title: HIV-1 Infection Primes Macrophages Through STAT Signaling to Promote Enhanced Inflammation and Viral Replication.
abstract: Macrophages play important roles in HIV-1 pathogenesis as targets for viral replication and mediators of chronic inflammation. Similar to IFNγ-priming, HIV-1 primes macrophages, resulting in hyperresponsiveness to subsequent toll-like receptor (TLR) stimulation and increased inflammatory cytokine production. However, the specific molecular mechanism of HIV-1 priming and whether cells must be productively infected or if uninfected bystander cells also are primed by HIV-1 remains unclear. To explore these questions, human macrophages were primed by IFNγ or infected with HIV-1 before activation by TLR ligands. Transcriptome profiling by microarray revealed a gene expression profile for IFNγ-primed cells that was further modulated by the addition of lipopolysaccharide (LPS). HIV-1 infection elicited a gene expression profile that correlated strongly with the profile induced by IFNγ (r = .679, p = .003). Similar to IFNγ, HIV-1 enhanced TLR ligand-induced tumor necrosis factor (TNF) protein expression and release. Increased TNF production was limited to productively infected cells. Specific signal transducer and activator of transcription (STAT)1 and STAT3 inhibitors suppressed HIV-1-mediated enhancement of TLR-induced TNF expression as well as HIV-1 replication. These findings indicate that viral replication and inflammation are linked through a common IFNγ-like, STAT-dependent pathway and that HIV-1-induced STAT1 and STAT3 signaling are involved in both inflammation and HIV-1 replication. Systemic innate immune activation is a hallmark of active HIV-1 replication. Our study shows that inflammation may develop as a consequence of HIV-1 triggering STAT-IFN pathways to support viral replication.
authors.affiliation: 1 Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida , Gainesville, Florida.
authors.forename: K Sofia
authors.initials: KS
authors.lastname: Appelberg
authors.affiliation: 1 Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida , Gainesville, Florida.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wallet
authors.affiliation: 1 Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida , Gainesville, Florida.
authors.forename: Jared P
authors.initials: JP
authors.lastname: Taylor
authors.affiliation: 1 Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida , Gainesville, Florida.
authors.forename: Melanie N
authors.initials: MN
authors.lastname: Cash
authors.affiliation: 2 Division of Allergy, Department of Pediatrics, Immunology, and Pulmonary Medicine, School of Medicine, Duke University , Durham, North Carolina.
authors.forename: John W
authors.initials: JW
authors.lastname: Sleasman
authors.affiliation: 1 Department of Pathology, Immunology, and Laboratory Medicine, College of Medicine, University of Florida , Gainesville, Florida.
authors.forename: Maureen M
authors.initials: MM
authors.lastname: Goodenow
mesh_terms: D002478:Cells, Cultured; D020869:Gene Expression Profiling; D015658:HIV Infections / Q000473:pathology* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D007249:Inflammation / Q000473:pathology; D007371:Interferon-gamma / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology*; D046228:Microarray Analysis; D050794:STAT1 Transcription Factor / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D014779:Virus Replication
chemical_list: D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D007371:Interferon-gamma
keywords: HIV; STAT; macrophages; priming; transcriptome