Mechanism of inhibition of the human immunodeficiency virus type 1 by the oxygen radical generating agent bleomycin.
Alternative targets of attack of the human immunodeficiency virus (HIV) are necessary in light of infection persistence due to onset of resistance after conventional reverse transcriptase and protease inhibitor therapy. We have recently shown that the cancer chemotherapeutic agent bleomycin (BLM) dose-dependently inhibits HIV-1 replication. The mechanism of this viral inhibition in vitro was investigated. Cell-free wild-type virions were affected directly by BLM in the presence of H2O2, as shown by a 38% decrease of viral infectivity. Viral inhibition by BLM did not proceed via NF-kappaB inhibition. The viral R/U5 DNA product was reduced by 70% without any effect on reverse transcriptase activity. In both a cell-free system as well as two-cell systems the antiviral dependence of BLM on iron and oxidant species was demonstrated. Bleomycin seems to inhibit HIV-1 replication through the same properties that make it a suitable anti-cancer agent. The results presented in this study describe a novel mechanism of HIV-1 inhibition with potential application in viral infections. The anti-HIV effects of BLM in patients receiving this drug in combination with HAART should be carefully monitored in order to evaluate the clinical significance of the findings described in this study.
Eijkman-Winkler Center for Microbiology, Infectious Diseases and Inflammation, University Medical Center Utrecht, Utrecht, The Netherlands.
Niki A
NA
Georgiou
Tjomme
T
van der Bruggen
Maroeska
M
Oudshoorn
Prim
P
de Bie
Christine A
CA
Jansen
Hans S L M
HS
Nottet
Joannes J M
JJ
Marx
B Sweder
BS
van Asbeck
D019380:Anti-HIV Agents / Q000494:pharmacology*; D001761:Bleomycin / Q000494:pharmacology*; D015687:Cell Hypoxia; D002478:Cells, Cultured; D004249:DNA Damage; D004279:DNA, Viral / Q000096:biosynthesis / Q000187:drug effects; D016655:HIV Core Protein p24 / Q000032:analysis; D016325:HIV Long Terminal Repeat; D054303:HIV Reverse Transcriptase / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007501:Iron / Q000494:pharmacology; D016328:NF-kappa B / Q000378:metabolism; D016877:Oxidants / Q000494:pharmacology; D010084:Oxidation-Reduction; D017382:Reactive Oxygen Species / Q000494:pharmacology; D038301:Virus Inactivation; D014779:Virus Replication / Q000187:drug effects*
D019380:Anti-HIV Agents; D004279:DNA, Viral; D016655:HIV Core Protein p24; D016328:NF-kappa B; D016877:Oxidants; D017382:Reactive Oxygen Species; D001761:Bleomycin; D006861:Hydrogen Peroxide; D007501:Iron; D054303:HIV Reverse Transcriptase