Inhibition of human immunodeficiency virus type-1 by cdk inhibitors

Human immunodeficiency virus type 1 (HIV-1) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS). Current therapies are capable of controlling viral infection but do not represent a definitive cure. The virus has proven to be capable of developing resistance to therapy, evading the immune response, altering cellular immune function and protecting infected cells from apoptosis. HIV-1 is inherently capable of accomplishing these functions with a limited genome that expresses only nine proteins. As such, the HIV-1 must make extensive use of cellular pathways and subvert native molecular processes for its own purposes.Expression of the HIV-1 proviral genome requires host cell transcription factors as well as the Tat viral transactivator (reviewed in [1-3]). Tat stimulates formation of full-length transcripts from the HIV-1 promoter [4,5] by promoting efficient transcriptional elongation (reviewed in [1,2]). Tat interacts with the bulge of the transactivation response element (TAR) RNA, a hairpin-loop structure at the 5'-end of all nascent viral transcripts [6-9]. Full functional activity of Tat requires host cell cofactors, which interacts with the loop of TAR RNA hairpin (reviewed in [1,2]) as well as other site on the LTR. Tat also associates with a protein kinase that phosphorylates the C-terminal domain (CTD) of RNA Polymerase II (RNA Pol II) called Tat associated kinase (TAK) [10]. The CTD consists of heptapeptide repeats, Tyr1-Ser2-Pro3-Tyr4-Ser5-Pro6-Ser7, which are phosphorylated on serine 2 (Ser-2) and serine 5 (Ser-5) during transcription [11,12]. Recently, serine 7 (Ser-7) has been shown to be phosphorylated by cdk7 [13,14]. Previously, it has also been shown that partially purified TAK and the loop-binding factor represent the same protein complex, cdk9/cyclin T1 [15-17]. Tat associates with cdk9 [16,17] through interaction with cyclin T1 which interacts with the TAR RNA loop structure [15]. Tat interacts with human cyclin T1 through a critica