TAT-INDEPENDENT REPLICATION OF HUMAN IMMUNODEFICIENCY VIRUSES

The replication of human immunodeficiency retroviruses involves a comp lex series of events that is regulated at both transcriptional and pos ttranscriptional levels. The tat gene product is a potent trans-activa tor of viral transcription and therefore an attractive target for the development of antiviral drugs. Tat-defective HIV-1 proviral DNA clone s have been shown previously to be replication defective. In this stud y, 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 cel ls, tat-defective HIV-1 can replicate without any stimulation. The vir uses recovered from MT-4 cells remained tat defective defined by their inability to infect T cell lines (e.g., Molt 4/8) although replicatio n 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 impor tant implications for targeting tat as a therapeutic strategy for AIDS .