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Titolo:
ANTIRETROVIRAL EFFECTS OF DEOXYHYPUSYL HYDROXYLASE INHIBITORS - A HYPUSINE-DEPENDENT HOST-CELL MECHANISM FOR REPLICATION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1)
Autore:
ANDRUS L; SZABO P; GRADY RW; HANAUSKE AR; HUIMABYRON T; SLOWINSKA B; ZAGULSKA S; HANAUSKEABEL HM;
Indirizzi:
CORNELL UNIV,COLL MED,DEPT PEDIAT,DIV ENDOCRINOL,MBL,RM LC-604,525 E 68TH ST NEW YORK NY 10021 CORNELL UNIV,NEW YORK HOSP,COLL MED,DEPT PEDIAT NEW YORK NY 00000 CORNELL UNIV,NEW YORK HOSP,COLL MED,DEPT MED NEW YORK NY 00000 NEW YORK BLOOD CTR NEW YORK NY 10021 TECH UNIV MUNICH,DEPT MED D-8000 MUNICH GERMANY
Titolo Testata:
Biochemical pharmacology
fascicolo: 11, volume: 55, anno: 1998,
pagine: 1807 - 1818
SICI:
0006-2952(1998)55:11<1807:AEODHI>2.0.ZU;2-K
Fonte:
ISI
Lingua:
ENG
Soggetto:
INITIATION-FACTOR 5A; CHRONICALLY INFECTED-CELLS; VIRAL MESSENGER-RNA; REV TRANS-ACTIVATOR; T-CELL; GENE-EXPRESSION; SACCHAROMYCES-CEREVISIAE; SPLICING PATTERNS; COMPLEX-FORMATION; NUCLEAR EXPORT;
Keywords:
HIV/AIDS; APOPTOSIS; ANTIVIRAL AGENTS; DEFERIPRONE; MIMOSINE; HYPUSINE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Science Citation Index Expanded
Citazioni:
79
Recensione:
Indirizzi per estratti:
Citazione:
L. Andrus et al., "ANTIRETROVIRAL EFFECTS OF DEOXYHYPUSYL HYDROXYLASE INHIBITORS - A HYPUSINE-DEPENDENT HOST-CELL MECHANISM FOR REPLICATION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 (HIV-1)", Biochemical pharmacology, 55(11), 1998, pp. 1807-1818

Abstract

The HIV-1 protein Rev, critical for translation of incompletely spliced retroviral mRNAs encoding capsid elements, requires a host cell protein termed ''eukaryotic initiation factor 5A'' (eIF-5A). This is the only protein containing hypusine, a lysine derived hydroxylated residue that determines its proposed bioactivity, the translation of a subset of cellular mRNAs controlling G(1)-to-S transit of the cell cycle. We postulated that inhibiting the hypusine-forming deoxyhypusyl hydroxylase (DOHH) should, by depleting eukaryotic initiation factor 5A, compromise Rev function and thus reduce HIV-1 multiplication. We now report that the alpha-hydroxypyridones, specifically mimosine, a natural product, and deferiprone, an experimental drug, inhibited deoxyhypusyl hydroxylase in T-lymphocytic and promonocytic cell lines and, in a concentration-dependent manner, suppressed replication of HIV-1. However, the alpha-hydroxypyridones did not affect the formation of unspliced or multiply spliced HIV-1 transcripts. Rather, these agents caused Rev dependent incompletely spliced HIV-1 mRNA such as gag, but not cellular ''housekeeping'' mRNAs, to disappear from polysomes. Consequently, alpha-hydroxypyridone-mediated depletion of eIF-5A decreased biosynthesis of structural HIV-1 protein encoded by gag, measured as p24, whereas the induced formation of cellular protein like tumor necrosis factoralpha remained unaffected. By interfering with the translation of incompletely spliced retroviral mRNAs, these compounds restrict HIV-1 to the early, nongenerative phase of its reproductive cycle. In the inducibly HIV-1 expressing T-cell line ACH-2, the deoxyhypusyl hydroxylase inhibitors triggered extensive apoptosis, particularly of cells that actively produce HIV-1. Selective suppression of retroviral protein biosynthesis and preferential apoptosis of retrovirally infected cells byalpha-hydroxypyridones point to a novel mode of antiretroviral action. (C) 1998 Elsevier Science Inc.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 18/09/20 alle ore 17:16:12