Abstract
Current therapy for human immunodeficiency virus (HIV-1) infection relies primarily on the administration of anti-retroviral nucleoside analogues, either alone or in combination with HIV-protease inhibitors. Although these drugs have a clinical benefit, continuous therapy with the drugs leads to drug-resistant strains of the virus. Recently, significant progress has been made towards the development of natural and synthetic agents that can directly inhibit HIV-1 replication or its essential enzymes. We previously reported on the pharmacological cyclin-dependent kinase inhibitor (PCI) r-roscovitine as a potential inhibitor of HIV-1 replication. PCIs are among the most promising novel antiviral agents to emerge over the past few years. Potent activity on viral replication combined with proliferation inhibition without the emergence of resistant viruses, which are normally observed in HAART patients; make PCIs ideal candidates for HIV-1 inhibition. To this end we evaluated twenty four cdk inhibitors for their effect on HIV-1 replication in vitro. Screening of these compounds identified alsterpaullone as the most potent inhibitor of HIV-1 with activity at 150 nM. We found that alsterpaullone effectively inhibits cdk2 activity in HIV-1 infected cells with a low IC50 compared to control uninfected cells. The effects of alsterpaullone were associated with suppression of cdk2 and cyclin expression. Combining both alsterpaullone and r-roscovitine (cyc202) in treatment exhibited even stronger inhibitory activities in HIV-1 infected PBMCs.
Highlights
Human immunodeficiency virus type 1 (HIV-1) is the causative agent of Acquired Immunodeficiency Syndrome (AIDS)
These results imply that cdk2 inhibitors that target the G1/S and early S phases may effectively block viral replication in primary cells when infected with HIV-1 field isolates
We investigated whether targeting the cdk/cyclin axis could inhibit the growth of HIV-1 infected cells and assessed this hypothesis using multiple cdk inhibitors
Summary
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. Expression of the HIV-1 proviral genome requires host cell transcription factors as well as the Tat viral transactivator (reviewed in [1,2,3]). Tat stimulates formation of full-length transcripts from the HIV-1 promoter [4,5] by promoting efficient transcriptional elongation
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