concept that I have set in motion my future PhD and life’s work, let alone been witness to the birth of a global pandemic.

Brisbane, 2013. Fast-forward 27 years and HIV/AIDS ranks as one of the biggest killers of any infectious disease. More than 35 million people have died. But, compared with the fear and hysteria of the virus’ early years, the community has a better understanding of how HIV/AIDS spreads and a more reasonable attitude towards its victims. Medical experts know how to keep patients alive for longer with an expensive cocktail of antiretroviral drugs they take for the rest of their lives – if they’re lucky enough to live in the First World.

But for many of the world’s poorest, AIDS remains a death sentence. And a cure remains elusive.

So when decades of studying the virus recently culminated in one crucial moment in my lab at the QIMR Berghofer Medical Research Institute, the excitement was palpable.

The Problem with HIV Infection

Being infected with the human immunodeficiency virus (HIV) is a lifelong affair. HIV cripples a person’s immune system, making even the most common illnesses potentially life-threatening.

HIV infection occurs through the transfer of body fluids – via sexual contact, a blood transfusion, sharing of needles or through the placenta from mother to unborn child. The virus lives permanently in the human chromosomes as integrated proviral DNA.

It is estimated that without therapy an infected person produces an astonishing ten billion new virus particles every day. Inevitably the immune system succumbs, and the victim becomes susceptible to opportunistic infection.

As a result, an HIV patient becomes immersed in the health care system. Doctors monitor patient viral loads (the amount of HIV in their blood and CD4 cell numbers (to gauge the health of the immune system) to make decisions about medications and how to manage side-effects that range from mild to severe.

The Berlin Patient

Timothy Ray Brown of San Francisco was first diagnosed with HIV in 1995. He was living in Germany and was also diagnosed with leukaemia. His specialist, Dr Gero Hutter, offered a standard cancer therapy – a bone marrow transplant – but with a twist.

Some people carry a moderately rare CCR5 gene mutation that provides some natural resistance to HIV infection. Only about 1% of the Western European population has the mutated CCR5Δ32 gene.

Hutter conceived that since HIV needs both the CCR5 receptor and the CD4 receptor to gain entry into cells, a bone marrow transplant from a donor with the mutated CCR5Δ32 gene might protect immune cells from further HIV infection. After receiving chemotherapy, radiation and the experimental bone marrow transplant in 2006, Timothy Ray Brown, known as”‘the Berlin Patient”, takes no antiretroviral medication and has no HIV detectable anywhere in his body.

There are serious caveats to this therapeutic approach. A compatible bone marrow donor must also have the rare CCR5Δ32 phenotype, making this possibility a “million-to-one” chance. Furthermore some HIV strains use CCR4 instead of CCR5, nullifying the strategy. And bone marrow transplants can cause life threatening graft-versus-host-disease. Not

unexpectedly, this procedure requires medications before, during and after therapy, and continued monitoring by medical professionals.

Nevertheless, Timothy Ray Brown’s recovery highlighted the potential of a type of “natural” gene therapy. “The Berlin Patient” came to represent hope that HIV is curable.

Recently, doctors in Boston used bone marrow transplantation without the CCR5Δ32 mutation and the results were somewhat unexpected and outstanding: so far there is no detectable HIV in these patients after cessation of anti-HIV medication for several months.

Let’s Give It One Last Shot

Today, much scientific effort is being directed at discovering a way to treat a patient’s immune cells to make them HIV-resistant. Gene therapy of this kind would introduce a synthetic gene that can make antiviral proteins or RNA which prevents viral growth in cells. Investigators worldwide have also pursued proteins that can block the HIV life cycle. Essentially, researchers are trying to find the chink in HIV’s armour.

My old boss at UCLA , Richard Gaynor, was the first person I’d every heard discuss the notion of using HIV against itself, effectively “fighting fire with fire”. Why couldn’t we take a virus protein and make it a virus inhibitor?

For the next few decades, as I moved from California to Texas, and then from the USA to Australia, that thought niggled and began to constitute a major part of my research. All my early experiments said the strategy could work but at the time I lacked the technology that is now available to obtain a definitive answer. By 1997 I had developed a synthetic mutated protein that I named Nullbasic, but it took another 10 years of finessing to come up with its final form.

By now I was facing a lot of pressure from contemporaries around the world to abandon this research. I was accused of wasting time, and of damaging my career by chasing a pipedream. I began to believe them, and by 2007 I had all but given up hope.

I decided to give Nullbasic one last shot, aware that if it was an HIV inhibitor, technology had finally advanced enough to show me whether it was effective or not.

I designed an experiment for a PhD student in my QIMR Berghofer laboratory, but was not feeling especially hopeful. It was a short experiment; we’d know within weeks whether Nullbasic should be abandoned once and for all.

Then came the day when he sought me out to tell me: “Wow, it really worked”. I didn’t believe him. I made him do the experiment again and again, and it worked every time. Not just a little bit. Really well. The mutated protein was showing remarkable abilities to stop the virus, and not just in a single step.

Nullbasic was inhibiting three separate steps of the virus replication in primary CD4+ T cells. Human immune cells with Nullbasic were showing remarkable resistance to HIV infection.

Science is all about perseverance: 99.9% of what we do fails. Real Eureka moments are rare; most advancements are based on incremental changes in our understanding. But you’re always keeping your eyes open for the unusual event. And I’ll never forget that day in the lab.

So the door opens a little wider for a potential new treatment. In theory, a person with HIV would receive this modified protein as stem cell gene therapy, and the virus would remain latent. It wouldn’t wake up, and wouldn’t develop into AIDS. You would maintain a healthy immune system that would protect you from the opportunistic infections that lead to AIDS.

We are several years from human trials. First, we’ll use “humanised” mice – special immune-depleted mice that can be infused with human immune cells treated with Nullbasic – to mimic (to a certain degree) what might happen in a person after being infected with HIV. We expect that Nullbasic-treated human cells will resist HIV infection. It’s going to take time, money, and careful research, but the signs are good.

Over the decades of my working life I’ve never given up hope for new treatments for HIV/AIDS. But there is definitely a new spring in my step, and a genuine excitement that we’re onto something. Hang in there with us. We’ll keep you posted.

David Harrich is Group Leader of Molecular Virology at the QIMR Berghofer Medical Research Institute. Kirsten MacGregor assisted in writing the story.