PMID- 23409116
OWN - NLM
STAT- MEDLINE
DCOM- 20130805
LR  - 20211021
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 8
IP  - 2
DP  - 2013
TI  - Novel gene therapy viral vector using non-oncogenic lymphotropic herpesvirus.
PG  - e56027
LID - 10.1371/journal.pone.0056027 [doi]
LID - e56027
AB  - Despite the use of retroviral vectors, efficiently introducing target genes into 
      immunocytes such as T cells is difficult. In addition, retroviral vectors carry 
      risks associated with the oncogenicity of the native virus and the potential for 
      introducing malignancy in recipients due to genetic carryover from immortalized 
      cells used during vector production. To address these issues, we have established 
      a new virus vector that is based on human herpesvirus 6 (HHV-6), a non-oncogenic 
      lymphotropic herpesvirus that infects CD4(+) T cells, macrophages, and dendritic 
      cells. In the present study, we have altered the cell specificity of the 
      resulting recombinant HHV-6 by knocking out the U2-U8 genes. The resulting virus 
      proliferated only in activated cord blood cells and not in peripheral blood 
      cells. Umbilical cord blood cells produced replication-defective recombinant 
      virus in sufficiently high titer to omit the use of immortalized cells during 
      vector production. HHV-6 vectors led to high rates (>90%) of gene transduction in 
      both CD4(+) and CD8(+) T cells. These viruses showed low-level replication of 
      viral DNA that supported greater expression of the induced genes than that of 
      other methods but that was insufficient to support the production of 
      replication-competent virus. Furthermore, HHV-6 vectors containing short hairpin 
      RNAs against CD4 and HIV Gag remarkably inhibited the production of these 
      proteins and HIV particles. Here we demonstrate the utility of HHV-6 as a new 
      non-carcinogenic viral vector for immunologic diseases and immunotherapy.
FAU - Shimizu, Akihiro
AU  - Shimizu A
AD  - Department of Virology, The Jikei University School of Medicine, Tokyo, Japan.
FAU - Kobayashi, Nobuyuki
AU  - Kobayashi N
FAU - Shimada, Kazuya
AU  - Shimada K
FAU - Oura, Kuniaki
AU  - Oura K
FAU - Tanaka, Tadao
AU  - Tanaka T
FAU - Okamoto, Aikou
AU  - Okamoto A
FAU - Kondo, Kazuhiro
AU  - Kondo K
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130211
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 9008-11-1 (Interferons)
SB  - IM
MH  - Cytopathogenic Effect, Viral
MH  - Gene Expression
MH  - Gene Expression Regulation
MH  - Gene Order
MH  - Genetic Therapy
MH  - Genetic Vectors/*genetics
MH  - Genome, Viral
MH  - Herpesvirus 6, Human/*genetics
MH  - Humans
MH  - Interferons/pharmacology
MH  - Leukocytes, Mononuclear/drug effects/metabolism/virology
MH  - Lymphocytes/metabolism/virology
MH  - RNA Interference
MH  - Transgenes
MH  - *Viral Tropism
MH  - Virus Replication
PMC - PMC3569415
COIS- Competing Interests: The authors have read the journal's policy and have the 
      following conflicts. Kazuhiro Kondo has submitted an application for a patent on 
      the HHV-6 viral vector (PCT/JP2004/12487). The other authors have declared that 
      no competing interests exist. This does not alter the authors' adherence to all 
      the PLOS ONE policies on sharing data and materials.
EDAT- 2013/02/15 06:00
MHDA- 2013/08/06 06:00
PMCR- 2013/02/11
CRDT- 2013/02/15 06:00
PHST- 2012/10/05 00:00 [received]
PHST- 2013/01/04 00:00 [accepted]
PHST- 2013/02/15 06:00 [entrez]
PHST- 2013/02/15 06:00 [pubmed]
PHST- 2013/08/06 06:00 [medline]
PHST- 2013/02/11 00:00 [pmc-release]
AID - PONE-D-12-30665 [pii]
AID - 10.1371/journal.pone.0056027 [doi]
PST - ppublish
SO  - PLoS One. 2013;8(2):e56027. doi: 10.1371/journal.pone.0056027. Epub 2013 Feb 11.