Tat-independent replication of human immunodeficiency viruses.
The replication of human immunodeficiency retroviruses involves a complex series of events that is regulated at both transcriptional and posttranscriptional levels. The tat gene product is a potent trans-activator of viral transcription and therefore an attractive target for the development of antiviral drugs. Tat-defective HIV-1 proviral DNA clones have been shown previously to be replication defective. In this study, we report that tat-defective HIV-1 and HIV-2 viral DNA transfected into U937 cells can direct efficient viral replication in the presence of transcriptional stimulators such as TNF-alpha and PMA. In MT-4 cells, tat-defective HIV-1 can replicate without any stimulation. The viruses recovered from MT-4 cells remained tat defective defined by their inability to infect T cell lines (e.g., Molt 4/8) although replication could be rescued with cytokines. Limited replication was observed in primary mononuclear cells. Furthermore, we showed that Ro 24-7429, a potent tat antagonist and antiviral compound, failed to suppress HIV-1 replication in TNF-alpha-stimulated T cells. These results have important implications for targeting tat as a therapeutic strategy for AIDS.
Luznik
L
L
Department of Medicine, University of California, School of Medicine, San Diego 92093.
Kraus
G
G
Guatelli
J
J
Richman
D
D
Wong-Staal
F
F
D001569:Benzodiazepines / Q000494:pharmacology*; D002460:Cell Line; D003673:Defective Viruses / Q000254:growth & development; D004336:Drug Antagonism; D015696:Gene Products, tat / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006678:HIV / Q000254:growth & development*; D015497:HIV-1 / Q000254:growth & development; D015498:HIV-2 / Q000254:growth & development; D006801:Humans; D009000:Monocytes / Q000821:virology*; D011758:Pyrroles; D013601:T-Lymphocytes / Q000821:virology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014162:Transfection; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D014779:Virus Replication; D054322:tat Gene Products, Human Immunodeficiency Virus
D015696:Gene Products, tat; D011758:Pyrroles; D014409:Tumor Necrosis Factor-alpha; D054322:tat Gene Products, Human Immunodeficiency Virus; D001569:Benzodiazepines; C070024:Ro 24-7429; D013755:Tetradecanoylphorbol Acetate