Mechanism for the establishment of transcriptional HIV latency in the brain in a simian immunodeficiency virus-macaque model.
BACKGROUND
The 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.


METHODS
Gene-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.


RESULTS
Interferon-beta (IFN-beta) and myxovirus A (MxA) mRNA are produced in the brain during acute SIV infection. IFN-beta both suppresses SIV LTR activity and induces expression of the dominant-negative isoform of CCAAT/enhancer-binding protein-beta (C/EBP-beta). C/EBP-beta 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.


CONCLUSIONS
Innate 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.
Barber
Sheila A
SA
Department of Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Gama
Lucio
L
Dudaronek
Justyna M
JM
Voelker
Tauni
T
Tarwater
Patrick M
PM
Clements
Janice E
JE
D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000821:virology*; D022782:CCAAT-Enhancer-Binding Protein-beta / Q000032:analysis / Q000378:metabolism; D002460:Cell Line; D047369:Chromatin Immunoprecipitation; D004279:DNA, Viral / Q000032:analysis; D024202:Electrophoretic Mobility Shift Assay; D015870:Gene Expression; D006801:Humans; D007113:Immunity, Innate; D016899:Interferon-beta / Q000235:genetics / Q000276:immunology; D008254:Macaca nemestrina; D012367:RNA, Viral / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D020079:Terminal Repeat Sequences; D014764:Viral Proteins / Q000032:analysis; D017735:Virus Latency / Q000502:physiology*
D022782:CCAAT-Enhancer-Binding Protein-beta; D004279:DNA, Viral; D012367:RNA, Viral; D014764:Viral Proteins; D016899:Interferon-beta