Stavudine selectively induces apoptosis in HIV type 1-infected cells.
We evaluated the cytotoxic effects of various human immunodeficiency virus (HIV-1) reverse transcriptase inhibitors (zidovudine, didanosine, zalcitabine, stavudine, and nevirapine) on HIV-1-infected and uninfected T cell lines. Among the compounds, only stavudine (not the others) proved to be more cytotoxic to MOLT-4/IIIB cells (MOLT-4 cells chronically infected with HIV-1) than to uninfected MOLT-4 cells. Its 50% cytotoxic concentrations were 59.8 and 2.2 microM for MOLT-4 and MOLT-4/IIIB cells, respectively. Stavudine was also more cytotoxic to CEM/ROD (CEM cells chronically infected with HIV type 2) than to uninfected CEM cells. Microscopic analysis revealed that stavudine induced apoptosis in MOLT-4/IIIB cells. Apparent chromatin condensation in the nucleus was observed by electron microscopy. Furthermore, a DNA fragmentation ladder was detected by agarose gel electrophoresis. Addition of thymidine to the culture medium could rescue the cells from stavudine-induced apoptosis. The expression of anti-apoptotic protein Bcl-2 was partially downregulated in MOLT-4/IIIB cells after treatment with stavudine. This downregulation was not identified in MOLT-4 cells. These results indicate that stavudine selectively induces apoptosis in HIV-1-infected T cells and may have potential as a novel strategy for effective chemotherapy of the acquired immune deficiency syndrome (AIDS).
Hashimoto
K I
KI
Department of Microbiology, Fukushima Medical College, Japan.
Tsunoda
R
R
Okamoto
M
M
Shigeta
S
S
Baba
M
M
D019380:Anti-HIV Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D053938:DNA Fragmentation; D016049:Didanosine / Q000494:pharmacology; D015536:Down-Regulation; D054303:HIV Reverse Transcriptase / Q000037:antagonists & inhibitors*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D019829:Nevirapine; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011725:Pyridines / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D018119:Stavudine / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000821:virology; D013936:Thymidine / Q000494:pharmacology; D016047:Zalcitabine / Q000494:pharmacology; D015215:Zidovudine / Q000494:pharmacology
D019380:Anti-HIV Agents; D019253:Proto-Oncogene Proteins c-bcl-2; D011725:Pyridines; D018894:Reverse Transcriptase Inhibitors; D015215:Zidovudine; D016047:Zalcitabine; D019829:Nevirapine; D018119:Stavudine; D054303:HIV Reverse Transcriptase; D016049:Didanosine; D013936:Thymidine