The discovery of antibodies that bind to a hitherto unknown 鈥渨eak spot鈥� on HIV has revived hopes that a potent vaccine is within reach.
Now that the weak spot 鈥� common to many strains 鈥� has been discovered, researchers can aim for vaccines that trick people into making their own antibodies to target it.
鈥淚t鈥檚 the discovery of the target that鈥檚 the key thing,鈥� says Wayne Koff, senior vice president of research and development at the in New York, and a key member of the team reporting the breakthrough.
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Vaccine developers have been beset by one failure after another. One explanation for the failures is that HIV rapidly mutates to escape detection by the immune system. As a result, many of the mutated strains are no longer recognised by antibodies.
But lab tests show the new antibodies bind to many more strains and variants of HIV than usual, potentially giving patients protection against any strains that infect them, or any new mutants that evolve in their own bodies.
Binding site
Led by Dennis Burton of the Scripps Research Institute in La Jolla, California, the team screened blood from 1800 infected individuals for antibodies.
They found that about 10 per cent of the donors made so-called 鈥渂roadly-neutralising antibodies鈥� (bNAbs) that recognise multiple strains of HIV. Eventually the researchers whittled these down to two extremely potent antibodies 鈥� both from the same African donor 鈥� that massively outperformed the others.
One, codenamed PG9, neutralised 127 of 162 HIV strains and the other, codenamed PG16, neutralised 119.
More importantly, detailed lab analyses revealed exactly which part of the virus the antibodies recognised, and it turned out to be a region hitherto unrecognised as a binding site.
Linked units
It was a region on gp120, the protein that forms 鈥渟pikes鈥� on the surface of the virus, and which enables the virus to bind to and infect a cell.
Even more important, the binding site was on a variant of gp120 that consists of three linked units of gp120 鈥� a so-called trimer.
This variant is the way gp120 appears on the virus itself and on infected cells 鈥� and therefore the way it will appear to someone鈥檚 immune system. By contrast, most previous searches for potent antibodies have focused on whether they attach to a single unit of gp120, called a monomer.
In lab tests, neither of the new antibodies bound to the monomer, demonstrating that their potency would have been missed if they鈥檇 been subjected to this standard screening test.
Common element
Now, thanks to the antibodies, researchers have realised that the trimer is a viral weak spot because it鈥檚 indispensable to the virus. So unlike many other targets on the virus, it鈥檚 shared by many, if not all, strains of HIV.
鈥淭he key is the trimer,鈥� says Koff. 鈥淥ur hypothesis now is that if you bind to the trimer, you neutralise the virus, as that鈥檚 how it appears on the surface of the virus.鈥�
The antibodies are only a starting point, however, and the race is on now to develop synthetic vaccines that have the same shape as the 鈥渨eak spot鈥�, or epitope, so people receiving vaccinations make antibodies that recognise it when the real virus comes along.
More weak spots
鈥淭he identity of this epitope is a major advance and will lead many groups to explore ways to produce new vaccines,鈥� says of the Beth Israel Deaconess Medical Center in Boston, Massachusetts, and leader of a recent study exploring why one of the leading vaccine candidates was a failure. 鈥淚t shows exactly the site on HIV that broadly neutralising antibodies can target.鈥�
Koff says follow-up studies are now under way at IAVI鈥檚 Neutralizing Antibody Center at Scripps 鈥� due to open officially on 24 September 鈥� to screen for more broadly neutralising antibodies, hopefully revealing yet more sites on the viral anatomy that are indispensable.
鈥淭he expectation is that we鈥檒l find more,鈥� he says. 鈥淲e hope there will be a number of sites that are vulnerable, and we鈥檒l know that in a few months鈥� time.鈥�
It is impossible to predict when the first vaccines targeting 鈥渨eak spots鈥� might go into trials. But Koff says: 鈥淲e鈥檙e cautiously optimistic we鈥檙e now turning in the right direction.鈥�
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