Immune Escape via a Transient Gene Expression Program Enables Productive Replication of a Latent Pathogen.
How type I and II interferons prevent periodic reemergence of latent pathogens in tissues of diverse cell types remains unknown. Using homogeneous neuron cultures latently infected with herpes simplex virus 1, we show that extrinsic type I or II interferon acts directly on neurons to induce unique gene expression signatures and inhibit the reactivation-specific burst of viral genome-wide transcription called phase I. Surprisingly, interferons suppressed reactivation only during a limited period early in phase I preceding productive virus growth. Sensitivity to type II interferon was selectively lost if viral ICP0, which normally accumulates later in phase I, was expressed before reactivation. Thus, interferons suppress reactivation by preventing initial expression of latent genomes but are ineffective once phase I viral proteins accumulate, limiting interferon action. This demonstrates that inducible reactivation from latency is only transiently sensitive to interferon. Moreover, it illustrates how latent pathogens escape host immune control to periodically replicate by rapidly deploying an interferon-resistant state.
Department of Microbiology, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA.
Jessica A
JA
Linderman
Laboratory of Molecular Neuro-Oncology & Howard Hughes Medical Institute, The Rockefeller University, 1230 York Ave., Box 226, New York, NY 10065, USA.
Mariko
M
Kobayashi
Department of Microbiology, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA; Kimmel Center for Biology & Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA.
Vinayak
V
Rayannavar
Laboratory of Molecular Neuro-Oncology & Howard Hughes Medical Institute, The Rockefeller University, 1230 York Ave., Box 226, New York, NY 10065, USA.
John J
JJ
Fak
Laboratory of Molecular Neuro-Oncology & Howard Hughes Medical Institute, The Rockefeller University, 1230 York Ave., Box 226, New York, NY 10065, USA.
Robert B
RB
Darnell
Department of Cell Biology, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA; Department of Physiology, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA; Department of Neuroscience, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA; Department of Psychiatry, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA; Kimmel Center for Biology & Medicine at the Skirball Institute of Biomolecular Medicine, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA.
Moses V
MV
Chao
Department of Microbiology, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center at NYU Medical Center, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA.
Angus C
AC
Wilson
Department of Microbiology, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA; Laura and Isaac Perlmutter Cancer Center at NYU Medical Center, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA. Electronic address: ian.mohr@med.nyu.edu.
Ian
I
Mohr
D000818:Animals; D002478:Cells, Cultured; D004261:DNA Replication / Q000276:immunology*; D015870:Gene Expression / Q000276:immunology*; D016679:Genome, Viral / Q000276:immunology; D018259:Herpesvirus 1, Human / Q000276:immunology; D007370:Interferon Type I / Q000276:immunology; D007371:Interferon-gamma / Q000276:immunology; D009474:Neurons / Q000276:immunology / Q000821:virology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014158:Transcription, Genetic / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology; D014775:Virus Activation / Q000276:immunology; D017735:Virus Latency / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology*
D007370:Interferon Type I; D014764:Viral Proteins; D007371:Interferon-gamma
gene expression; herpesvirus; interferon; latency; neurons; reactivation