Innate immune responses and control of acute simian immunodeficiency virus replication in the central nervous system.
Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) can invade the central nervous system (CNS) during acute infection but virus replication is apparently controlled because clinical and pathological manifestations of CNS disease in HIV/SIV-infected individuals usually present later in infection, coincident with immunosuppression and acquired immuno-deficiency syndrome (AIDS). Using an established SIV/macaque model of HIV dementia, the authors recently demonstrated that acute virus replication is down-regulated (to undetectable viral RNA levels) in the brain, but not the periphery, as early as 21 days post inoculation (p.i.). Viral DNA levels in the brain remain constant, suggesting that infected cells persist in the CNS and that replication is inhibited largely at a transcriptional level. In vitro, active replication of HIV in macrophages can be inhibited by treatment with interferon (IFN)beta via a mechanism involving induction of a dominant-negative form of the transcription factor C/EBP (CCAAT/enhancer-binding protein)beta. Because macrophages are the primary cell types infected with HIV/SIV in the CNS and HIV replication in macrophages requires C/EBP sites within the viral long terminal repeat (LTR), the authors considered the possibility that suppression of C/EBP-dependent transcription contributes to the mechanism by which acute HIV/SIV replication is inhibited in the CNS. Here, the authors report that IFNbeta can also inhibit ongoing SIV replication in macaque macrophages in vitro. Further, the authors demonstrate that IFNbeta levels in the brain increase between 7 and 21 days p.i. in parallel with increased expression of the dominant-negative isoform of C/EBPbeta. These results suggest that innate immune responses involving IFNbeta may contribute to the mechanism(s) controlling acute SIV replication in the CNS.
Barber
Sheila A
SA
Department of Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
Herbst
David S
DS
Bullock
Brandon T
BT
Gama
Lucio
L
Clements
Janice E
JE
D000208:Acute Disease; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D001921:Brain / Q000821:virology*; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004279:DNA, Viral / Q000032:analysis; D015870:Gene Expression / Q000276:immunology; D016899:Interferon-beta / Q000235:genetics / Q000494:pharmacology; D008253:Macaca mulatta; D008264:Macrophages / Q000821:virology; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology* / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects / Q000254:growth & development* / Q000276:immunology*; D051742:Transcription Factor CHOP; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects
D000998:Antiviral Agents; D022762:CCAAT-Enhancer-Binding Proteins; D004279:DNA, Viral; D014157:Transcription Factors; D051742:Transcription Factor CHOP; D016899:Interferon-beta