Mechanism for the Establishment of Transcriptional HIV Latency in the Brain in a Simian Immunodeficiency Virus–Macaque Model

• Published in: The Journal of infectious diseases 2006-04, Vol.193 (7), p.963-970
• Main Authors: Barber, Sheila A., Gama, Lucio, Dudaronek, Justyna M., Voelker, Tauni, Tarwater, Patrick M., Clements, Janice E.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Blotting, Western; Brain; Brain - virology; CCAAT-Enhancer-Binding Protein-beta - analysis; CCAAT-Enhancer-Binding Protein-beta - metabolism; Cell Line; Central nervous system; Chromatin Immunoprecipitation; DNA; DNA, Viral - analysis; Electrophoretic Mobility Shift Assay; Fundamental and applied biological sciences. Psychology; Gene Expression; Histones; HIV; HIV 1; HIV/AIDS; Human immunodeficiency virus; Humans; Immunity, Innate; Infections; Infectious diseases; Interferon-beta - genetics; Interferon-beta - immunology; Macaca nemestrina; Macrophages; Medical sciences; Microbiology; Miscellaneous; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral - analysis; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - virology; Simian immunodeficiency virus; Simian Immunodeficiency Virus - genetics; Simian Immunodeficiency Virus - immunology; Simian Immunodeficiency Virus - physiology; Terminal Repeat Sequences; Transfection; Viral Proteins - analysis; Virology; Virus Latency - physiology; Viruses
• ISSN: 0022-1899; 1537-6613
• DOI: 10.1086/500983

BackgroundThe brain is considered to be a reservoir of latent human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). We examined the mechanism by which innate immune responses contribute to the establishment of this reservoir MethodsGene-specific RNA and DNA were quantitated using real-time reverse-transcription polymerase chain reaction (RT-PCR). Protein expression was examined using Western blot analysis. Binding to and regulation of the SIV long terminal repeat (LTR) was examined using electrophoretic mobility shift assay, luciferase reporter constructs, and chromatin immunoprecipitation assay ResultsInterferon-β (IFN-β) and myxovirus A (MxA) mRNA are produced in the brain during acute SIV infection. IFN-β both suppresses SIV LTR activity and induces expression of the dominant-negative isoform of CCAAT/enhancer-binding protein–β (C/EBP-β). C/EBP-β and its dominant-negative isoform respectively enhance and suppress histone acetylation at the SIV LTR and are present at the SIV LTR in vivo. SIV DNA persists when viral RNA is undetectable in the brain, and activation of the LTR is suppressed at the level of histone acetylation ConclusionInnate immune responses to virus infection that suppress acute virus replication in the brain also facilitate transcriptional latency of SIV. These data provide the first mechanistic model of HIV latency in the brain