PMID- 20018916
OWN - NLM
STAT- MEDLINE
DCOM- 20100323
LR  - 20240419
IS  - 1528-0020 (Electronic)
IS  - 0006-4971 (Print)
IS  - 0006-4971 (Linking)
VI  - 115
IP  - 8
DP  - 2010 Feb 25
TI  - A highly efficient short hairpin RNA potently down-regulates CCR5 expression in 
      systemic lymphoid organs in the hu-BLT mouse model.
PG  - 1534-44
LID - 10.1182/blood-2009-04-215855 [doi]
AB  - Inhibiting the expression of the HIV-1 coreceptor CCR5 holds great promise for 
      controlling HIV-1 infection in patients. Here we report stable knockdown of human 
      CCR5 by a short hairpin RNA (shRNA) in a humanized bone marrow/liver/thymus (BLT) 
      mouse model. We delivered a potent shRNA against CCR5 into human fetal 
      liver-derived CD34(+) hematopoietic progenitor/stem cells (HPSCs) by lentiviral 
      vector transduction. We transplanted vector-transduced HPSCs solidified with 
      Matrigel and a thymus segment under the mouse kidney capsule. Vector-transduced 
      autologous CD34(+) cells were subsequently injected in the irradiated mouse, 
      intended to create systemic reconstitution. CCR5 expression was down-regulated in 
      human T cells and monocytes/macrophages in systemic lymphoid tissues, including 
      gut-associated lymphoid tissue, the major site of HIV-1 replication. The 
      shRNA-mediated CCR5 knockdown had no apparent adverse effects on T-cell 
      development as assessed by polyclonal T-cell receptor Vbeta family development 
      and naive/memory T-cell differentiation. CCR5 knockdown in the secondary 
      transplanted mice suggested the potential of long-term hematopoietic 
      reconstitution by the shRNA-transduced HPSCs. CCR5 tropic HIV-1 infection was 
      effectively inhibited in mouse-derived human splenocytes ex vivo. These results 
      demonstrate that lentiviral vector delivery of shRNA into human HPSCs could 
      stably down-regulate CCR5 in systemic lymphoid organs in vivo.
FAU - Shimizu, Saki
AU  - Shimizu S
AD  - Department of Medicine, Division of Hematology-Oncology, UCLA AIDS Institute, 
      David Geffen School of Medicine, University of California-Los Angeles, 615 
      Charles E. Young Drive South, Los Angeles, CA 90095, USA.
FAU - Hong, Patrick
AU  - Hong P
FAU - Arumugam, Balamurugan
AU  - Arumugam B
FAU - Pokomo, Lauren
AU  - Pokomo L
FAU - Boyer, Joshua
AU  - Boyer J
FAU - Koizumi, Naoya
AU  - Koizumi N
FAU - Kittipongdaja, Panyamol
AU  - Kittipongdaja P
FAU - Chen, Angela
AU  - Chen A
FAU - Bristol, Greg
AU  - Bristol G
FAU - Galic, Zoran
AU  - Galic Z
FAU - Zack, Jerome A
AU  - Zack JA
FAU - Yang, Otto
AU  - Yang O
FAU - Chen, Irvin S Y
AU  - Chen IS
FAU - Lee, Benhur
AU  - Lee B
FAU - An, Dong Sung
AU  - An DS
LA  - eng
GR  - R01 HL086409-04/HL/NHLBI NIH HHS/United States
GR  - P50 CA086306/CA/NCI NIH HHS/United States
GR  - P30 AI028697/AI/NIAID NIH HHS/United States
GR  - T32 AR 053463/AR/NIAMS NIH HHS/United States
GR  - R01 AI100652/AI/NIAID NIH HHS/United States
GR  - R01 HL086409-03/HL/NHLBI NIH HHS/United States
GR  - CA 086306/CA/NCI NIH HHS/United States
GR  - AI 028697/AI/NIAID NIH HHS/United States
GR  - R01 HL086409-03S1/HL/NHLBI NIH HHS/United States
GR  - T32 AR053463/AR/NIAMS NIH HHS/United States
GR  - 1R01 HL 086409/HL/NHLBI NIH HHS/United States
GR  - R01 HL086409/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20091217
PL  - United States
TA  - Blood
JT  - Blood
JID - 7603509
RN  - 0 (Receptors, Antigen, T-Cell, alpha-beta)
RN  - 0 (Receptors, CCR5)
SB  - IM
MH  - Animals
MH  - Bone Marrow/*metabolism
MH  - Cell Differentiation/genetics
MH  - Disease Models, Animal
MH  - Down-Regulation
MH  - Gene Knockdown Techniques
MH  - HIV Infections/genetics/*metabolism
MH  - *HIV-1
MH  - *Hematopoietic Stem Cell Transplantation
MH  - Hematopoietic Stem Cells/metabolism
MH  - Humans
MH  - Immunologic Memory/genetics
MH  - Lentivirus
MH  - Liver/*metabolism
MH  - Mice
MH  - Mice, Inbred NOD
MH  - Receptors, Antigen, T-Cell, alpha-beta/metabolism
MH  - Receptors, CCR5/*biosynthesis/genetics
MH  - T-Lymphocytes/metabolism
MH  - Thymus Gland/*metabolism
MH  - Transduction, Genetic
MH  - Transplantation, Heterologous
PMC - PMC2830759
EDAT- 2009/12/19 06:00
MHDA- 2010/03/24 06:00
PMCR- 2011/02/25
CRDT- 2009/12/19 06:00
PHST- 2009/12/19 06:00 [entrez]
PHST- 2009/12/19 06:00 [pubmed]
PHST- 2010/03/24 06:00 [medline]
PHST- 2011/02/25 00:00 [pmc-release]
AID - S0006-4971(20)56723-2 [pii]
AID - 2009/215855 [pii]
AID - 10.1182/blood-2009-04-215855 [doi]
PST - ppublish
SO  - Blood. 2010 Feb 25;115(8):1534-44. doi: 10.1182/blood-2009-04-215855. Epub 2009 
      Dec 17.