AIDS and Animal Models
Looking for the perfect challenge. A conversation with Charles River CSVP Colin Dunn about his early years researching HIV.
It was about a decade after the first cases of AIDS began surfacing in US emergency rooms that Colin Dunn, a young veterinarian from Northern Ireland landed, quite unexpectedly, at a virology lab in eastern France. Colin had always intended to start a mixed veterinary practice in the UK, but like so many specialists around the world his focus veered toward AIDS, a mysterious condition that was quickly escalating into one of the worst pandemics in human history.
Scientists knew by then that HIV was the cause of AIDS, and scientists were hoping to identify animal models that could be used to test AIDS vaccine candidates.This was the key objective of Colin’s lab and he ended up earning a PhD on HIV vaccines in large animals of pathogenesis using the simian equivalents and genetically engineered viruses combined from HIV and SIV.
The vaccine hunt remained elusive—in fact there is still no commercially available AIDS vaccine in circulation today—but the science from Colin’s lab was still uniquely valuable in helping to inform our understanding of HIV.
Colin eventually left France to study exotic viruses in the UK, and today he is the Corporate Senior Vice President of Global Research Models Services at Charles River. With World AIDS Day approaching on Dec. 1, we connected with Colin to talk about his early years in HIV research, and the important role that animals played in researching it.
Your early research career was spent working on HIV vaccines at the Université Louis Pasteur lab in Strasbourg, France. What was the specific focus of those experiments?
CD: The key objective was to develop animal models which could eventually allow testing of an HIV-1 vaccine and to understand more about the pathogenesis of the viral infection in a large animal species. Back in the early 1990s there wasn’t a consensus that the viral replication was sufficient to destroy the key immune cells in infected people, CD4 lymphocytes, so certain animal models of SIV were important to show the link of viral replication and a decline of CD4 lymphocytes in the acute phase of infection. Given there was little information on any correlates of immune response and the decline of viral replication in the early phases of the infection, many laboratories were funded by governments globally to investigate the acute phases in large animals using the naturally occurring equivalent viruses.
What did you learn from studying HIV/SIV viruses in large animals and were you eventually able to translate the findings into the development of an AIDS vaccine candidate?
CD: The animal models in the 1990s showed just how challenging it was to obtain a vaccine that would give “sterile immunity.” Numerous candidate vaccines were trialed in certain large animals and at that time the only approach that appeared to be efficacious was a live attenuated vaccine (actually shown first at NE Regional Primate Research Centre) but this would have been much too risky in humans given there was no guarantee such attenuated vaccines would not revert to the wild type during a person’s lifespan. Furthermore some critical studies at Dana Farber in Boston showed these vaccines to be pathogenic in newborn animals so this illustrated the huge risks of taking such an approach. Many other vaccine combinations using inactivated viruses, recombinant poxviruses, different adjuvants, gene therapy approaches with modified viruses, subunit vaccines and DNA vaccines just had almost no impact on viral load in the animal models so attempting clinical trials in humans was regarded as high risk should the person receiving vaccine perceive they may be “protected” and so change lifestyle. People used to have endless debates about the difference between an immunogen and a vaccine.
At the time did you and your colleagues think the discovery of an AIDS vaccine would be so difficult?
CD: It was well known in the field that any prophylactic vaccine was a monumental challenge to such an extent parallels were drawn with the “Manhatten Project” in terms of resourcing required for such an epidemic. I think this triggered much more effort toward antiviral agents to suppress viral load. A significant problem was always to trigger immunity at the mucosal surface of vagina or rectum given the sexual route of transmission in the Western world and Africa but the intravenous drug contamination directly into the blood was also a challenge due to the likely high virus challenge. Live attenuated viruses, which were the approaches used for diseases such as smallpox and poliovirus, were simply too risky for HIV. There was no known prior public health challenge like this one, which makes achievements in public health related to smallpox, polio and measles decades and even centuries ago so astonishing, and I suppose the gratitude is marked in many countries on bank notes and street names in big cities; “Boyleston Street” is one such example related to small pox in Boston! It’s really the same in animal health and food production. Innovation in vaccines preceded any knowledge of the structure of DNA, let alone molecular biology.
Given that this was pretty early days in the AIDS pandemic, what was the mood like in your lab? There must have been a lot of pressure to find solutions to the growing crisis.
CD: I got to do a PhD thanks to international collaborations in Europe, and although there was intense intellectual competition between labs, there was also a strong collaborative spirit. Many researchers had switched from the study of other viruses into HIV. My own supervisor was the world expert on another virus; she gave all that up to work in an entirely new field, letting go of her prior life’s work as the lab was given a new mission. I think there were many researchers like that.
If you don’t mind my asking, did you know people at the time who died of AIDS?
CD: Thankfully no, but I think I might have had a cat die of the feline equivalent! However like many people my age, it came as a shock back then that some celebrities so familiar in music or film contracted HIV or became advocates for their sexuality … time has moved on in society and I think the AIDS pandemic forced some of that discussion.
And yet, you were also able to witness a real turnaround in the epidemic, not with a vaccine but with so-called AIDS cocktails that provided a life preserver to millions of infected individuals. What was it like for you to see the needle shift?
CD: As I was wrapping up my PhD and moving back to the veterinary field, new molecular techniques to quantify the viral RNA in human plasma had been made to work and this showed conclusively that viral replication was working continuously at a very high level even during the asymptomatic chronic phase of the infection. This coincided with new approaches to chemotherapy and combination chemotherapy, so the idea that suppressing viral replication could be effective lead to many new paths. It also illustrated the importance of medicine alongside more fundamental research. The isolation of RNA and running very sensitive PCR assays was novel at that time.
From your perspective, how integral were animals to the development of those early antiretroviral therapies?
CD: I think a lot of the key work was done in the clinic, the early antiretrovirals were available for other retroviral diseases so the trials were really “indications discovery” type of work. I wasn’t so close to how the safety assessment was done, but some use of animal models in large animals was done to show suppression of viral load.
So a lot of people owe their lives to the early work done in these animals?
CD: I think the work in the animal models helped make the early links to the virus causing the disease at a time when there were other theories that the virus only triggered some sort of autoimmune disease resulting in AIDS. It also supported an understanding of the risks of clinical trials of vaccines, thus informing the direction of other public health investment.
Lastly, with World AIDS Day upon us, would you say your work on AIDS changed you and if so how?
CD: I had the privilege of working on a PhD in an inspirational field and with some amazing people who trained and mentored me. You gain a sense of perspective knowing that AIDS today is the major cause for children becoming orphans in Africa.