PMID- 28202752
OWN - NLM
STAT- MEDLINE
DCOM- 20170515
LR  - 20181113
IS  - 1098-5514 (Electronic)
IS  - 0022-538X (Print)
IS  - 0022-538X (Linking)
VI  - 91
IP  - 9
DP  - 2017 May 1
TI  - Human Herpesvirus 6A Exhibits Restrictive Propagation with Limited Activation of 
      the Protein Kinase R-eIF2alpha Stress Pathway.
LID - 10.1128/JVI.02120-16 [doi]
LID - e02120-16
AB  - The eIF2alpha protein plays a critical role in the regulation of translation. The 
      production of double-stranded RNA (dsRNA) during viral replication can activate 
      protein kinase R (PKR), which phosphorylates eIF2alpha, leading to inhibition of the 
      initial step of translation. Many viruses have evolved gene products targeting 
      the PKR-eIF2a pathway, indicating its importance in antiviral defense. In the 
      present study, we focused on alternations of PKR-eIF2a pathway during human 
      herpesvirus 6A (HHV-6A) infection while monitoring viral gene expression and 
      infectious viral yields. We have found increased phosphorylated PKR as well as 
      phosphorylated eIF2alpha coincident with accumulation of the late gp82-105 viral 
      protein. The level of total PKR was relatively constant, but it decreased by 144 
      h postinfection. The phosphorylation of eIF2a led to a moderate increase in 
      activating transcription factor 4 (ATF4) accumulation, indicating moderate 
      inhibition of protein translation during HHV-6A infection. The overexpression of 
      PKR led to decreased viral propagation coincident with increased accumulation of 
      phosphorylated PKR and phosphorylated eIF2a. Moreover, addition of a dominant 
      negative PKR mutant resulted in a moderate increase in viral replication. HHV-6A 
      exhibits relatively low efficiency of propagation of progeny virus secreted into 
      the culture medium. This study suggests that the replicative strategy of HHV-6A 
      involves a mild infection over a lengthy life cycle in culture, while preventing 
      severe activation of the PKR-eIF2alpha pathway.IMPORTANCE Human herpesvirus 6A 
      (HHV-6A) and HHV-6B are common, widely prevalent viruses, causing from mild to 
      severe disease. Our study focused on the PKR-eIF2alpha stress pathway, which limits 
      viral replication. The HHV-6 genome carries multiple genes transcribed from the 
      two strands, predicting accumulation of dsRNAs which can activate PKR and 
      inhibition of protein synthesis. We report that HHV-6A induced the accumulation 
      of phosphorylated PKR and phosphorylated eIF2alpha and a moderate increase of 
      activating transcription factor 4 (ATF4), which is known to transcribe stress 
      genes. Overexpression of PKR led to increased eIF2alpha phosphorylation and decreased 
      viral replication, whereas overexpression of a dominant negative PKR mutant 
      resulted in a moderate increase in viral replication. These results suggest that 
      the HHV-6A replication strategy involves restricted activation of the PKR-eIF2alpha 
      pathway, partial translation inhibition, and lower yields of infectious virus. In 
      essence, HHV-6A limits its own replication due to the inability to bypass the 
      eIF2alpha phosphorylation.
CI  - Copyright (c) 2017 Sharon and Frenkel.
FAU - Sharon, Eyal
AU  - Sharon E
AD  - Department of Cell Research and Immunology and S. Daniel Abraham Institute for 
      Molecular Virology, Tel Aviv University, Tel Aviv, Israel.
FAU - Frenkel, Niza
AU  - Frenkel N
AD  - Department of Cell Research and Immunology and S. Daniel Abraham Institute for 
      Molecular Virology, Tel Aviv University, Tel Aviv, Israel 
      nfrenkel@post.tau.ac.il.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20170413
PL  - United States
TA  - J Virol
JT  - Journal of virology
JID - 0113724
RN  - 0 (ATF4 protein, human)
RN  - 0 (Eukaryotic Initiation Factor-2)
RN  - 0 (RNA, Viral)
RN  - 145891-90-3 (Activating Transcription Factor 4)
RN  - EC 2.7.11.1 (eIF-2 Kinase)
SB  - IM
MH  - Activating Transcription Factor 4/*metabolism
MH  - Cells, Cultured
MH  - Eukaryotic Initiation Factor-2/*metabolism
MH  - Gene Expression Regulation, Viral/*genetics
MH  - Herpesvirus 6, Human/*genetics/*growth & development
MH  - Humans
MH  - Phosphorylation
MH  - Protein Biosynthesis/genetics
MH  - RNA, Viral/genetics
MH  - Virus Replication
MH  - eIF-2 Kinase/genetics/*metabolism
PMC - PMC5391470
OTO - NOTNLM
OT  - ATF4
OT  - HHV-6
OT  - PKR
OT  - TCID50
OT  - eIF2alpha
OT  - viral replication
EDAT- 2017/02/17 06:00
MHDA- 2017/05/16 06:00
PMCR- 2017/04/13
CRDT- 2017/02/17 06:00
PHST- 2016/10/31 00:00 [received]
PHST- 2017/02/06 00:00 [accepted]
PHST- 2017/02/17 06:00 [pubmed]
PHST- 2017/05/16 06:00 [medline]
PHST- 2017/02/17 06:00 [entrez]
PHST- 2017/04/13 00:00 [pmc-release]
AID - JVI.02120-16 [pii]
AID - 02120-16 [pii]
AID - 10.1128/JVI.02120-16 [doi]
PST - epublish
SO  - J Virol. 2017 Apr 13;91(9):e02120-16. doi: 10.1128/JVI.02120-16. Print 2017 May 
      1.