Cyclin-dependent kinases as therapeutic targets for HIV-1 infection

ABSTRACT

Introduction: A number of cyclin-dependent kinases (CDKs) mediate key steps in the HIV-1 replication cycle and therefore have potential to serve as therapeutic targets for HIV-1 infection, especially in HIV-1 cure strategies. Current HIV-1 cure strategies involve the development of small molecules that are able to activate HIV-1 from latent infection, thereby allowing the immune system to recognize and clear infected cells.

Areas covered: The role of seven CDK family members in the HIV-1 replication cycle is reviewed, with a focus on CDK9, as the mechanism whereby the viral Tat protein utilizes CDK9 to enhance viral replication is known in considerable detail.

Expert opinion: Given the essential roles of CDKs in cellular proliferation and gene expression, small molecules that inhibit CDKs are unlikely to be feasible therapeutics for HIV-1 infection. However, small molecules that activate CDK9 and other select CDKs such as CDK11 have potential to reactivate latent HIV-1 and contribute to a functional cure of infection.

KEYWORDS:

• HIV
• latency
• HIV cure
• shock and kill
• CDK
• CDK9
• Cyclin T1
• P-TEFb
• CDK11
• latency reversing agents

Article highlights

• The HIV-1 replication cycle

• Seven CDK family members are involved in the HIV-1 replication cycle

• CDK9 and Cyclin T1 comprise a factor named P-TEFb that mediates HIV-1 Tat protein activation of RNAP II elongation of the integrated HIV-1 provirus

• CDK9/P-TEFb is down-regulated in CD4⁺ T cells that harbor latent HIV-1 and this CDK must be up-regulated for the activation of latent viruses

• The development of small molecules that activate CDK9/P-TEFb have potential in HIV-1 cure strategies

CDK11 has recently been shown to be essential in the 3' end processing of the HIV-1 RNA genome and future studies are needed to determine if this CDK family member is a feasible target for HIV cure strategies

This box summarizes key points contained in the article.

Acknowledgements

I thank Carolyn Rice for comments on the manuscript.

Declaration of interest

Research carried out in A. Rice’s laboratory has been supported by National Institutes of Health grants AI116173, AI124866 and P30AI1036211 (Baylor-UT Houston Center for AIDS Research). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This paper was funded in part by the National Institute of Allergy and Infectious Diseases (AI116173, AI124866 and P30AI1036211).