Toll-Like Receptor 3 Signalling Up-Regulates Expression of the HIV Co-Receptor G-Protein Coupled Receptor 15 on Human CD4+ T Cells

Miriam Kiene,Rebecka Lantto,Marianne Jansson,Bence Rethi,Stephanie Dillon,Francesca Chiodi,Cara Wilson,Stefan Pöhlmann,Eric Lee

doi:10.1371/journal.pone.0088195

Abstract

BackgroundMany HIV-2 and SIV isolates, as well as some HIV-1 strains, can use the orphan 7-transmembrane receptor GPR15 as co-receptor for efficient entry into host cells. GPR15 is expressed on central memory and effector memory CD4+ T cells in healthy individuals and a subset of these cells is susceptible to HIV-1 and SIV infection. However, it has not been determined whether GPR15 expression is altered in the context of HIV-1 infection.ResultsHere, we show that GPR15 expression in CD4+ T cells is markedly up-regulated in some HIV-1 infected individuals compared to the rest of the infected patients and to healthy controls. Infection of the PM1 T cell line with primary HIV-1 isolates was found to up-regulate GPR15 expression on the infected cells, indicating that viral components can induce GPR15 expression. Up-regulation of GPR15 expression on CD4+ T cells was induced by activation of Toll-like receptor 3 signalling via TIR-domain-containing adapter-inducing interferon-β (TRIF) and was more prominent on gut-homing compared to lymph node-homing CD4+ T cells.ConclusionThese results suggest that infection-induced up-regulation of GPR15 expression could increase susceptibility of CD4+ T cells to HIV infection and target cell availability in the gut in some infected individuals.

Highlights

The envelope glycoprotein (Env) of the simian and human immunodeficiency virus (HIV and SIV) mediates host cell entry
It is conceivable that targeting of CCR5 and CXCR4 [17] during HIV-1 antiretroviral therapy could potentially select for viruses which either use CCR5/CXCR4 in the drug-bound state or engage alternative co-receptors for entry
A similar expression pattern was observed for HIV-1 infected individuals (ART treated and non-treated individuals) (Figure 1C), with no significant differences when comparing the levels to the non-infected controls

Summary

Introduction

The envelope glycoprotein (Env) of the simian and human immunodeficiency virus (HIV and SIV) mediates host cell entry. For this purpose, Env interacts with CD4 and a co-receptor, usually CCR5 and/or CXCR4 [1]. Many HIV-2 and SIV isolates, as well as some HIV-1 strains, can use the orphan 7-transmembrane receptor GPR15 as co-receptor for efficient entry into host cells. GPR15 is expressed on central memory and effector memory CD4+ T cells in healthy individuals and a subset of these cells is susceptible to HIV-1 and SIV infection. It has not been determined whether GPR15 expression is altered in the context of HIV-1 infection

Methods

Results

Conclusion