title: Toll-like receptor-3 mediates HIV-1 transactivation via NFκB and JNK pathways and histone acetylation, but prolonged activation suppresses Tat and HIV-1 replication.
abstract: TLR3 has been implicated in the pathogenesis of several viral infections, including SIV- and HIV-1-induced inflammation and AIDS. However the molecular mechanisms of these TLR3-mediated effects are not known, and it is not known whether HIV interacts with cellular TLR3 to affect disease process. Here we investigate the effects of TLR3 ligands on HIV-1 transactivation using both primary human macrophages and cells containing integrated copies of the HIV-1 promoter. We demonstrate that TLR3 activation induced upregulation of transcription factors such as c-Jun, CCAAT/enhancer-binding protein alpha (CEBPA), signal transducer and activator of transcription (STAT)-1, STAT-2, RELB, and nuclear factor kappa-B1 (NFκB1), most of which are known to regulate the HIV promoter activity. We also demonstrate that TLR3 activation increased HIV-1 transactivation via the c-Jun N-terminal kinase (JNK) and NFκB pathways. This was associated with epigenetic modifications, including decreased histone deacetylase activity, increased histone acetyl transferase (HAT) activity, and increased acetylation of histones H3 and H4 at lysine residues in the nucleosome-0 and nucleosome-1 of the HIV-1 promoter. However, prolonged TLR3 activation decreased HIV-1 transactivation, decreased HAT activity and Tat transcription, and suppressed viral replication. Overall, data suggests that TLR3 can act as viral sensor to mediate viral transactivation, cellular signaling, innate immune response, and inflammation in HIV-infected humans. Our study provides novel insights into the molecular basis for these TLR3-mediated effects.
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA. Electronic address: bbhargavan@unmc.edu.
authors.forename: Biju
authors.initials: B
authors.lastname: Bhargavan
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA. Electronic address: swoollar@unmc.edu.
authors.forename: Shawna M
authors.initials: SM
authors.lastname: Woollard
authors.affiliation: Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-5800, USA. Electronic address: gkanmogne@unmc.edu.
authors.forename: Georgette D
authors.initials: GD
authors.lastname: Kanmogne
mesh_terms: D000107:Acetylation; D002478:Cells, Cultured; D044127:Epigenesis, Genetic; D015967:Gene Expression Regulation, Viral; D015497:HIV-1 / Q000235:genetics* / Q000502:physiology; D051548:Histone Acetyltransferases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D008264:Macrophages / Q000201:enzymology / Q000378:metabolism / Q000821:virology; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D051196:Toll-Like Receptor 3 / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation; D020298:U937 Cells; D014779:Virus Replication; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000096:biosynthesis / Q000235:genetics
chemical_list: D006657:Histones; D016328:NF-kappa B; D016755:Proto-Oncogene Proteins c-jun; D051196:Toll-Like Receptor 3; D014157:Transcription Factors; D054322:tat Gene Products, Human Immunodeficiency Virus; D051548:Histone Acetyltransferases; D048031:JNK Mitogen-Activated Protein Kinases
keywords: Epigenetics; HIV; Histone acetylation; Human monocyte-derived macrophages; JNK; LTR; NFκB; STAT1; TLR3; TZM-bl; U38 cells; Viral transactivation