Abstract
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. 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. 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.
Highlights
Direct cell-cell spread of Human Immunodeficiency Virus Type-1 (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
T cell-T cell spread of HIV-1 is sensitive to antibodymediated inhibition We compared a group of broadly neutralising antibodies (bNabs) targeting different epitopes on HIV-1 envelope protein (Env) for their ability to inhibit cell-cell spread of HIV-1 between T cells
We find that J3, a highly broadly neutralising llama antibody induced by immunisation that targets the CD4 binding site can potently neutralise cell-cell HIV-1 spread between physiologically relevant human cell types including T cells and macrophages
Summary
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. Much HIV-1 vaccine research involves the study of broadly neutralising antibodies (bNabs) that arise in certain patients with the [9,10,11,12,13,14], with the increased infection kinetics of cell-cell spread attributed to a combination of factors including polarised budding of the virus towards the target cell, receptor clustering on the target cell enriching for viral entry receptors, and the close physical contact between cells limiting the requirement for prolonged virus diffusion [5,10,14,15]. Cell-cell spread of HIV-1 has been suggested to be a means by which HIV-1 may evade neutralising antibodies, and it has been reported that antibodies targeting the CD4 binding site are less able to neutralise infection by cell-cell spread than antibodies targeting other sites on HIV-1 [18]
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