Breaching HIV's defences
New research from Max Crispin and colleagues has confirmed a potential Achilles' heel in HIV that could be exploited for vaccine design against AIDS.
The groups' studies, published in five papers over the past four months (1-5), show that the glycosylation signature of HIV's envelope spike glycoprotein, Env, may be a promising target for vaccine design.
Env is a trimeric glycoprotein that enables the virus to enter host cells and is the primary target for neutralising antibodies. The glycans on this heavily glycosylated molecule, which are synthesised using host cell glycosylation machinery, shield the underlying protein epitopes from recognition by antibodies (3,5). Paradoxically, however, many potent broadly neutralising antibodies isolated from patients target this glycan shield.
Building on earlier work led by the late Dr Chris Scanlan, Dr Crispin and colleagues, together with Dr Katie Doores at King's College London, explored this further. Their paper in J. Virology describes the glycosylation signature of a component of the functional, cleaved Env known as gp120 (1). They found that the majority of glycans have not undergone typical cellular processing and are virus-specific with remarkably homogenous 'oligomannose-type' glycans.
This is an important discovery, as Dr Crispin explains: 'HIV is incredibly diverse - there is more virus diversity within a patient than there is diversity of the flu virus across populations. So the challenge is to find something that is conserved and non-self.'
The divergence of gp120 glycosylation from host-cell glycosylation revealed how HIV might be vulnerable to neutralising antibodies and appeared to present a new way of addressing this challenge. Supporting the presence of a glycan signature that can be targeted by antibodies is the identification of a growing number of broadly neutralising antibodies with specificity to the viral glycans.
In the Cell Reports paper, the researchers investigated the structural arrangement of the trimeric glycoprotein in collaboration with researchers at The Scripps Research Institute and Cornell (2). They found that the extent of processing correlated with the configuration of the Env glycoprotein - where there were structural barriers, there was less cellular processing leaving a largely oligomannose profile. In their studies, they showed that leading vaccine candidates, known as SOSIP trimers, contain predominantly oligomannose glycans that mimic the virus. This is important information, as it will help to prioritise leading vaccine candidates for clinical development.
Functional spikes require furin-cleavage which commits Env to form a compact structure with a high level of oligomannose-type glycans (green). From Pritchard et al. Cell Reports 2015 (Click to enlarge)
In the Nature Communications paper, the researchers teamed up with Oxfordshire-based analytics company Ludger Ltd (3). They explored the contribution of individual glycosylation sites to formation of the oligomannose region and the impact on recognition by a panel of broadly neutralising antibodies targeting this region. The group found that even when some sites are lost, the effect on the oligomannose region is limited and that the antibodies largely tolerate the subsequent structural changes.
In a further paper in J.Virology, they show how the glycan heterogeneity can explain how certain viruses with identical genomes differ in their sensitivity to broadly neutralising antibodies (4).
Overall, their work supports the use of the oligomannose region as a stable, exploitable region for vaccine development and will help in the design of future candidate immunogens. Dr Crispin and Dr Doores have summarised the current efforts towards a carbohydrate-based vaccine against HIV in a review in Current Opinions in Virology (5).
For Dr Crispin, the next steps will be to explore how to enhance the immune response to these glycans. He adds: 'A picture is emerging that the antibodies against these viral glycans will have to be elicited as part of an effective vaccine. We need to find a way to trick the immune system into recognising these self-like structures.'
Dr Crispin and his team are funded by the International AIDS Vaccine Initiative Neutralizing Antibody Consortium (IAVI NAC), through a grant from the Collaboration for AIDS Vaccine Discovery (CAVD), and the Scripps Center for HIV/AIDS Vaccine Immunology & Immunogen Discovery (CHAVI-ID).
Whilst at a recent AIDS conference, Dr Crispin was asked to appear in a video put together by HIV/AIDS organisations and initiatives to mark HIV Vaccine Awareness Day (18 May). The video features short clips of researchers including Dr Crispin explaining their commitment to helping find a vaccine.
Cellular and protein-directed glycosylation of native cleaved HIV-1 envelope. Pritchard LK, Harvey DJ, Bonomelli C, Crispin M, Doores KJ. J Virol. 2015 Jun 17. pii: JVI.01190-15. [Epub ahead of print]
Structural Constraints Determine the Glycosylation of HIV-1 Envelope Trimers.Pritchard LK, Vasiljevic S, Ozorowski G, Seabright GE, Cupo A, Ringe R, Kim HJ, Sanders RW, Doores KJ, Burton DR, Wilson IA, Ward AB, Moore JP, Crispin M. Cell Rep. 2015 Epub 2015 Jun 4.
Glycan clustering stabilizes the mannose patch of HIV-1 and preserves vulnerability to broadly neutralizing antibodies. Pritchard LK, Spencer DI, Royle L, Bonomelli C, Seabright GE, Behrens AJ, Kulp DW, Menis S, Krumm SA, Dunlop DC, Crispin DJ, Bowden TA, Scanlan CN, Ward AB, Schief WR, Doores KJ, Crispin M. Nat Commun. 2015 Jun 24;6:7479. doi: 10.1038/ncomms8479.
Glycan Microheterogeneity at the PGT135 Antibody Recognition Site on HIV-1 gp120 Reveals a Molecular Mechanism for Neutralization Resistance. PritchardLK, Spencer DI, Royle L, Vasiljevic S, Krumm SA, Doores KJ, Crispin M. J Virol. 2015 Jul 1;89(13):6952-9. doi: 10.1128/JVI.00230-15. Epub 2015 Apr 15.
Targeting host-derived glycans on enveloped viruses for antibody-based vaccine design. Crispin M, Doores KJ. Curr Opin Virol. 2015 Apr;11:63-69. Epub 2015 Mar 6.