Molecular Virology & Microbiology
The Identification and Characterization of TAK, a Cellular Factor that Mediates
HIV Tat Transcriptional Activation
Drs. Herrmann and Andrew Rice identified a crucial cellular co-factor required for productive infection by human immunodeficiency virus (HIV).
The HIV virus particle contains genomic RNA which upon entry into susceptible cells is copied into cDNA and inserted into a cellular chromosome by viral enzymes. The integrated HIV genome is transcribed by cellular RNA polymerase. Efficient transcription of the HIV genome requires a virus-encoded protein named Tat. Tat is unique among transcriptional activators in that its cis-acting target is RNA rather than DNA.
Through the development of an in vitro binding assay, Drs. Rice and Herrmann identified a cellular factor that binds to and mediates the transcriptional activation function of the HIV Tat protein. The Tat co-factor is a complex of proteins termed TAK, for Tat-associated kinase. TAK is composed of catalytic and regulatory subunits known as Cdk9 and cyclin T1, respectively. TAK possesses kinase activity towards the largest subunit of RNA polymerase and phosphorylates it in a manner that is known to activate transcription. Drs. Herrmann and Rice have also demonstrated that TAK is highly regulated in cells of the human immune system. The induction of TAK in these cells correlates with their ability to support productive HIV infection.
The discovery of TAK as the cellular target of the HIV Tat protein has been a major contribution to AIDS research and has identified a new target for the development of anti-viral drugs.
Drs. Herrmann and Rice’s nomination was based on the following publications:
Yang X, Herrmann CH, Rice AP. The human immunodeficiency virus Tat proteins specifically associate with TAK in vivo and require the carboxyl-terminal domain of RNA polymerase II for function. J Virol. 1996 Jul;70(7):4576-84.
Yang X, Gold MO, Tang DN, Lewis DE, Aguilar-Cordova E, Rice AP, Herrmann CH. TAK, an HIV Tat-associated kinase, is a member of the cyclin-dependent family of protein kinases and is induced by activation of peripheral blood lymphocytes and differentiation of promonocytic cell lines. Proc Natl Acad Sci U S A. 1997 Nov 11;94(23):12331-6.
Gold MO, Yang X, Herrmann CH, Rice AP. PITALRE, the catalytic subunit of TAK, is required for human immunodeficiency virus Tat transactivation in vivo. J Virol. 1998 May;72(5):4448-53.