The Achilles Heel of the Trojan Horse Model of HIV-1 trans-Infection

Marielle Cavrois,Warner C Greene,Jason Neidleman,B Brett Finlay

doi:10.1371/journal.ppat.1000051

Marielle Cavrois, Warner C Greene + Show 2 more

Open Access

https://doi.org/10.1371/journal.ppat.1000051

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Abstract

To ensure their survival, microbial pathogens have evolved diverse strategies to subvert host immune defenses. The human retrovirus HIV-1 has been proposed to hijack the natural endocytic function of dendritic cells (DCs) to infect interacting CD4 T cells in a process termed trans-infection. Although DCs can be directly infected by certain strains of HIV-1, productive infection of DCs is not required during trans-infection; instead, DCs capture and internalize infectious HIV-1 virions in vesicles for later transmission to CD4 T cells via vesicular exocytosis across the infectious synapse. This model of sequential endocytosis and exocytosis of intact HIV-1 virions has been dubbed the “Trojan horse” model of HIV-1 trans-infection. While this model gained rapid favor as a strong example of how a pathogen exploits the natural properties of its cellular host, our recent studies challenge this model by showing that the vast majority of virions transmitted in trans originate from the plasma membrane rather than from intracellular vesicles. This review traces the experimental lines of evidence that have contributed to what we view as the “rise and decline” of the Trojan horse model of HIV-1 trans-infection.

Highlights

Dendritic cells (DCs) play a central role in initiating the adaptive immune response that counters pathogen infection
In addition to replicating at low levels in DCs, HIV-1 has been proposed to exploit these cells for a novel form of viral spread involving the initial capture and internalization of intact virions, followed later by the transfer of virions across synapses formed by CD4 T cells scanning the DCs for cognate antigen
PLoS Pathogens | www.plospathogens.org between interacting CD4 T cells and DCs [21]. These studies gave rise to the widely accepted concept of the ‘‘Trojan horse’’ model of trans-infection in which exocytosis of virion-laden vesicles into the synapse promoted highly efficient infection of CD4 T cells

Summary

Introduction

Dendritic cells (DCs) play a central role in initiating the adaptive immune response that counters pathogen infection. In addition to replicating at low levels in DCs, HIV-1 has been proposed to exploit these cells for a novel form of viral spread involving the initial capture and internalization of intact virions, followed later by the transfer of virions across synapses formed by CD4 T cells scanning the DCs for cognate antigen. This mechanism of viral spread is termed trans-infection. These studies gave rise to the widely accepted concept of the ‘‘Trojan horse’’ model of trans-infection in which exocytosis of virion-laden vesicles into the synapse promoted highly efficient infection of CD4 T cells

Diversity of DC Receptors Involved in transInfection

Mature MDDCs

Findings

Internalization Is Likely a Dead End for transInfection