1. Regulation of Mycobacterium tuberculosis-Dependent HIV-1 Transcription Reveals a New Role for NFAT5 in the Toll-Like Receptor Pathway
- Author
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Shahin Ranjbar, Luke D. Jasenosky, Anne E. Goldfeld, and Nancy A. Chow
- Subjects
Male ,Bacterial Diseases ,Viral Diseases ,HIV Infections ,Virus Replication ,0302 clinical medicine ,RNA interference ,Gene expression ,Promoter Regions, Genetic ,lcsh:QH301-705.5 ,Cells, Cultured ,Regulation of gene expression ,0303 health sciences ,Toll-Like Receptors ,Tumor Necrosis Factor Receptor-Associated Peptides and Proteins ,3. Good health ,Cell biology ,Interleukin-1 Receptor-Associated Kinases ,Infectious Diseases ,030220 oncology & carcinogenesis ,Medicine ,Female ,Signal Transduction ,Research Article ,lcsh:Immunologic diseases. Allergy ,Toll-Like Receptor Pathway ,Immunology ,NFAT5 Gene ,Biology ,Microbiology ,03 medical and health sciences ,Virology ,Genetics ,Humans ,Tuberculosis ,Gene silencing ,Molecular Biology ,Transcription factor ,030304 developmental biology ,Mycobacterium tuberculosis ,Molecular biology ,Immunity, Innate ,Gene Expression Regulation ,lcsh:Biology (General) ,Viral replication ,Myeloid Differentiation Factor 88 ,HIV-1 ,Parasitology ,lcsh:RC581-607 ,Transcription Factors - 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., Author Summary The major cause of AIDS deaths globally has been tuberculosis (TB), which is caused by the bacterium Mycobacterium tuberculosis (MTb). Co-infection with MTb exacerbates human immunodeficiency virus type1 (HIV-1) replication and disease progression via both innate and adaptive host immune responses to MTb infection. In this report, we present evidence that the transcription factor NFAT5 plays a crucial role in MTb-induced HIV-1 replication in human peripheral blood cells and monocytes. We also show that MTb infection itself stimulates NFAT5 gene expression in human monocytes and that its expression involves the TLR signalling pathway and requires the downstream adaptor proteins MyD88, IRAK1, and TRAF6. This identification of a novel role for NFAT5 in TB/HIV-1 co-infection reveals that NFAT5 is a major mediator of TLR-dependent gene expression and thus provides a potential new therapeutic target for treatment of HIV-1 and possibly other diseases.
- Published
- 2012