CDK9/Cyclin T1: A Host Cell Target for Antiretroviral Therapy

Abstract

Hijacking of the host cell’s signal transduction machinery has been increasingly regarded as an important strategy for facilitating virus propagation. The positive-transcription elongation factor (P-TEFb) complex, cyclin-dependent kinase (CDK)9/cyclin T1, is an example of such an attack by HIV. Upon infection of cells, the HIV protein transactivator of transcription (Tat) forms a highly specific complex with the two host cell proteins CDK9 and cyclin T1. This complex ensures phosphorylation of the native CDK9 substrate, RNA polymerase II, leading to productive elongation of viral RNA in the host cell. Although challenging, inhibition of CDK9 activity with small molecules is a therapeutically valid strategy to inhibit HIV replication. Other than direct antiviral agents, that inhibit HIV replication through a direct interaction with viral proteins, CDK9 inhibitors might not suffer from the emergence of resistant virus strains. This review outlines the advantages and prospects of selective CDK9 inhibitors in the management of HIV infections.

A novel drug discovery concept for tuberculosis: Inhibition of bacterial and host cell signalling

“…Ref. [2]. Pathogens are typically hijacking the host cell signalling machinery to ensure their propagation.…”

Direct inhibition of CDK9 blocks HIV-1 replication without preventing T-cell activation in primary human peripheral blood lymphocytes

“…The most common therapeutic method to reduce HIV-1 viral loads is Highly Active AntiRetroviral Therapy (HAART), which combines drugs that directly target at least two HIV-1 proteins, the reverse transcriptase (RT) and the protease (Pro) (reviewed in Klebl and Choidas, 2006). However, one major problem associated with the current HAART is the appearance of, and selection for novel HIV-1 strains resistant to current antiretroviral drugs.…”

“…Thus, there is an urgent need for development of drugs with novel mechanisms of action. In particular, it has become increasingly apparent, that "indirect cellular targets" (nonviral) may represent a solution to this problem (reviewed in Klebl and Choidas, 2006). One potential "indirect target" is the cyclin T1/CDK9 complex.…”

Generation and validation of the first predictive pharmacophore model for cyclin-dependent kinase 9 inhibitors

“…Currently, there are thirteen known members in the CDK family [1]. As one of the transcriptional CDKs, CDK9 complexes with cyclin T or cyclin K to form the positive transcription elongation factor b (P-TEFb), and promotes efficient mRNA elongation by phosphorylating the carboxy-terminal domain (CTD) of RNA polymerase II (RNAPII).…”

“…In particular, as a kinase discovered in HIV pathogenesis, CDK9 has demonstrated a unique functional role in HIV-1 transcription and replication. The viral transcription would be aborted by negative elongation factors unless the viral protein, transactivator of transcription (Tat), binds to the nascent transactivation-responsive (TAR) RNA and recruits P-TEFb to the HIV-1 LTR promoter, which specifically activates HIV-1 transcription [1,2]. Therefore, inhibition of CDK9 activity would have potential therapeutic applications in the management of HIV infections.…”