Document Detail


Synergistic drug interactions of an HIV-1 protease inhibitor with AZT in different in vitro models of HIV-1 infection.
MedLine Citation:
PMID:  7692816     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Synthetic peptide mimetic inhibitors of HIV-1 protease effectively block spread of infectious virus in acutely infected T-cells. These compounds also inhibit production of infectious virions from chronically infected T-cell lines. In order to determine the potential for drug interaction effects on antiviral activity, an HIV-1 protease inhibitor (SK&F 108922) and AZT were studied in three different in vitro models of HIV-1 infection of T-cell lines, specifically, (1) acutely infected cells infected at low multiplicity, (2) HIV-1 chronically-infected cells and (3) co-cultivations of chronically infected with non-infected cells. Upon co-treatment, these compounds demonstrated synergy in Molt4 or H9 cells acutely infected with HIV-1 strain IIIB. Either compound alone was a potent inhibitor of HIV-1 in co-cultivations of uninfected and chronically infected cells. In combination treatments of co-cultures, SK&F 108922 demonstrated strong synergy with AZT. Treatment of H9/IIIB chronically infected cells demonstrated no inhibitory effect by AZT treatment (EC50 = > 100 microM) whereas SK&F 108922 was inhibitory (EC50 = 3 microM). Upon co-treatment of H9/IIIB chronically infected cultures with both compounds, the antiviral activity was similar to that of the protease inhibitor alone suggesting no drug interaction. In the co-cultivation experiments, AZT's antiviral effect was most likely due to blocking spread of acute infection to uninfected cells in the culture. No antagonistic effects were observed with AZT and SK&F 108922 co-treatments. These results clearly demonstrate that an HIV-1 protease inhibitor can exert a potent antiviral effect on chronically infected T-cells in contrast to AZT and is capable of potent synergy with AZT in acute and co-culture in vitro infection models.
Authors:
D M Lambert; H Bartus; A V Fernandez; C Bratby-Anders; J J Leary; G B Dreyer; B W Metcalf; S R Petteway
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Publication Detail:
Type:  Comparative Study; Journal Article    
Journal Detail:
Title:  Antiviral research     Volume:  21     ISSN:  0166-3542     ISO Abbreviation:  Antiviral Res.     Publication Date:  1993 Aug 
Date Detail:
Created Date:  1993-11-12     Completed Date:  1993-11-12     Revised Date:  2007-11-15    
Medline Journal Info:
Nlm Unique ID:  8109699     Medline TA:  Antiviral Res     Country:  NETHERLANDS    
Other Details:
Languages:  eng     Pagination:  327-42     Citation Subset:  IM; X    
Affiliation:
Department of Molecular Virology and Host Defense, SmithKline Beecham Research Laboratories, King of Prussia, PA 19406.
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MeSH Terms
Descriptor/Qualifier:
Acquired Immunodeficiency Syndrome / drug therapy*
Amino Acid Sequence
Cell Line
Chronic Disease
Drug Synergism
HIV Protease Inhibitors / pharmacology*
HIV Reverse Transcriptase
HIV-1 / drug effects,  enzymology
Humans
Models, Biological
Molecular Sequence Data
Oligopeptides / pharmacology*
RNA-Directed DNA Polymerase / biosynthesis,  metabolism
Virus Replication / drug effects
Zidovudine / pharmacology*
Chemical
Reg. No./Substance:
0/HIV Protease Inhibitors; 0/Oligopeptides; 146794-68-5/SK&F 108922; 30516-87-1/Zidovudine; EC 2.7.7.49/HIV Reverse Transcriptase; EC 2.7.7.49/RNA-Directed DNA Polymerase

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