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
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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