Professor Robin Weiss is a leading researcher whose discoveries transformed our understanding of HIV during its early years in the 1980s. This work paved the way for changes in HIV testing and treatment that saved lives.
Robin has been a key collaborator and mentor of i-sense researchers working on the development of HIV diagnostics.
During this interview, Robin shares with us his remarkable career spanning 50 years; working on various retroviruses before applying his vast knowledge to HIV, and how his research is now being applied across several pathogenic infectious diseases like Ebola.
Robin reminds us how far we’ve come, but also the obstacles we still face, in reaching the ultimate goal of eradicating HIV and AIDS.
You’ve had a truly remarkable research career; how was it that you came to work on HIV?
I have spent almost all of my research career working with retroviruses, particularly HIV. For the first 18 years, I was working with retroviruses that cause cancer in chickens, and then in 1980, the first human retrovirus was discovered by Robert Gallo in the US, which causes a form of leukaemia. It was then that I switched to human retroviruses and a few years later HIV was discovered.
At the time of the HIV discovery, I was Director of the Institute of Cancer Research (ICR) and we were one of the few labs in the UK with genuine expertise in retroviruses. We dived right in, were able to obtain the virus in 1984, and found we could grow it to high titre. With Richard Tedder, clinical virologist at UCL, we developed the first really good diagnostic test. This test detected antibodies produced by the body in reaction to the virus. It was based on a radio-immunoassay and was converted into the then novel ELISA method. The test went into blood donor screening in 1985, across most countries in the British Commonwealth.
What was the impact of this new diagnostic test?
Before we developed this test, you couldn’t screen blood donors for HIV. So, you could have 1,000 donors going to one commercial batch of clotting factors for haemophilia with no way to track whether they had HIV and those that needed blood and blood products were being infected. About 35 per cent of patients with haemophilia in the UK had become infected with HIV before this test was developed.
The test itself worked very well. It has limitations as it takes a few weeks for newly infected people to produce antibodies so there is that window of time where people may be diagnosed incorrectly. In those days, there were no nucleic acid-based tests available to test for how much virus was present in the blood (known as viral load) and the antibody test was the best available at the time.
You made an even bigger scientific discovery that same year, one that many feel is one of the most significant breakthroughs in our understanding of HIV. Can you tell us a little more about it?
Yes, we identified the cell surface receptor that HIV uses to dock onto human cells, known as CD4. I think that’s what I’m best known for. CD4 is an antigen found on the surface of CD4 T-helper cells in the body, which play a major role in protecting us from infection. In patients with AIDS, there is a severe depletion of CD4-positive cells. If it falls below a certain level (from ~1200 to ~200) you tend to develop symptoms of AIDS or other opportunistic infections.
This discovery matched what little we knew about the disease and measuring CD4 cell counts became a vital part of HIV prognosis. Even today, more than 30 years later, doctors need to know what a patient’s viral load is and what their CD4 count is. It also tells us a lot about the cell biology of HIV, and it still has major implications for health and medicine.
In 1986, we published a paper reporting that while the CD4 antigen is a component of the HIV receptor, it was not sufficient by itself for the virus to enter cells; it needed an extra unknown factor. It took another 10 years before the second factor was identified as a chemokine co-receptor was discovered by Ed Berger at NIH. With hindsight, our predictions were quite smart!
A pioneering breakthrough and very ahead of its time! How was it you came to discover this?
Our retrovirus lab collaborated with a very good immunology lab at UCL led by Peter Beverley and he had all the monoclonal antibodies known in 1984 to T-cell surface antigens that we needed. We screened all 160 of them all blind and picked out 14 that blocked HIV infection. When we deciphered the code each of those 14 was an anti-CD4 antibody - a clear-cut result!
What was it like in the early days of HIV research?
It was exciting and a little bit frightening! We didn’t know how to handle this virus in the lab. Every six weeks we would screen everyone in the lab with our provisional diagnostic test as we didn’t want to become infected or give it to our partners; it was always a nervous day when the results came out. We couldn’t send it off or receive results anonymously - there were only five of us and we were the only ones with the test.
Yet scientifically it was exciting. The CD4 discovery came quickly, the following year we published on neutralising antibodies (ones that block infection) and proved that although people living with HIV showed high levels of antibodies, they only have very low levels of protective antibodies, which was very different to other human retroviruses we knew about. This still remains a major challenge in vaccine development.
There was also a lot of fear and we had a role in trying to inform behavioural understanding. As some of the only spokespeople in the UK for HIV, we received a lot of queries. For example, school teachers asking whether they could treat the grazed knee of an infected child. Very simple instructions like ‘put a plaster on it, wash your hands and you’ll be fine’ went a long way.
What tools, technologies and techniques that are available now do you wish you had back in 1984?
Oh, the molecular techniques without a doubt. I’m talking about DNA-based PCR tests, let alone next generation deep sequencing, bioinformatics, nanotechnology; things have changed immeasurably.
However, I’m a one technique person, specifically something known as Pseudotyping. This is where we take a model virus and put envelopes of other viruses on it, which enables us to test for receptors on cells and for antibodies that can neutralise viruses. This is something I used from the beginning with avian viruses, and we adapted it for HIV.
My most recent work before my lab closed a few years ago was applying all the work I had learned about HIV envelopes to other viruses: Rabies, SARS, H5N1 influenza, and two of my former postdocs have done this with Ebola. It is useful for high throughput and because the pseudotypes themselves do not require high containment.
This might be quite difficult to pin down, but what for you has been your greatest accomplishment?
For me, my biggest discovery was actually one I made when I was still a PhD student at UCL, when I was able to deduce that some retroviruses are inherited in as viral genomes integrated into host chromosomal DNA. Now we know that ~8% of the human genome derives from ‘fossil’ retroviruses. I was the first to see this and it was my first ever virus paper published in 1967, so last year we celebrated 50 years since this discovery! Working together with a chicken geneticist, Jim Payne, we later proved through crosses between two breeds of chicken that the endogenous retroviruses are inherited as individual Mendelian loci.
This is specifically referring to retroviruses in animals. Did it have any impact on our understanding or practice around human health?
This is still relevant today. For example, much later in the mid-1990s, gung-ho scientists and immunologists started doing what is called xenotransplantation, transplanting animal cells or tissues into people. There is a shortage of human organs for transplantation so the idea is that since pigs are similar to humans and their organs have the same functions, let’s grow nice clean pigs and put their tissues and organs into people.
The US Food and Drug Administration (FDA) left this to the judgement of local ethical committees. But I knew that the pigs, like chickens, carried inherited viruses and moreover, they could become reactivated to infectious form. So we tested those viruses and found that there are three different strains, two of which infect human cells in culture. We published this research in 1997 and it rapidly led to international changes in safety regulations. We were not saying don’t do it; we were saying you need to learn more about infection hazards first. It had a big impact.
United Nations AIDS has an ambitious 90-90-90 target to reach by 2020, to help end the AIDS epidemic. What is the biggest challenge for HIV eradication?
For me, it’s developing a vaccine. I believe prevention is better than cure; an old adage but still very true.
You may prevent HIV infection in a number of ways: by encouraging changing sexual behaviours, drug-taking behaviours, condoms, etc. There’s also pre-exposure prophylaxis (PrEP), with the idea that if you widely administer drugs used to treat HIV to people who are at high risk of contracting the virus before they become infected, you help prevent it.
However, these treatments are expensive, they’re slightly toxic, and you have to be on these drugs for life. A vaccine would dramatically improve quality of life and to my mind, it’s the only sure way to eradication. However, it’s a huge technical challenge. I think we will get there one day, hopefully in my lifetime.
What would you say is the biggest success story?
I am amazed how far we have come with HIV treatment, with antiretroviral therapy (ART) and how it has been rolled out across Africa and some of the poorest nations. We now have nearly 50 per cent of people who know they’re infected on treatment. I never thought these high-tech, very expensive drugs could be rolled out at this scale, but they have been. There has been a lot of commitment and funding from across governments, charities and companies to make this happen and it is a huge public health success. Sadly, these funds are diminishing as industrialised nations become more inward looking.
It is one of the reasons why diagnostics, like the ones i-sense is developing can be so useful. Now, if you know you’re infected, you can be treated and live a relatively normal life. In the early days, people didn’t bother to get tested because it was just a future death sentence. The accessibility to ART has given a new push to diagnostics research.
The next step is the development of rapid, hand-held, portable diagnostics that can be used in remote locations to make sure as many people as possible get tested. Then we can give them drugs and it will prevent future infections.
What do you think are the capabilities of the digital health revolution in viral diagnosis?
I think mobile phones have huge capability to benefit disease diagnosis and control. For highly contagious infections they can be used for contact tracing combined with diagnostics. For example, during the Ebola epidemic my daughter, who is an epidemiologist at the London School of Hygiene and Tropical Medicine, went to Sierra Leone where people were doing contact tracing with bits of paper to try and track who was likely to develop the virus. She went there and converted this process to mobile phones.
Mobile phones are so universal, even in a country as poor as Sierra Leone. And that was just using them to find people. The integration of nanotechnology methods with mobile phones, as i-sense is doing, can take testing out of the big clinics, away from the big machines and into the fields, and that’s terrific.
You have had a long career with many roles over the years; what for you has been the most rewarding one?
Without a doubt, my most rewarding role has been acting as a mentor to young scientists. I am very proud of my scientific children and grandchildren, so to speak. To see young scientists come up and do well is a great feeling.
As I mentioned, I was Director of the Institute of Cancer Research in London, with 600+ employees for 10 years. I think I did a pretty good job, so that is also satisfying.
Since retiring from laboratory research, I’ve served on international advisory committees, such as the chairing the International AIDS Vaccine Initiative and being a founder member on the Board of the new Africa Health Research Institute (AHRI). While I still possess my mental marbles it’s rewarding to be able to offer advice and expertise on research and management, especially in Africa, where TB and HIV epidemics are most alarming. Currently, I advise the Indian HIV Translational Antibody Research laboratory and I’m a member of the Nuffield Council on Bioethics. Not least, I enjoy being affiliated to i-Sense owing to my expertise on llama single-chain antibodies, sometimes called nanobodies.
