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Titolo:
Antiviral chemokines: Intracellular life of recombinant C-C chemokine RANTES
Autore:
Owais, M; Arya, SK;
Indirizzi:
NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA
Titolo Testata:
JOURNAL OF HUMAN VIROLOGY
fascicolo: 5, volume: 2, anno: 1999,
pagine: 270 - 282
SICI:
1090-9508(199909/10)2:5<270:ACILOR>2.0.ZU;2-W
Fonte:
ISI
Lingua:
ENG
Soggetto:
SMALL-MOLECULE INHIBITOR; LONG TERMINAL REPEAT; HIV-1 ENTRY; RECEPTOR CXCR4; ENDOPLASMIC-RETICULUM; SIGNAL-TRANSDUCTION; GENE-EXPRESSION; T-CELLS; CCR5; CORECEPTOR;
Keywords:
chemokines; HIV; mutational analysis; lentiviral vector;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
56
Recensione:
Indirizzi per estratti:
Indirizzo: Arya, SK NCI, Basic Res Lab, NIH, Bethesda, MD 20892 USA NCI Bethesda MD USA 20892 c Res Lab, NIH, Bethesda, MD 20892 USA
Citazione:
M. Owais e S.K. Arya, "Antiviral chemokines: Intracellular life of recombinant C-C chemokine RANTES", J HUMAN VIR, 2(5), 1999, pp. 270-282

Abstract

Objective: Select C-C and C-X-C chemokines can suppress HN infection. Thisis because their receptors are the gateways for HIV-1 entry, determinants of viral tropism and sensitivity. C-C chemokines are most effective againstmacrophage-tropic viruses, and C-X-C chemokines are most effective againstT-tropic viruses. The epitopes on the chemokine molecule responsible for virus inhibition and for chemokines' specificities are not known. The objective of this study was to map the functional domains of prototypic antiviralchemokine, namely, RANTES (regulated-on-activation normal T-expressed and secreted). Study Design: Optimal folding of the chemokine molecule is thought to be important for its biologic activity. Anticipating that it will provide a native milieu for folding, we expressed recombinant RANTES molecules in an HIV-2-derived lentivirus mammalian expression system. We focused on the structural landmarks of RANTES to determine their role in its life and function. Results: We found that the flexible amino-terminal region of RANTES was not important for its structural integrity or antiviral activity, either positively or negatively. It was also not important for binding to the CCR5 receptor. Modification of all other domains was detrimental, implying a functional role. However, a more careful analysis revealed that these domains were crucial for controlling stability, transport, and secretion of the molecule. Although all recombinant clones contained signal sequence and were transcriptionally active, they presented three different phenotypes: normal synthesis and secretion, normal synthesis but blocked secretion, and presumed normal synthesis but rapid degradation. Structural considerations and preliminary experiments showing a lack of effect of proteasome inhibitors suggested that the signal recognition particle pathway of translocation and proteasomal pathway of destruction may not be the major determinant of the life of the chemokine. Conclusions: The amino-terminal domain of RANTES was not essential for itsantiviral activity of for its binding to the CCR5 receptor. Although the I-domain of the core and carboxyterminal domain may contribute to the antiviral activity of RANTES, they were more important for its intracellular life.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 04/07/20 alle ore 18:28:41