Inhibition of human immunodeficiency virus type 1 replication by combination of transcription inhibitor K-12 and other antiretroviral agents in acutely and chronically infected cells.
8-Difluoromethoxy-1-ethyl-6-fluoro-1,4-dihydro-7-[4-(2-methoxyp hen yl)-1- piperazinyl]-4-oxoquinoline-3-carboxylic acid (K-12) has recently been identified as a potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) transcription. In this study, we examined several combinations of K-12 and other antiretroviral agents for their inhibitory effects on HIV-1 replication in acutely and chronically infected cell cultures. Combinations of K-12 and a reverse transcriptase (RT) inhibitor, either zidovudine, lamivudine, or nevirapine, synergistically inhibited HIV-1 replication in acutely infected MT-4 cells. The combination of K-12 and the protease inhibitor nelfinavir (NFV) also synergistically inhibited HIV-1, whereas the synergism of this combination was weaker than that of the combinations with the RT inhibitors. K-12 did not enhance the cytotoxicities of RT and protease inhibitors. Synergism of the combinations was also observed in acutely infected peripheral blood mononuclear cells. The combination of K-12 and cepharanthine, a nuclear factor kappa B inhibitor, synergistically inhibited HIV-1 production in tumor necrosis factor alpha-stimulated U1 cells, a promonocytic cell line chronically infected with the virus. In contrast, additive inhibition was observed for the combination of K-12 and NFV. These results indicate that the combinations of K-12 and clinically available antiretroviral agents may have potential as chemotherapeutic modalities for the treatment of HIV-1 infection.
Division of Human Retroviruses, Faculty of Medicine, Kagoshima University, Japan.
M
M
Okamoto
T
T
Okamoto
M
M
Baba
D000470:Alkaloids / Q000494:pharmacology; D019380:Anti-HIV Agents / Q000494:pharmacology*; D000890:Anti-Infective Agents / Q000494:pharmacology*; D044182:Benzylisoquinolines; D002460:Cell Line; D004357:Drug Synergism; D024841:Fluoroquinolones; D017320:HIV Protease Inhibitors / Q000494:pharmacology; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D016328:NF-kappa B / Q000494:pharmacology; D019888:Nelfinavir / Q000494:pharmacology; D019829:Nevirapine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects*; D015215:Zidovudine / Q000494:pharmacology; D052117:Benzodioxoles
D000470:Alkaloids; D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D044182:Benzylisoquinolines; D024841:Fluoroquinolones; D017320:HIV Protease Inhibitors; D054303:HIV Reverse Transcriptase; D019259:Lamivudine; D016328:NF-kappa B; D019888:Nelfinavir; D019829:Nevirapine; D010879:Piperazines; D018894:Reverse Transcriptase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D015215:Zidovudine; C117028:K-12, fluoroquinolone; C006947:cepharanthine; D052117:Benzodioxoles