An inhibitor of c-Jun N-terminal kinases (CEP-11004) counteracts the anti-HIV-1 action of trichosanthin.
Trichosanthin (TCS) is a type I ribosome-inactivating protein possessing multiple biological and pharmacological activities. One of its major actions is inhibition of human immunodeficiency virus (HIV) replication. The mechanism is still not clear. It is generally believed that this action is mediated via ribosome inactivation. Recently, we found that some TCS mutants with full ribosome inactivating activity were devoid of anti-HIV-1 effect. This suggested that there might be other mechanisms contributing to the anti-HIV-1 action. This study showed that a commonly used c-Jun N-terminal kinases inhibitor (CEP-11004) could counteract the antiviral action of TCS in C8166 cells. CEP-11004 alone had no effect on HIV-1 replication and TCS alone significantly inhibited this process. When CEP-11004 was used together with TCS, the antiviral action of TCS was much reduced. Two methods were used to assess viral replication. (1) By measuring the HIV-1 reverse transcriptase, TCS on the average reduced viral replication to 52+/-4%. With CEP-11004 pretreatment, TCS appeared to lose the HIV-1 inhibitory activity with viral replication stood at 101+/-7%. (2) By measuring HIV-1 p24, TCS reduced viral replication to 68+/-4%. With CEP-11004 pretreatment, TCS again seemed to lose its anti-HIV-1 activity with HIV-1 replication rose back to 101+/-4%. Both indexes indicated that CEP-11004 counteracted the antiviral action of TCS. Phosphorylation of JNK on the other hand was only slightly elevated by 1.5-fold by TCS and CEP-11004 inhibited this elevation. These results suggested that the anti-HIV-1 effect of TCS may be related to the MAPK signal process downstream from the point of CEP inhibition.
Ouyang
Dong-Yun
DY
Laboratory of Molecular Immunopharmacology, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650223, China.
Chan
Herman
H
Wang
Yuan-Yuan
YY
Huang
Hai
H
Tam
Siu-Cheung
SC
Zheng
Yong-Tang
YT
D019380:Anti-HIV Agents / Q000494:pharmacology*; D002227:Carbazoles / Q000494:pharmacology*; D002460:Cell Line; D004336:Drug Antagonism; D016655:HIV Core Protein p24 / Q000378:metabolism; D054303:HIV Reverse Transcriptase / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation; D015978:Trichosanthin / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D019380:Anti-HIV Agents; C469298:CEP-11004; D002227:Carbazoles; D016655:HIV Core Protein p24; D007211:Indoles; D015978:Trichosanthin; D048031:JNK Mitogen-Activated Protein Kinases; D054303:HIV Reverse Transcriptase