Cell-Cell Transmission Enables HIV-1 to Evade Inhibition by Potent CD4bs Directed Antibodies

Alexandra Trkola,Lucy Reynell,Peter Rusert,Irene A. Abela,Huldrych F. Günthard,Livia Berlinger,Merle Schanz

doi:10.1371/journal.ppat.1002634

Alexandra Trkola, Lucy Reynell + Show 5 more

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https://doi.org/10.1371/journal.ppat.1002634

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Abstract

HIV is known to spread efficiently both in a cell-free state and from cell to cell, however the relative importance of the cell-cell transmission mode in natural infection has not yet been resolved. Likewise to what extent cell-cell transmission is vulnerable to inhibition by neutralizing antibodies and entry inhibitors remains to be determined. Here we report on neutralizing antibody activity during cell-cell transmission using specifically tailored experimental strategies which enable unambiguous discrimination between the two transmission routes. We demonstrate that the activity of neutralizing monoclonal antibodies (mAbs) and entry inhibitors during cell-cell transmission varies depending on their mode of action. While gp41 directed agents remain active, CD4 binding site (CD4bs) directed inhibitors, including the potent neutralizing mAb VRC01, dramatically lose potency during cell-cell transmission. This implies that CD4bs mAbs act preferentially through blocking free virus transmission, while still allowing HIV to spread through cell-cell contacts. Thus providing a plausible explanation for how HIV maintains infectivity and rapidly escapes potent and broadly active CD4bs directed antibody responses in vivo.

Highlights

The Human Immunodeficiency Virus (HIV) spreads in vitro very efficiently, if not preferentially, by cell-cell contacts
The relative contribution of cell-cell and cell-free virus transmission in acquisition of HIV infection and viral dissemination during human infection remain undefined. This gap in knowledge poses a conceptual problem for neutralizing antibody based HIV vaccine and entry inhibitor design, as it remains uncertain whether both cell-free and cell-cell spread of HIV must be blocked with equal efficacy, or whether only the dominant transmission mode needs to be targeted and if so which
The primary aim of our current study was to dissect the efficacy of neutralizing antibodies and entry inhibitors in the context of cell-cell transmission of HIV

Summary

Introduction

The Human Immunodeficiency Virus (HIV) spreads in vitro very efficiently, if not preferentially, by cell-cell contacts. Viral transmission from infected to non-infected cells occurs via formation of virological synapses – organized contact areas which concentrate cellular entry receptors and virions [1,2,3,4,5] - and via transient cell-cell contacts and longer-range intercellular interactions including nanotubes and filopodia [6,7,8] Virus transmission through these points of contiguity has been proven in vitro to be more efficient and rapid than infection by cell-free viruses [9,10,11,12,13,14], supporting the notion that cell-cell transmission may be a relevant if not dominant mode of virus dissemination in infected individuals. This gap in knowledge poses a conceptual problem for neutralizing antibody based HIV vaccine and entry inhibitor design, as it remains uncertain whether both cell-free and cell-cell spread of HIV must be blocked with equal efficacy, or whether only the dominant transmission mode needs to be targeted and if so which

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