Topotecan inhibits human immunodeficiency virus type 1 infection through a topoisomerase-independent mechanism in a cell line with altered topoisomerase I.
Topotecan (TPT), a known inhibitor of topoisomerase I, has previously been shown to inhibit the replication of several viruses. The mechanism of inhibition was proposed to be the inhibition of topoisomerase I. We report that TPT decreased replication of human immunodeficiency virus type 1 (HIV-1) in CPT-K5, a cell line with a topoisomerase I mutation. TPT inhibited production of HIV-1 RNA and p24 in CPT-K5 and wild-type cells equally effectively. The antiviral effects of TPT were observed not only in the topoisomerase-mutated CPT-K5 line but also in peripheral blood mononuclear cells (PBMC) acutely infected with clinical isolates and in OM10.1 cells latently infected with HIV and activated by tumor necrosis factor alpha. Little toxicity from TPT was noted in HIV-1-infected PBMC and in CPT-K5 and OM10.1 cells as measured by cell growth and proliferation assays. These observations suggest that TPT targets factors in virus replication other than cellular topoisomerase I and inhibits cytokine-mediated activation in latently infected cells by means other than cytotoxicity. These results suggest a potential for TPT and for other camptothecins in anti-HIV therapy alone and in combination with other antiretroviral drugs.
Zhang
J L
JL
Division of Infectious Diseases, Charles A. Dana Research Institute, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Sharma
P L
PL
Li
C J
CJ
Dezube
B J
BJ
Pardee
A B
AB
Crumpacker
C S
CS
D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000188:drug therapy*; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D059004:Topoisomerase I Inhibitors; D019772:Topotecan; D014409:Tumor Necrosis Factor-alpha / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D014409:Tumor Necrosis Factor-alpha; D019772:Topotecan; D002166:Camptothecin