Host-cell positive transcription elongation factor b kinase activity is essential and limiting for HIV type 1 replication.
HIV-1 gene expression and viral replication require the viral transactivator protein Tat. The RNA polymerase II transcriptional elongation factor P-TEFb (cyclin-dependent kinase 9/cyclin T) is a cellular protein kinase that has recently been shown to be a key component of the Tat-transactivation process. For this report, we studied the requirement for P-TEFb in HIV-1 infection, and we now show that P-TEFb is both essential and limiting for HIV-1 replication. Attenuation of P-TEFb kinase activity either by expression of a dominant-negative cyclin-dependent kinase 9 transgene or through the use of small-molecule inhibitors suppresses HIV-1 gene expression and HIV-1 replication. Inhibition of HIV-1 replication is affected in a manner consistent with a direct and specific effect on P-TEFb and the known functional role of P-TEFb in Tat-activated transcription. Tat-activated expression of HIV-1 genes seems uniquely dependent on P-TEFb, as inhibition of P-TEFb activity and HIV-1 replication can be achieved without compromising cell viability or RNA polymerase II-dependent cellular gene transcription. Selective inhibition of the P-TEFb kinase may therefore provide a novel approach for developing chemotherapeutic agents against HIV-1.
Flores
O
O
Department of Biology, Tularik, Inc., South San Francisco, CA 94080, USA.
Lee
G
G
Kessler
J
J
Miller
M
M
Schlief
W
W
Tomassini
J
J
Hazuda
D
D
D002460:Cell Line; D056906:Cyclin T; D016213:Cyclins / Q000502:physiology; D015967:Gene Expression Regulation, Viral / Q000502:physiology; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D042925:Positive Transcriptional Elongation Factor B; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D014162:Transfection; D014779:Virus Replication
C503684:CCNT1 protein, human; D056906:Cyclin T; D016213:Cyclins; D042925:Positive Transcriptional Elongation Factor B; D017346:Protein Serine-Threonine Kinases