Cyclin dependent kinases (Cdks) are essential for the control of cell cycle progression. Inhibitors of these enzymes are anticipated to possess therapeutic utility against a wide variety of proliferative diseases, and consequently almost 20 inhibitors from this family of enzymes are in various stages of pharmaceutical development for the treatment of neoplastic disease. Less well exploited is the ability of Cdk inhibition to prevent viral replication. As mammalian cells progress through the cell cycle, their ability to support DNA replication alters and it is only during the S-phase that the full repertoire of molecules necessary to achieve this function is present. Since viruses are dependent on the host's machinery for DNA replication, viral replication occurs most efficiently in the S-phase. This is true for HSV replication, which has long been associated with cellular functions known to be involved in cell cycle progression. In 1998, researchers from the University of Pennsylvania reported the breakthrough finding that Cdk inhibitors were able to block HSV replication. More importantly, drug resistance was not a problem. In the following year the same group reported that HSV failed to develop resistance to Cdk inhibitors since they exerted their antiviral effect by blocking cellular rather that viral Cdk activity. Moreover, several HSV replicative functions require the activities of the Cdks inhibited by these drugs and consequently multiple mutations would be required to achieve resistance to a single drug. More recently, the University of Pennsylvania group and two other groups (Dr. Fatah Kashanchi, and Dr. Peter Nelson) have shown that inhibitors of human Cdks block HIV-1 as well as HSV-1. Furthermore the anti-HSV effects of these inhibitors and a conventional antiherpesvirus drug, acyclovir, were additive, demonstrating that the two drugs act by distinct mechanisms. The global impact of HIV-1 infection has been well documented, as has the success of HAART therapy. Where available, HAART has increased life expectancy and delayed the onset of AIDs however due in part to the increased life expectancy of patients with HIV-infection, the incidence of drug resistance has become a major issue. A second factor related to prolonged survival of HIV-1 infected patients is an increased incidence of HSV infection. HSV increases HIV replication by as much as 3.4-fold. Consequently, HIV patients have been shown to benefit if they are treated with the anti-herpes treatment, acyclovir. In some studies, the successful prevention of sexually transmitted diseases reduced the incidence of HIV infection by 42%. Thus the data reported by the University of Pennsylvania group and its collaborators is important for three major reasons. Firstly, since the effects of HAART and Cdk inhibitors are likely to be additive, the latter could be included in current antiviral treatments. Secondly, the use of Cdk inhibitors may avoid the drug resistance problems of HAART therapy thus providing an alternative if first line therapies start to fail. Thirdly, the use of Cdk inhibitors could reduce the load of both HIV and HSV thus limiting the problems specific to this particular comorbitity. Moreover, many viral diseases involve cell proliferation as part of their pathology (such as HPV-induced cervical carcinomas, KSHV-induced Kaposi’s sarcoma, EBV-induced Burkitt’s lymphoma, HTLV-induced Adult T cell Leukemia, etc.). Cdk inhibitors would be able to treat both the primary cause (ie viral infection) and the effect (ie proliferative disease) of these pathologies and could therefore be used as preferred drugs to treat such infections. Despite these advantages antiviral activity has yet to feature significantly in the indications of Cdk inhibitors. Addressing this issue could dramatically increase the benefit of such drugs.

Adapted from Schang et al*, Journal of Virology, August 2002, p. 7874-7882, Vol. 76, No. 15

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