APHS can act synergically with clinically available HIV-1 reverse transcriptase and protease inhibitors and is active against several drug-resistant HIV-1 strains in vitro.
OBJECTIVE
The use of multiple drug combinations in current anti-human immunodeficiency virus (HIV) therapy allows lower dosages of individual drugs and results in enhancement of the therapeutic effect due to synergic interactions between different drugs. We have shown that o-(acetoxyphenyl)hept-2-ynyl sulphide (APHS), a recently developed non-steroidal anti-inflammatory drug, shows anti-HIV activity in a dose-dependent manner. The first aim of this study was to investigate whether APHS can act synergically with the clinically available reverse transcriptase and protease inhibitors (RTIs and PIs, respectively) in vitro. Because of the increasing prevalence of RTI- and PI-resistant HIV-1 strains, the second aim of this study was to assess the antiviral activity of APHS against drug-resistant HIV-1 strains in vitro.


METHODS
HIV-infected peripheral blood mononuclear cells (PBMC) were treated for 7 days with different combinations of APHS and RTIs or PIs. The MT-2 cell line was infected with different HIV-1 strains and treated with APHS for 5 days.


RESULTS
APHS showed synergic interactions with the RTIs zidovudine, lamivudine and efavirenz and with the PIs indinavir and ritonavir. The 50% inhibitory concentration (IC50) of APHS in this assay dropped from 13 microM when used alone, to 5 micro M after combination with an RTI or PI. In combination with APHS the IC50 of the RTI and PI drugs tested also dropped. APHS inhibits the replication of HIV-1 strains resistant to zidovudine, lamivudine, stavudine, didanosine, zalcitabine and ritonavir.


CONCLUSIONS
These results indicate that APHS can be combined with RTIs and PIs and can inhibit several NRTI and PI-resistant HIV-1 strains.
Pereira
Cândida F
CF
Eijkman-Winkler Center, Hp G04.614, University Medical Center Utrecht, Heidelberglaan 100, NL-3584 CX Utrecht, The Netherlands. c.f.pereira@lab.azu.nl
Paridaen
Judith T M L
JT
van de Bovenkamp
Marja
M
Middel
Jeena
J
Verhoef
Jan
J
Nottet
Hans S L M
HS
D000480:Alkynes; D024882:Drug Resistance, Viral; D004357:Drug Synergism; D004797:Enzyme-Linked Immunosorbent Assay; D016655:HIV Core Protein p24 / Q000378:metabolism; D017320:HIV Protease Inhibitors / Q000494:pharmacology*; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects*; D006536:Heptanes / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D009504:Neutrophils / Q000187:drug effects / Q000821:virology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D013440:Sulfides / Q000494:pharmacology*
D000480:Alkynes; D016655:HIV Core Protein p24; D017320:HIV Protease Inhibitors; D006536:Heptanes; D018894:Reverse Transcriptase Inhibitors; D013440:Sulfides; C112390:o-(acetoxyphenyl)hept-2-ynyl sulfide; D054303:HIV Reverse Transcriptase