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Titolo:
ANTI-HIV TYPE-1 ACTIVITY OF WILD-TYPE AND FUNCTIONAL DEFECTIVE RANTESINTRAKINE IN PRIMARY HUMAN-LYMPHOCYTES
Autore:
YANG AG; ZHANG X; TORTI F; CHEN SY;
Indirizzi:
WAKE FOREST UNIV,BOWMAN GRAY SCH MED,DEPT CANC BIOL,CTR COMPREHENS CANC,300 S HAWTHORNE RD WINSTON SALEM NC 27157 WAKE FOREST UNIV,BOWMAN GRAY SCH MED,DEPT CANC BIOL,CTR COMPREHENS CANC WINSTON SALEM NC 27157
Titolo Testata:
Human gene therapy
fascicolo: 14, volume: 9, anno: 1998,
pagine: 2005 - 2018
SICI:
1043-0342(1998)9:14<2005:ATAOWA>2.0.ZU;2-3
Fonte:
ISI
Lingua:
ENG
Soggetto:
IMMUNODEFICIENCY-VIRUS TYPE-1; CHEMOKINE RECEPTOR GENE; DISEASE PROGRESSION; DELETION ALLELE; VIRAL PHENOTYPE; T-LYMPHOCYTES; INFECTION; CELLS; THERAPY; EXPRESSION;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
47
Recensione:
Indirizzi per estratti:
Citazione:
A.G. Yang et al., "ANTI-HIV TYPE-1 ACTIVITY OF WILD-TYPE AND FUNCTIONAL DEFECTIVE RANTESINTRAKINE IN PRIMARY HUMAN-LYMPHOCYTES", Human gene therapy, 9(14), 1998, pp. 2005-2018

Abstract

We have developed a genetic ''intrakine'' strategy to inactivate the CC-chemokine receptor 5 (CCR-5), the principal coreceptor for macrophage (M)-tropic HIV-1 viruses (Yang et al., 1997). The inactivation of CCR-5 was achieved by targeting a modified CC-chemokine (RANTES) to thelumen of the endoplasmic reticulum (ER) to block the transport of thenewly synthesized CCR-5. The transduced lymphocytes with the phenotypic CCR-5 knockout were shown to be resistant to M-tropic HIV-1 infection. This study illustrated the feasibility of the intrakine strategy to block HIV-1 infection. In our current study, the potential clinical application of the intrakine approach was further evaluated in human peripheral blood lymphocytes (PBLs), PBLs were transduced with the RANTES intrakine gene by using retroviral vectors with the truncated low-affinity human nerve growth factor receptor (Delta NGFR) marker, and then isolated by an anti-NGFR antibody/magnetic bead method. The surfaceexpression of CCR-5 in the transduced lymphocytes was dramatically inhibited, as demonstrated by flow cytometric assays. The transduced PBLs were shown to resist various types of M-tropic HIV-1 virus infection. The cell viability, cell proliferation rates, and cell surface markers of the intrakine-transduced PBLs were shown to be comparable to those of control PBLs. The transduced PBLs were also found to respond to the stimulation of various CXC- and CC-chemokines, other than RANTES. The transduced PBLs responded to tetanus antigen stimulation by increasing IL-2 production and cell proliferation. In addition, a functionally defective mutant of RANTES that retains its binding activity to CCR-5, but loses its signaling ability, was used to generate a mutant RANTES intrakine. The primary lymphocytes transduced with the mutant RANTES intrakine were found to be resistant to M-tropic HIV-1 infection. From these results, we conclude that the primary human lymphocytes transduced with either the wild-type or functionally defective RANTES intrakine are resistant to M-tropic HIV-1 infection, and maintain their basic biological functions. This study, therefore, indicates the potential clinical application of the intrakine approach for HIV-1 gene therapy.

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Documento generato il 04/12/20 alle ore 06:55:31