How disaster pushes medicine forward

What incredible scientific advances will come from covid research? The HIV epidemic may hold some clues.

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In 2020, the world changed more than many of us could have imagined.

The pandemic tore apart social structures, grounded travel and led to the deaths of millions.

As tragic – and potentially avoidable – as that was, it also holds the seed of something amazing. In the quest to combat such a powerful foe, humans dedicated a jaw-dropping amount of funding, time and brainpower to understanding every possible facet of the virus and how it spread.

It’s through another such international effort that we already have effective vaccines developed at a speed many thought impossible. And such vaccine innovations are not only proving successful against SARS-CoV-2, it could also form part of our armoury against tricky extant diseases – not to mention diseases we’ve yet to encounter.

It will take many years to fully understand the extent of the benefits derived from such a single-minded, and well-resourced, devotion to a scientific question, but we may find clues in looking back at the last virus to warrant such a huge effort: the human immunodeficiency virus.

HIV is one of the most rigorously studied viruses in human history.

Since it was discovered four decades ago, more than 75 million people are thought to have contracted the virus, and billions of dollars have been devoted to understanding and combating it.

Professor Anthony Fauci, chief of the US National Institute of Allergy and Infectious Diseases (NIAID), is effusive about the benefits wrought from such an investment.

“The collateral advantages of this investment above and beyond HIV/AIDS have been profound, leading to insights and concrete advances in separate, diverse and unrelated fields of biomedical research and medicine,” he wrote in a 2019 perspective in The Journal of Infectious Diseases.

Dr Fauci, who is most recently famous for being the public face of the US government’s response to the covid pandemic, first rose to prominence as an AIDS researcher and was chair of the NIAID in 1984 when that epidemic first broke out.

Now he, and others, have had time to see the ripple effect of HIV research’s scientific advances, innovation and the cross-fertilisation on a range of other conditions.

Our immune system

Professor Tony Cunningham AO, director of the Centre for Virus Research at the Westmead Institute for Medical Research, was a postdoctoral student at Stanford University when HIV first hit.

“I saw the devastation, particularly amongst the gay community, there,” he says.

“In fact, the first HIV person I ever treated came to me with enlarged lymph nodes, and I checked against the usual things, and none of those were positive.”

Trying to care for patients with such a mysterious illness forced clinicians and researchers into a level of collaboration that may be rivalled only by today’s covid pandemic.

In the clinic, infectious diseases specialists were suddenly forced to care for patients with a chronic illness, and care of these patients more closely echoed cancer management than the “treat and discharge” approach that had dominated the specialty before.

While it would take years for investigators to discover the actual cause of AIDS, researchers and clinicians such as Professor Cunningham were closely studying immune cells and the effect of this disease on them.

“As far as science is concerned, it led to a flowering of the understanding of my particular specialty, viral immunology,” says the University of Sydney infectious diseases physician.

One such leap forward was discovering how viruses interact with immune cells – both in terms of how viruses such as HIV penetrate our defences, and how immune cells manage the invading pathogens.

“In the early days of virology, everybody was into sequencing viruses and molecular virology,” he says. “But HIV showed us that we needed to understand how viruses interacted with the immune system: it wasn’t just antibodies, it was all the other arms of the immune system that were important.”

The benefits were wide-reaching.

Congenital immunodeficiencies, Dr Fauci notes, can be thought of as “‘experiments of nature’ whereby a specific defect in a single component of the complex immune system sheds light on the entire system”.

Likewise, HIV is another natural experiment that illuminates the complexity of the human immune system.

For example, the virus selectively infects and destroys the CD4+ subset of T lymphocytes, devastating our body’s defences.

Studying the opportunistic infections and tumours occurring in people with HIV drives home just how important this cell type is, says the immunologist and infectious diseases expert.

Research into the expansive ways this pathogen undermines our immune system also highlighted the role those defences play in fending off other neoplastic diseases such as non-Hodgkin lymphoma and Kaposi sarcoma, says Dr Fauci. “As a result of its association with HIV/AIDS, Kaposi sarcoma was discovered to be caused by human herpes virus.”

Sequencing viruses

By 1983, researchers had discovered that there were multiple different variations of the virus responsible for AIDS.

Sequencing the DNA of the virus that had infected individuals, and using that to diagnose and manage the disease, was the beginning of the era we now think of as “precision medicine”, says Professor Cunningham.

This was possible only thanks to the then-recently discovered polymerase chain reaction (PCR) technique, which amplifies the RNA and DNA of viruses. Folding this tool into clinical practice allowed doctors to detect tiny amounts of HIV markers, and determine the virus variant and the level of infection in the blood.

It was an “incredibly” important tool to determine which patients were responding to which strain and with what drugs they should be treated, says Professor Cunningham.

It may seem obvious now, but using PCR helped clinicians realise that when viral loads rose, the infection had rebounded and the disease would probably soon flare up.

This meant that at the time of diagnosis, and periodically, the virus could be sequenced to determine if it was (or had become) resistant to certain drugs, and which alternative medications could help. This ultimately improved the long-term health outcomes of people with the infection.

“A lot of these techniques started in HIV and then the potential was spotted and they grew substantially,” says Dr Nicholas Medland, president of the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine (ASHM).

In recent years, sequencing viral infections has been used to, confidentially, trace virus transmission through communities to better understand how epidemics spread and how to stop them, says Dr Medland. “We’ve seen sequencing used invaluably in Australia to determine where a new covid infection came from and then go looking for the sources.”

Antivirals

By 1984, shortly after the cause of AIDS was discovered, the US Secretary of Health and Human Services proclaimed that a vaccine would be ready within two years.

And while this claim was miraculously apt for covid, it sadly remains untrue for HIV even decades later.

“The reason for that is HIV is at the heart of the immune response, and it’s got an incredibly complex relationship with our immune response,” says Professor Cunningham. “It knocks it out.”

When it became increasingly apparent that a vaccine for HIV wasn’t coming quickly, scientists’ attention turned sharply to mitigating the spread of the virus.

“With the human race’s typical ingenuity, we’ve come up with ‘treatment as cure’ – which is rolling out antiretrovirals,” Professor Cunningham says.

Back then, antivirals existed. But they were primitive compared with the ones we have today.

When it came to HIV-specific drugs, it was years from the discovery of the virus to the FDA approving the first antiretroviral: the cancer drug zidovudine, otherwise known as azidothymidine (AZT).

While the medication slowed the progression to AIDS by weeks or months, it came with a host of side effects – and the virus often mutated and became resistant to the therapy.

New antivirals were discovered and combined to control the number of people dying, but it wasn’t until the mid-90s when things really changed.

“HIV was really the first viral infection where highly effective antivirals were developed that completely controlled the virus’ replication,” says Professor Sharon Lewin AO, director of the Peter Doherty Institute for Infection and Immunity.

This was thanks to what is known as rational drug design.

“You image the part of the virus that you want to target, and then you form a molecule that fits into the image, to block it, basically,” says the Melbourne University professor of medicine.

This gave us a new antiretroviral class, the protease inhibitors, which Professor Lewin believes to be the first intervention to truly revolutionise the treatment of HIV.

In the decades that followed, regulators approved dozens more drugs that interfered with different stages of the HIV replication cycle and effectively prevented those infected with the virus from developing AIDS. 

Both the knowledge and the actual drugs designed to fight AIDS have been used in the management of other diseases.

Some HIV drugs have become hepatitis B medications, and the design method is to thank for the “fabulous” hepatitis C drugs that cure patients, with minimal side effects, in as little as two or three months, says Professor Lewin, who still works to discover a cure for HIV.

And antivirals had other benefits.

Professor Cunningham recalls watching a presentation in which the researcher proposed that if patients could drastically lower their viral loads using combination treatment, they may be able to reduce levels of HIV in bodily secretions and prevent transmission.

The trials were done, and the theory was vindicated.

Antivirals had never really been used in that way before: reducing rather than eliminating the virus, to reduce the risk of transmission.

“It was really out of desperation,” he explains. There was no vaccine, and the virus was spreading through Africa, Western countries and other parts of the globe.

This was the era of potent antivirals, and a new approach to preventing the spread of chronic infectious diseases when vaccines aren’t available.

This approach could, in theory, be applied to any chronic infectious disease. Perhaps we may have wound up with covid antivirals if no vaccine had been found.

Now, remarkably, we have pills that HIV-negative people can take if they fear they’ve been exposed to the virus, and regular pre-exposure prophylaxis (PrEP) if they are at a high risk of being exposed. 

Antibodies

Another major breakthrough in HIV research, says Professor Lewin, was in monoclonal antibodies.

In the search for a vaccine or an effective alternative to antivirals, a lot of work went into making designer antibodies.

Along the way, researchers realised antibodies were powerful against other infections, and could be easier to develop than small molecule drugs, because they didn’t need to go through the repeated safety and toxicity studies, says Professor Lewin.

“So a lot of investment has gone towards antibodies for treatments, or vaccines, and more recently, as a cure for HIV,” she says.

This approach became hugely helpful in 2014 and 2018 when Ebola broke out in Africa.

“People started very rapidly working on antibodies using the same technologies to fish out the antibody-making factories in people that are infected, find the good antibodies and then turn them into therapeutics,” says Professor Lewin.

These antibody cocktails were “extremely potent”, becoming the preferred treatment for Ebola, she says.

The same method was used when the SARS-CoV-2 pandemic hit, ultimately leading to the Regeneron’s antibody cocktail taken by former US president Donald Trump.

Our greater understanding of the B cell repertoire, the system responsible for producing antibodies, has also been vital to our understanding of infectious diseases such as influenza and Zika, as well as autoimmune and noncommunicable diseases.

Structure-based vaccine design

It might have once been unthinkable to hear people on television talking about spike proteins, but the coronavirus has made these tiny, yet powerful, surface structures almost a household name.

Many years before, the quest to understand similar features of the AIDS virus sparked other feverish investigations. Researchers turned to imaging technologies such as protein X-ray crystallography and cryoelectron microscopy to study the virus.

“In their efforts to develop vaccines, one of the things that people have really pushed ahead with is understanding the three-dimensional structure of viruses,” says Professor Cunningham.

Now, vaccine developers can analyse the atomic structure of the proteins that viruses use to bind to human cells, and design vaccines that interfere with that process.

For example, after half a century of failing to find a way with traditional methods, scientists have recently used structure-based vaccine design to create an experimental vaccine for respiratory syncytial virus.

For Dr Medland, the crop of new mRNA vaccines is “perhaps the single most memorable scientific advance of the past year”.

“Decades of HIV vaccine research have not produced an effective vaccine against HIV, but they have produced a lot of the techniques and advances that were used for covid vaccines,” he says.

“This is a perfect example of unanticipated cross-over,” he says. “A year ago, there was no idea that this benefit was sitting there. But because of the search for HIV vaccines, the whole vaccine sector was well funded and ready to go when covid came along.”

Genetic therapy

One of today’s most exciting therapeutic possibilities also has its origins in HIV: gene therapy.

What better way to modify someone’s genes – replacing the defective genes with healthy ones – than to use an entity specifically evolved for that purpose?

HIV is masterful at getting inside a human cell and changing its DNA. Thanks to decades of studying the virus, researchers realised that they could replace the parts that would deliver the HIV payload into the cells, and instead give it a different – therapeutic – genetic cargo to deliver, says Associate Professor Stuart Turville, a researcher who specialises in HIV and gene therapy at the Kirby Institute at UNSW.

These HIV-based vectors can either be directly injected into the patient, or cells can be removed from the body and exposed to this tweaked virus before being injected back into the patient.

So far, this technique is showing promise in many incurable and hard to treat diseases, such as cancer. And right now, it’s in clinical trials for HIV.

“We’re using components of HIV to actually fight HIV,” says Professor Turville.

Public health

It wasn’t just hard science that has progressed in the quest to combat the HIV epidemic.

For Dr Bridget Haire, senior research fellow at the Kirby Institute, the first unanticipated benefit of the crisis that comes to mind is the “absolutely revolutionary community engagement in research and medical care”.

Because so much was unknown at the beginning of the epidemic, from its actual cause – whether it was virus, bacteria or cancer, the route of transmission to the proportion of people who would become sick and die – communities were highly motivated to find practical ways to protect themselves.

Affected communities became so engaged with prevention and treatment efforts that they produced reasonably accurate safe sex resources prior to HIV even being identified as the virus causing AIDS, says Dr Haire.

So, in a quite unique move, governments both here in Australia and overseas sought out collaboration with queer communities, injecting drug users and sex workers to have them involved in their own public health response management.

One laudable step at the time was that Australian politicians took a bipartisan approach, deciding to let evidence, rather than politics, drive the response.

“It’s hard to overstate the importance of this, though it doesn’t sound as sexy as vaccines,” says Dr Medland, of ASHM.

Close collaboration between government leadership, funding, clinicians, researchers and community ensured that interventions adhered to the latest science and that there were no barriers to rolling out effective interventions, he says.

“PrEP in Australia is the perfect example of this. Covid is obviously bigger and faster than HIV, but many of the partners have been the same partners,” he adds. “So, both the existing working strategies and the lessons on how to get things done on a large scale with everyone’s support were definitely a product of Australia’s HIV response.”

Our approach to testing also drastically changed because of HIV.

Initially some community groups actively discouraged testing, arguing that there was no point knowing you were positive if there were no effective treatments. For safe sex, this argument went, everyone should assume their sex partner was of the opposite serostatus.

Once effective treatment became available, however, there were strong reasons to know your status.

To control the epidemic, people living in low-income or remote areas needed an easy way to get diagnosed and be monitored. This pushed tests to become easier, cheaper and quicker. The same technology underpins our now excellent capacity to diagnose covid.

Contact tracing is another huge area of improvement.

“This has been the strength in HIV and sexual health for decades,” says Dr Medland. “Each of Australia’s state health departments had groups whose full-time job was to interview people newly diagnosed with HIV or STIs and then cautiously and confidentially follow up those leads.

“When covidcame around, the same groups were suddenly staffed-up and expanded, but basically operating in the same ways and by the same people, methodically following up every lead.”

But not without lessons learnt from collaboration with communities. Dealing with the stigma associated with HIV led to some important insights that we still use today – namely, the utmost respect for privacy, confidentiality and rights.

The intense stigma around HIV drove public health officials to make it safer for people to test and seek treatment, explains Dr Haire, a former president of the Australian Federation of AIDS Organisations (AFAO).

One innovation was to identify people with public health codes rather than their full names.

“We saw in South Australia, with the situation in the takeaway pizza shop, that if people are scared about the consequences, they won’t share information and the public health response goes off in the wrong direction,” says Medland.

“HIV really taught us that if you try to be punitive you take a big risk. You need to be supportive – which is good for the public health response, it is good for the relationship between health officials and the affected communities, and it is good for the individuals involved.”

Trials

Clinical trials also underwent an important transformation in the HIV era, says Dr Haire. The fatally long waits between drug trials and FDA approval for promising therapies prompted intense activist backlash, as did the traditional approach of using death as a study endpoint. These caused devastating delays for people stricken with such a fast-moving illness and led to a rethinking of what were dubbed “body-bag” trials, says Dr Haire.

“One of the big transformations was to vastly increase the size of trials and reduce the duration.”

Final lessons

Professor Cunningham attributed our good fortune around covid to our pandemic preparedness plan. But it’s all too easy to look at our neighbours in India and the US to see how easy it is to be complacent, and how dangerous that can be.

“When I first came here and directed the state virology lab, I opened my filing cabinet and there was a letter from a person in the health department, dated 1984, saying all infectious diseases had now been conquered. Then we got HIV. We got hepatitis C. We got Zika. We got Ebola. We got SARS … And now we’ve got covid.

“Human beings tend to forget. It’s very important we don’t.”