2G12-expressing B cell lines may aid in HIV carbohydrate vaccine design strategies.

Title2G12-expressing B cell lines may aid in HIV carbohydrate vaccine design strategies.
Publication TypeJournal Article
Year of Publication2013
AuthorsDoores KJ, Huber M, Le KM, Wang S-K, Doyle-Cooper C, Cooper A, Pantophlet R, Wong C-H, Nemazee D, Burton DR
JournalJ Virol
Volume87
Issue4
Pagination2234-41
Date Published02/01/2013
ISSN1098-5514
KeywordsAIDS Vaccines, Animals, Antibodies, Monoclonal, B-Lymphocytes, Carbohydrates, Cell Line, Drug Discovery, Gene Expression, HIV Envelope Protein gp120, HIV-1, Lymphocyte Activation, Mice
Abstract

The highly conserved cluster of high-mannose glycans on the HIV-1 envelope glycoprotein, gp120, has been highlighted as a target for neutralizing antibodies. 2G12, the first HIV-1 antiglycan neutralizing antibody described, binds with an unusual domain-exchanged structure that creates a high-affinity multivalent binding surface. It is an interesting challenge for rational vaccine design to generate immunogens capable of eliciting domain-exchanged 2G12-like responses. We recently showed that di-mannose recognition by the variable domains of 2G12 is independent of domain exchange but that exchange is critical for virus neutralization. Carbohydrate-based immunogens aimed at inducing 2G12-like antibodies may need to drive both di-mannose recognition and domain exchange through interactions with B cell receptors. Here we assessed the ability of such immunogens to activate mouse B cell lines displaying domain-exchanged wild-type 2G12 (2G12 WT), a non-domain-exchanged Y-shaped variant (2G12 I19R), and germ line 2G12 (2G12 gl). We show that several immunogens, including heat-killed yeast and bacteria, can activate both 2G12 WT and 2G12 I19R B cells. However, only discrete clusters of high-mannose glycans, as on recombinant forms of the HIV-1 envelope trimer and oligodendrons, activate 2G12 WT B cells. Furthermore, no immunogen tested activated 2G12 gl cells. Our results support the hypothesis that in order to drive domain exchange of an antimannose antibody response, a boost with an immunogen displaying discrete clusters of high-mannose glycans not recognized by conventional Y-shaped antibodies will be required. Additionally, a molecule capable of activating 2G12 gl cells might also be required. The results highlight broadly neutralizing antibody-expressing mouse B cells as potentially useful tools for carbohydrate immunogen screening.

DOI10.1128/JVI.02820-12
Alternate JournalJ. Virol.
PubMed ID23221565
PubMed Central IDPMC3571453
Grant List5R01 AI033292 / AI / NIAID NIH HHS / United States
5U01 AI078224 / AI / NIAID NIH HHS / United States
AI073148 / AI / NIAID NIH HHS / United States
R01 AI072155 / AI / NIAID NIH HHS / United States
UM1AI100663 / AI / NIAID NIH HHS / United States
CHAVI-ID: 
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