The Regulated Secretory Pathway in CD4+ T cells Contributes to Human Immunodeficiency Virus Type-1 Cell-to-Cell Spread at the Virological Synapse

Clare Jolly,Quentin J Sattentau,Stefanie Michor,Sonja Welsch,Thomas Hope

doi:10.1371/journal.ppat.1002226

Abstract

Direct cell-cell spread of Human Immunodeficiency Virus type-1 (HIV-1) at the virological synapse (VS) is an efficient mode of dissemination between CD4+ T cells but the mechanisms by which HIV-1 proteins are directed towards intercellular contacts is unclear. We have used confocal microscopy and electron tomography coupled with functional virology and cell biology of primary CD4+ T cells from normal individuals and patients with Chediak-Higashi Syndrome and report that the HIV-1 VS displays a regulated secretion phenotype that shares features with polarized secretion at the T cell immunological synapse (IS). Cell-cell contact at the VS re-orientates the microtubule organizing center (MTOC) and organelles within the HIV-1-infected T cell towards the engaged target T cell, concomitant with polarization of viral proteins. Directed secretion of proteins at the T cell IS requires specialized organelles termed secretory lysosomes (SL) and we show that the HIV-1 envelope glycoprotein (Env) localizes with CTLA-4 and FasL in SL-related compartments and at the VS. Finally, CD4+ T cells that are disabled for regulated secretion are less able to support productive cell-to-cell HIV-1 spread. We propose that HIV-1 hijacks the regulated secretory pathway of CD4+ T cells to enhance its dissemination.

Highlights

Viral replication is a complex series of well-orchestrated events culminating in the release of progeny virions from infected cells
We show that Human Immunodeficiency Virus type-1 (HIV-1) proteins associate with cellular compartments that are involved in regulated secretion and that CD4+ T cells from patients with a genetic defect in this pathway are less able to support spreading infection
We conclude that HIV-1 hijacks elements of the T cell regulated secretory pathway to promote T cell-to-T cell transmission at virological synapses

Summary

Introduction

Viral replication is a complex series of well-orchestrated events culminating in the release of progeny virions from infected cells. It is becoming increasingly clear that cell-to-cell spread is an important mechanism of viral dissemination [1] and has a number of advantages for viruses, including more rapid and efficient uptake by permissive target cells. This process requires an exquisite level of regulation to polarize virus assembly and release towards engaged target cells at sites of cell-cell contact. Direct spread of Human Immunodeficiency Virus type-1 (HIV-1) between CD4+ T cells takes place across a supramolecular structure called the ‘‘virological synapse’’ (VS) [2]. Once at the VS, cell-to-cell spread of HIV-1 is by polarized assembly and budding of virions into the synaptic cleft and subsequent fusion with the target cell plasma membrane either at the cell surface or from within an endosomal compartment [9,10]

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