Neutralisation of HIV-1 cell-cell spread by human and llama antibodies

Retrovirology

Clare Jolly³  Robin A Weiss³  Lucy Rutten²  Theo Verrips²  Hans de Haard¹  Christophe Blanchetot¹  Elisabetta Groppelli³  Laura E McCoy⁴ 

[1] ArGEN-X BVBA, Zwijnaarde, Ghent, Belgium;QVQ bv, Utrecht, 3584CH, The Netherlands;Division of Infection and Immunity, University College London, London WC1E 6BT, United Kingdom;Current address: Department of Immunology and Microbial Science, The Scripps Research Institute, La Jolla 92037, CA, USA

关键词: VHH;    CD4;    Neutralisation;    Cell-cell;    Virological synapse;    Antibody;    HIV-1;   

Others  :  1152286
DOI  :  10.1186/s12977-014-0083-y

 received in 2014-05-12, accepted in 2014-09-08,  发布年份 2014

【 摘 要 】

Background

Direct cell-cell spread of HIV-1 is a very efficient mode of viral dissemination, with increasing evidence suggesting that it may pose a considerable challenge to controlling viral replication in vivo. Much current vaccine research involves the study of broadly neutralising antibodies (bNabs) that arise during natural infection with the aims of eliciting such antibodies by vaccination or incorporating them into novel therapeutics. However, whether cell-cell spread of HIV-1 can be effectively targeted by bNabs remains unclear, and there is much interest in identifying antibodies capable of efficiently neutralising virus transmitted by cell-cell contact.

Results

In this study we have tested a panel of bNAbs for inhibition of cell-cell spread, including some not previously evaluated for inhibition of this mode of HIV-1 transmission. We found that three CD4 binding site antibodies, one from an immunised llama (J3) and two isolated from HIV-1-positive patients (VRC01 and HJ16) neutralised cell-cell spread between T cells, while antibodies specific for glycan moieties (2G12, PG9, PG16) and the MPER (2F5) displayed variable efficacy. Notably, while J3 displayed a high level of potency during cell-cell spread we found that the small size of the llama heavy chain-only variable region (VHH) J3 is not required for efficient neutralisation since recombinant J3 containing a full-length human heavy chain Fc domain was significantly more potent. J3 and J3-Fc also neutralised cell-cell spread of HIV-1 from primary macrophages to CD4+ T cells.

Conclusions

In conclusion, while bNabs display variable efficacy at preventing cell-cell spread of HIV-1, we find that some CD4 binding site antibodies can inhibit this mode of HIV-1 dissemination and identify the recently described llama antibody J3 as a particularly potent inhibitor. Effective neutralisation of cell-cell spread between physiologically relevant cell types by J3 and J3-Fc supports the development of VHH J3 nanobodies for therapeutic or prophylactic applications.

【 授权许可】

   
2014 McCoy et al.; licensee BioMed Central Ltd.

【 图 表 】

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