1st International AIDS Society Conference on HIV Pathogenesis and Treatment Buenos Aires, Argentina - July 8-11, 2001

[ABSTRACT:] The Tat and Rev regulatory proteins encoded by HIV-1 are both expressed early in the viral life cycle and are both essential for viral replication and progression to the late, structural phase of viral gene expression. Tat is a potent transcriptional activator of the HIV-1 long terminal repeat (LTR) promoter element that is recruited to the LTR by an RNA target site termed TAR. It is now clear that the role of Tat is to bind to the human protein cyclin T1, a component of the transcription elongation factor P-TEFb, and to thereby recruit P-TEFb to the LTR. Recruitment of P-TEFb induces phosphorylation of a sub-domain of RNA polymerase II and leads to efficient transcription of the HIV-1 provirus. P-TEFb recruitment appears to be the sole function of Tat, as tethering of P-TEFb to the LTR by other means, in the absence of Tat, results in the same level of activation of viral transcription.

In contrast to Tat, Rev acts at the posttranscriptional level and is essential for the nuclear export, and hence translation, of late viral mRNA species. Rev binds to these RNAs, via an RNA target termed the RRE, and also to a cellular factor termed Crm1, which mediates the actual RNA export. Recently, we have been able to construct an entirely synthetic Rev-like nuclear export factor that consists of a bacterial RNA binding domain linked to an heterologous Crm1 binding domain. The finding that this synthetic protein can fully substitute for Rev demonstrates that Crm1 recruitment is the sole function of HIV-1 Rev. Therefore, both Tat and Rev serve simply to target pre-existing cellular factors to novel RNA target sites present in the HIV-1 genome.

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