The infectious synapse formed between mature dendritic cells and CD4+T cells is independent of the presence of the HIV-1 envelope glycoprotein

Maria T Rodriguez-Plata,Javier Martinez-Picado,Itziar Erkizia,Jorge Carrillo,Bonaventura Clotet,Isabel Puigdomènech,Nuria Izquierdo-Useros,Maria C Puertas,Julià Blanco

doi:10.1186/1742-4690-10-42

Abstract

BackgroundSince cell-mediated infection of human immunodeficiency virus type 1 (HIV-1) is more efficient than cell-free infection, cell-to-cell propagation plays a crucial role in the pathogenesis of HIV-1 infection. Transmission of HIV-1 is enabled by two types of cellular contacts, namely, virological synapses between productively infected cells and uninfected target cells and infectious synapses between uninfected dendritic cells (DC) harboring HIV-1 and uninfected target cells. While virological synapses are driven by expression of the viral envelope glycoprotein on the cell surface, little is known about the role of envelope glycoprotein during contact between DC and T cells. We explored the contribution of HIV-1 envelope glycoprotein, adhesion molecules, and antigen recognition in the formation of conjugates comprising mature DC (mDC) and CD4+ T cells in order to further evaluate their role in mDC-mediated HIV-1 transmission at the immunological synapse.ResultsUnlike virological synapse, HIV-1 did not modulate the formation of cell conjugates comprising mDC harboring HIV-1 and non-activated primary CD4+ T cells. Disruption of interactions between ICAM-1 and LFA-1, however, resulted in a 60% decrease in mDC-CD4+ T-cell conjugate formation and, consequently, in a significant reduction of mDC-mediated HIV-1 transmission to non-activated primary CD4+ T cells (p < 0.05). Antigen recognition or sustained MHC-TcR interaction did not enhance conjugate formation, but significantly boosted productive mDC-mediated transmission of HIV-1 (p < 0.05) by increasing T-cell activation and proliferation.ConclusionsFormation of the infectious synapse is independent of the presence of the HIV-1 envelope glycoprotein, although it does require an interaction between ICAM-1 and LFA-1. This interaction is the main driving force behind the formation of mDC-CD4+ T-cell conjugates and enables transmission of HIV-1 to CD4+ T cells. Moreover, antigen recognition boosts HIV-1 replication without affecting the frequency of cellular conjugates. Our results suggest a determinant role for immune activation driven by mDC-CD4+ T-cell contacts in viral dissemination and that this activation likely contributes to the pathogenesis of HIV-1 infection.

Highlights

Since cell-mediated infection of human immunodeficiency virus type 1 (HIV-1) is more efficient than cell-free infection, cell-to-cell propagation plays a crucial role in the pathogenesis of HIV-1 infection
Our results suggest a determinant role of contact between mature DC (mDC) and CD4+ T cells in immune activation and viral dissemination, which likely contribute to the pathogenesis of HIV-1 infection
MDC-mediated HIV-1 trans-infection of primary CD4+ T cells is dependent on the interaction between intercellular adhesion molecule 1 (ICAM-1) and Leukocyte function-associated antigen 1 (LFA-1) and is enhanced by antigen recognition Once we confirmed that ICAM-1 and LFA-1 and not HIV-1 or antigen recognition modulate the formation of mDC-CD4+ T-cell conjugates, we investigated the role of these factors in mDC-mediated HIV-1 trans-infection of primary CD4+ T cells

Summary

Introduction

Since cell-mediated infection of human immunodeficiency virus type 1 (HIV-1) is more efficient than cell-free infection, cell-to-cell propagation plays a crucial role in the pathogenesis of HIV-1 infection. We explored the contribution of HIV-1 envelope glycoprotein, adhesion molecules, and antigen recognition in the formation of conjugates comprising mature DC (mDC) and CD4+ T cells in order to further evaluate their role in mDC-mediated HIV-1 transmission at the immunological synapse. The immunological synapse provides sustained T-cell signaling, leading to T-cell priming and TcR downregulation [6,7]. This specialized synapse consists of a highly stable and organized area of contact between the APC and the T cell, where the pMHC-TcR interaction, adhesion molecules, and co-stimulatory molecules play a major role [8,9]

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