Llamas, jungle fowl … and HIV
University College London virology professor Robin Weiss retires from research at the end of March after 30 years of continuous MRC funding. He tells Sarah Harrop about his eventful career, which has involved critical discoveries about HIV’s modus operandi, catching jungle fowl in Malaysia and developing microbicides based on llama antibodies.
The MRC runs through Robin’s career like the letters in a stick of rock, right back to his first ever job as a graduate research assistant in India with the now defunct MRC Experimental Genetics Unit in 1963.
During his PhD in cancer research, also funded by the MRC, he switched tracks to cancer-causing viruses, and the next two decades saw Robin carrying out virology research in other far flung corners of the globe. He did a postdoc in Prague “in the dark days after the Soviet tanks rolled in” and went on a field trip to Malaysia during which he lived with aboriginal people and caught wild jungle fowl to study the virus strains they were carrying in their DNA.
The advent of ‘slim disease’
However it was not until 1983, when he was Director of the Institute of Cancer Research in London, that Robin’s long and fruitful relationship with the MRC truly began. He heard about the discovery of a retrovirus in Paris — later named HIV — and also of a mysterious new ‘slim disease’ that was killing people in Africa. The MRC awarded him the first of a long string of grants “to see if HIV was involved”. It was a productive time; just a year later, Robin and clinical virologist Richard Tedder had developed the first effective blood screening assay for the infection.
“Wellcome Diagnostics commercialised it as an Enzyme Linked Immunosorbant Assay, or ELISA — which was relatively new technology in 1985. It made blood donations in the UK and Commonwealth safe again, and I think in terms of the number of lives saved that’s been the biggest contribution of my career,” Robin says.
He recalls well the moment that he first realised the sheer horrifying scale of the HIV epidemic in Africa.
“We worked with two young doctors in Uganda to test blood samples of people with ‘slim disease’ who were, as expected, all HIV positive. But our results seemed to show that 10 per cent of the ‘healthy’ control group were HIV positive too,” he explains.
“At first we just assumed that our test wasn’t specific enough, but then the penny dropped — the test was working fine, but 10 per cent of the entire young adult population in Kampala was infected by HIV. Only then did we realise what a huge problem AIDS would become. That’s not the sort of thing you forget.”
One receptor to rule them all?
Robin’s second big strike on HIV has been his critical discovery — along with Professor Peter Beverley and MRC Clinical Fellow Gus Dalgleish — that all strains of the virus lock onto the CD4 receptor on human T-helper lymphocyte cells in order to exert their deadly effects on the immune system. Two years on, in 1986, they made another breakthrough — HIV needed not only CD4 to gain entry to T-lymphocytes, but also a second receptor. However, it would be a decade before anyone discovered what that receptor was.
“1996 was a big year for HIV research. Not only was that second receptor, CCR5, finally identified by a number of labs — but combination anti-retroviral therapy came in and death rates from AIDS dropped by 75 per cent.”
The holy grail of HIV research is to develop a vaccine, and for the last 20 years this has been Robin’s main focus, in particular looking at humoral immunity — the identification of antibodies which ‘neutralise’, or inactivate, HIV.
“Neutralising activity of our antibodies against HIV is very weak, and that’s because HIV strains are very variable across the world — even more so than flu. However, since every HIV strain binds to CD4, we thought that it might offer a way for us to target them all. Unfortunately it didn’t turn out to be that simple. The HIV envelope has a protective carapace of carbohydrates like a tortoise’s shell, and the CD4 binding site sits inside a tiny cavity which makes it hard for antibodies to get in and do their job,” explains Robin.
Llamas to the rescue
Llamas and camels are unlikely heroes in the fight against HIV, but for the past seven years the MRC has been funding Robin, working with llama antibody expert Theo Verrips at Utrecht University, to research llama antibody fragments.
Because these are just a tenth of the size of human antibodies they are able to penetrate small spaces like the one the CD4 receptor sits in. Developing tiny antibody-like molecules based on llamas has applications for new HIV diagnostics, as tools for vaccine design and for development of vaginal microbicides to protect women from catching HIV from infected partners.
The vaccine part of this research is now being carried out by a large international consortium run by Robin and funded by the Bill and Melinda Gates Foundation, while the microbicide part is being financed by a European Framework grant overseen by Professor Charles Kelly at King’s College London.
End of an era
Of his 30-year relationship with the MRC, Robin says: “I’m tremendously grateful to the MRC for its support over the years. But, as I’m sure the MRC will testify, I am not averse to biting the hand that feeds me — I’ve been outspoken and forthright when I don’t agree with the MRC’s policies!”
Robin turns 73 this month, but even though he’s retiring from the lab he isn’t ready to hang up his leather elbow patches quite yet. He plans to continue teaching and working in an advisory capacity. As he puts it: “I’m closing my lab, but I shan’t be closing my mind or my mouth!”