Regulation of Mycobacterium tuberculosis-Dependent HIV-1 Transcription Reveals a New Role for NFAT5 in the Toll-Like Receptor Pathway

Shahin Ranjbar,Nancy Chow,Anne E Goldfeld,Luke D Jasenosky,Vojo Deretic

doi:10.1371/journal.ppat.1002620

Shahin Ranjbar, Nancy Chow + Show 3 more

Open Access

https://doi.org/10.1371/journal.ppat.1002620

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Journal: PLoS Pathogens	Publication Date: Apr 5, 2012
Citations: 106	License type: CC BY 4.0

Affiliation: Boston Children's Hospital, Harvard University

Abstract

Tuberculosis (TB) disease in HIV co-infected patients contributes to increased mortality by activating innate and adaptive immune signaling cascades that stimulate HIV-1 replication, leading to an increase in viral load. Here, we demonstrate that silencing of the expression of the transcription factor nuclear factor of activated T cells 5 (NFAT5) by RNA interference (RNAi) inhibits Mycobacterium tuberculosis (MTb)-stimulated HIV-1 replication in co-infected macrophages. We show that NFAT5 gene and protein expression are strongly induced by MTb, which is a Toll-like receptor (TLR) ligand, and that an intact NFAT5 binding site in the viral promoter of R5-tropic HIV-1 subtype B and subtype C molecular clones is required for efficent induction of HIV-1 replication by MTb. Furthermore, silencing by RNAi of key components of the TLR pathway in human monocytes, including the downstream signaling molecules MyD88, IRAK1, and TRAF6, significantly inhibits MTb-induced NFAT5 gene expression. Thus, the innate immune response to MTb infection induces NFAT5 gene and protein expression, and NFAT5 plays a crucial role in MTb regulation of HIV-1 replication via a direct interaction with the viral promoter. These findings also demonstrate a general role for NFAT5 in TLR- and MTb-mediated control of gene expression.

Highlights

Mycobacterium tuberculosis (MTb), the causative agent of tuberculosis (TB), is the most common co-infection and cause of death in patients infected with human immunodeficiency virus type 1 (HIV-1) [1,2]
We present evidence that the transcription factor nuclear factor of activated T cells 5 (NFAT5) plays a crucial role in MTb-induced HIV-1 replication in human peripheral blood cells and monocytes
We show that MTb infection itself stimulates NFAT5 gene expression in human monocytes and that its expression involves the toll-like receptor (TLR) signalling pathway and requires the downstream adaptor proteins MyD88, IRAK1, and TRAF6

Summary

Introduction

Mycobacterium tuberculosis (MTb), the causative agent of tuberculosis (TB), is the most common co-infection and cause of death in patients infected with human immunodeficiency virus type 1 (HIV-1) [1,2]. Inflammatory cytokines and chemokines produced by the human host in response to MTb infection activate signal transduction pathways in CD4 T cells and monocytic cells that result in transcriptional activation of the HIV-1 LTR [4,5,6]. Activation of HIV-1 replication via these MTb-induced pathways leads to higher viral loads and, in turn, expedited CD4 T cell loss and progression to AIDS ([7], reviewed in [8,9,10]). TRAF6 activates IkB kinase (IKK) and mitogenactivated protein (MAP) kinases that, in turn, induce activation of specific transcription factor families, including the NF-kB and AP-1 families, which have been shown to associate with the HIV-1 LTR and to drive its transcription ([22,25,26,27], reviewed in [10])

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