Corpus Christi College Oxford

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Student publication in J Virology

Mia Milne (2012, Biochemistry) who graduated from Corpus in July 2016 and Anna-Janina Behrens (2014, DPhil Biochemistry, Chris Scanlan Scholar) have had their paper Molecular architecture of the cleavage-dependent mannose patch on a soluble HIV-1 envelope glycoprotein trimer Anna-Janina Behrens, David Harvey, Emilia Milne, Albert Cupo, Abhinav Kumar, Nicole Zitzmann, Weston Struwe, John Moore, and Max Crispin published in the Journal of Virology


The importance of the study is set out here:

The envelope spike of the human immunodeficiency virus (HIV-1) is a target for antibody-based neutralization. In some patients infected with HIV-1, highly potent antibodies have been isolated that can neutralize a wide range of circulating viruses. It is a goal of HIV-1 vaccine research to elicit these antibodies by immunization with recombinant mimics of the viral spike. These antibodies have evolved to recognize the dense array of glycans that coat the surface of the viral molecule. The paper show's how the structure of these glycans are shaped by steric constraints imposed upon them by the native folding of the viral spike. This information is important in guiding the development of vaccine candidates.


Formal Abstract:

The formation of a correctly folded and natively glycosylated HIV-1 viral spike is dependent on protease cleavage of the gp160 precursor protein in the Golgi apparatus. Cleavage induces a compact structure, which not only renders the spike capable of fusion but also limits further maturation of its extensive glycosylation. The redirection of the glycosylation pathway to preserve underprocessed oligomannose-type glycans is an important feature in immunogen design as glycans contribute to or influence the epitopes of numerous broadly neutralizing antibodies. Here, we compare quantitative site-specific analysis of a recombinant, trimeric mimic of the native HIV-1 viral spike (BG505 SOSIP.664) to the corresponding uncleaved pseudotrimer and the matched gp120 monomer. We present a detailed molecular map of trimer-associated glycan remodelling which forms a localised subdomain of the native mannose patch. The formation of native trimers is a critical design feature in shaping the glycan epitopes presented on recombinant vaccine candidates.



Figure legend: Heat map on the surface of the trimer showing the increase in oligomannose glycans of BG505 SOSIP.664 trimers compared to (A) gp120 monomers and (B) uncleaved pseudotrimers. The increase in oligomannose content was calculated for sites where quantitative data were available. To derive the heat map, a percentage point is calculated at each glycosylation site corresponding to the arithmetic difference of two percentages; the percentage of oligomannose-type glycan for each of these sites on gp120 monomers or uncleaved (WT.SEKS) pseudotrimers was subtracted from the corresponding percentage for SOSIP.664 trimers.

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