PMID- 20404187
OWN - NLM
STAT- MEDLINE
DCOM- 20100608
LR  - 20211020
IS  - 1091-6490 (Electronic)
IS  - 0027-8424 (Print)
IS  - 0027-8424 (Linking)
VI  - 107
IP  - 18
DP  - 2010 May 4
TI  - Divergent susceptibilities of human herpesvirus 6 variants to type I interferons.
PG  - 8369-74
LID - 10.1073/pnas.0909951107 [doi]
AB  - Two distinct human herpesvirus 6 (HHV-6) variants infect humans. HHV-6B is the 
      etiologic agent of roseola and is associated with life-threatening neurological 
      diseases, such as encephalitis, as well as organ transplant failure. The 
      epidemiology and disease association for HHV-6A remain ill-defined. Specific 
      anti-HHV-6 drugs do not exist and classic antiherpes drugs have secondary effects 
      that are often problematic for transplant patients. Clinical trials using IFN 
      were also performed with inconclusive results. We investigated the efficacy of 
      type I IFN (alpha/beta) in controlling HHV-6 infection. We report that cells 
      infected with laboratory strains and primary isolates of HHV-6B are resistant to 
      IFN-alpha/beta antiviral actions as a result of improper IFN-stimulated gene 
      (ISGs) expression. In contrast, HHV-6A-infected cells were responsive to 
      IFN-alpha/beta with pronounced antiviral effects observed. Type II IFN 
      (gamma)-signaling was unaltered in cells infected by either variant. The HHV-6B 
      immediate-early 1 (IE1) physically interacts with STAT2 and sequestrates it to 
      the nucleus. As a consequence, IE1B prevents the binding of ISGF3 to 
      IFN-responsive gene promoters, resulting in ISG silencing. In comparison, HHV-6A 
      and its associated IE1 protein displayed marginal ISG inhibitory activity 
      relative to HHV-6B. The ISG inhibitory domain of IE1B mapped to a 41 amino acid 
      region absent from IE1A. Transfer of this IE1B region resulted in a gain of 
      function that conferred ISG inhibitory activity to IE1A. Our work is unique in 
      demonstrating type I IFN signaling defects in HHV-6B-infected cells and 
      highlights a major biological difference between HHV-6 variants.
FAU - Jaworska, Joanna
AU  - Jaworska J
AD  - Department of Microbiology-Infectiology-Immunology, Axe Infectiologie et 
      Immunologie, Centre Hospitalier Universitaire de Quebec Research Center, Laval 
      University, Quebec, Canada.
FAU - Gravel, Annie
AU  - Gravel A
FAU - Flamand, Louis
AU  - Flamand L
LA  - eng
GR  - MOP-89706/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100419
PL  - United States
TA  - Proc Natl Acad Sci U S A
JT  - Proceedings of the National Academy of Sciences of the United States of America
JID - 7505876
RN  - 0 (IRF9 protein, human)
RN  - 0 (Interferon-Stimulated Gene Factor 3, gamma Subunit)
RN  - 0 (Interferon-alpha)
RN  - 0 (STAT2 Transcription Factor)
RN  - 0 (STAT2 protein, human)
RN  - 77238-31-4 (Interferon-beta)
SB  - IM
MH  - Active Transport, Cell Nucleus
MH  - Cells, Cultured
MH  - Herpesvirus 6, Human/*physiology
MH  - Humans
MH  - Interferon-Stimulated Gene Factor 3, gamma Subunit/metabolism
MH  - Interferon-alpha/*metabolism
MH  - Interferon-beta/*metabolism
MH  - Protein Binding
MH  - Response Elements
MH  - STAT2 Transcription Factor/metabolism
MH  - Signal Transduction
PMC - PMC2889514
COIS- The authors declare no conflict of interest.
EDAT- 2010/04/21 06:00
MHDA- 2010/06/09 06:00
PMCR- 2010/11/04
CRDT- 2010/04/21 06:00
PHST- 2010/04/21 06:00 [entrez]
PHST- 2010/04/21 06:00 [pubmed]
PHST- 2010/06/09 06:00 [medline]
PHST- 2010/11/04 00:00 [pmc-release]
AID - 0909951107 [pii]
AID - 200909951 [pii]
AID - 10.1073/pnas.0909951107 [doi]
PST - ppublish
SO  - Proc Natl Acad Sci U S A. 2010 May 4;107(18):8369-74. doi: 
      10.1073/pnas.0909951107. Epub 2010 Apr 19.