Yang, YR;
McCoy, LE;
van Gils, MJ;
Andrabi, R;
Turner, HL;
Yuan, M;
Cottrell, CA;
... Ward, AB; + view all
(2020)
Autologous neutralizing antibody responses to an HIV envelope glycan hole are not easily broadened in rabbits.
Journal of Virology
10.1128/JVI.01861-19.
(In press).
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Abstract
Extensive studies with subtype A BG505-derived HIV Env immunogens have revealed that the dominant autologous neutralizing epitope in rabbits is located in an exposed region of the heavily glycosylated trimer that lacks potential N-linked glycosylation sites at positions 230, 241, and 289. The Env derived from B41, a subtype B virus, shares a glycan hole centered on positions 230 and 289. To test whether broader neutralization to the common glycan hole can be achieved, we immunized rabbits with B41 SOSIP alone, as well as B41 and BG505 co-immunization. We isolated autologous neutralizing antibodies (nAbs) and described their structure in complex with the B41 Env. Our data suggest that distinct autologous nAb lineages are induced by BG505 and B41 immunogens, even when both were administered together. In contrast to previously described BG505 glycan hole antibodies, the B41-specific nAbs accommodate the >97% conserved N241 glycan, which is present in B41. Single particle cryo-electron microscopy studies confirmed that B41 and BG505-specific nAbs bind to overlapping glycan hole epitopes. We then used our high-resolution data to guide mutations in the BG505 glycan hole epitope in an attempt to broaden the reactivity of a B41-specific nAb, but only recovered partial binding. Our data demonstrate that lack of cross-reactivity in glycan hole antibodies is due to amino acid differences within the epitope and our attempts to rationally design cross-reactive trimers resulted in only limited success. Thus, even for the immunodominant glycan hole shared between BG505 and B41 the prospect of designing prime-boost immunogens remains difficult.
| Type: | Article |
|---|---|
| Title: | Autologous neutralizing antibody responses to an HIV envelope glycan hole are not easily broadened in rabbits |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1128/JVI.01861-19 |
| Publisher version: | http://dx.doi.org/10.1128/JVI.01861-19 |
| Language: | English |
| Additional information: | © 2020 Yang et al. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license. |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Infection and Immunity |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10090635 |
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