Synergistic drug interactions of an HIV-1 protease inhibitor with AZT in different in vitro models of HIV-1 infection.

Abstract

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 Jr
• Journal: Antiviral research (Antiviral Res) Vol. 21 Issue 4 Pg. 327-42 (Aug 1993) ISSN: 0166-3542 [Print] Netherlands
• PMID: 7692816 (Publication Type: Comparative Study, Journal Article)

Chemical References

• HIV Protease Inhibitors
• Oligopeptides
• SK&F 108922
• Zidovudine
• HIV Reverse Transcriptase
• RNA-Directed DNA Polymerase

Topics

• 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)