Enhancing biological mimicry in HIV vaccine design
The antigenic protein surface of HIV (blue) is covered by the host-cell derived glycan shield (green). The sugars of HIV form a dense network of sugar-sugar interactions on the surface, packed together like trees in a forest.
A group of researchers in the Biochemistry Department has shown how it might be possible to exploit a weakness in the evasive strategies of Human Immunodeficiency Virus (HIV) to develop an effective vaccine against it.
University Researcher Lecturer Dr Chris Scanlan, along with Cameron Dunlop and Dr Max Crispin in his group, and colleagues in the Department's Glycobiology Institute, at Imperial College and at the Scripps Institute in the US, have recently published their findings in Glycobiology (1).
The key to their discoveries is the carbohydrate or sugar coating in which the HIV cloaks itself.
Most proteins on the surface of a cell have carbohydrates on them which are added as the newly-synthesised protein makes its way out of the cell. The proteins in HIV's envelope also acquire these carbohydrates before virus buds off from the infected cell.
“Most of the antigenic surface of HIV is covered by carbohydrates,” explains Dr Scanlan. “It's often called the glycan shield. The virus needs to be continually evading the immune system and this shield is perhaps its most effective strategy.”
“It's almost like HIV has overcooked it.”
As well as the shield, which allows the virus to go unseen in the body for very long periods of time, the host's immune system also has to contend with a virus that manages to stay one step ahead of it through mutational changes in the viral proteins.
The exceptionally dense packing of the carbohydrates on HIV's coat turns out to be a possible Achilles' Heel of the virus. As Dr Scanlan remarks, “it's almost like HIV has overcooked it.”
The carbohydrates on HIV's proteins are so densely packed that there is no room for the trimming and modification that would normally take place as the protein completes its journey out of the cell. HIV's proteins therefore retain their immature 'internal' carbohydrates – a carbohydrate array made up of mannose sugar residues.
This presents an opportunity for the immune system to 'see' a virus-specific signature on the cell. And unlike the constantly changing viral proteins, this carbohydrate structure is relatively fixed. 'You have "self-sugars" but they are in the wrong place,' explains Dr Scanlan. 'You would never normally see these internal-type sugars on the surface. They are available to the immune system for recognition.'
So are antibodies against these mannose sugars ever seen in patients? The answer is yes, but very rarely, because the HIV sugars unfortunately turn out to be poor at eliciting antibodies in patients.
One such antibody that has been isolated from patients is, as expected, effective against a wide range of HIV subtypes. It is one of only a handful of antibodies of this type, so-called 'broadly neutralising antibodies', found in patients.
Dr Scanlan explains the wider implication of the finding: “Although the antibody is not much use in patients who've got it because the virus manages to find a way around it, if you had this antibody first, you'd be protected from infection.”
“From a vaccine perspective, when you want to start looking at something which is going to work not just here in Oxford today but in sub-Saharan Africa and elsewhere, these sugars then suddenly become quite attractive unlike the protein surfaces which change rapidly over time.”
So the challenge has been to identify carbohydrates which are most efficient at eliciting antibodies in people and could be used as a vaccine to protect people against the virus.
Dr Scanlan and colleagues have taken a biological approach to this problem. Quite co-incidentally, it turns out that the polysaccharides coating a yeast cell are similar, though not identical, to the mannose residues on HIV's coat. The group has recently shown that the sugar-specific neutralising antibody against HIV also binds to these yeast polysaccharides.
One of HIV's sugars showing the tips of the branches (red) which the immune system can recognise and which happen to be similar to sugar structures found on yeast polysaccharides.
This has opened up the possibility of exploiting the mimicry of yeast to develop a vaccine. “If we can get defined polysaccharide structures that mimic HIV, this may be a route to immunisation,” says Dr Scanlan.
The group's recent paper in Glycobiology describes its attempt at altering the configuration of the yeast polysaccharides so that they resembles the structure of the HIV mannose residues more closely.
Dr Scanlan explains: “We did a very simple experiment. We took a natural yeast which looks slightly different from the HIV mannose structure and a yeast genetically modified to display polysaccharides that look a bit more like HIV sugars.”
When the researchers tested the antibodies raised against the two strains of yeast they found that only the antibodies against the modified yeast recognised the HIV mannose structure. These antibodies were also more effective at preventing HIV infection in a cell-culture model of infection.
The results suggest how it may be possible to generate an immune response that could protect against HIV. “We can now go through cycles to improve this further, and try and make it look more and more like HIV. We can see if we can bring the protection up to a higher level,” explains Dr Scanlan.
He is cautiously optimistic about developing this through to a preventative vaccine. “In terms of an AIDS vaccine, the responses we see are the kind we want – we just need more of them. An optimally modified polysaccharide structure would generate antibodies that would form a long-lived or memory response. You'd then be protected against infection.”
With an estimated 2 million deaths globally from AIDS in recent years, a vaccine is needed now as much as ever.
Dr Scanlan emphasises the stark reality of the situation. “Unfortunately, once you've got HIV you're probably stuck with it. There's no plausible mechanism, at least not at the moment, for clearing infection once it's in. So the only way you can really hit it in terms of sterilizing vaccination is to get it before it gets in. Any strategy based on clearing infected cells is kind of shutting the stable door after the horse has bolted.”
This work was supported by International AIDS Vaccine Initiative (IAVI), and Oxford Glycobiology Endowment and the Wellcome Trust.
1.'Polysaccharide mimicry of the epitope of the broadly neutralising anti-HIV antibody, 2G12, induces enhanced antibody responses to self oligomannose glycans'. Dunlop, D. C. et. al. Glycobiology 2010. (http://glycob.oxfordjournals.org/cgi/reprint/cwq020v1)