Immunocompromised individuals are at high risk for herpes zoster caused by reactivation of varicella zoster virus (VZV). Long-lasting pain, vision loss, encephalitis, dissemination, recurrence and persistence cause significant morbidity in AIDS patients and greatly impact their quality of life. Current treatments with acyclovir and its derivatives have met with some success, but pain and other sequelae often persist despite therapy. Research into new treatments that stop the spread of HZ lesions may reduce the suffering from complications that continue to place a burden on AIDS patients, their caregivers, and on society. A novel approach to preventing VZV replication is to treat the host cell with compounds that inhibit cyclin-dependent kinases, causing cell cycle arrest and blocking VZV growth. The primary hypothesis is that VZV replication is dependent on the activity of cellular and/or viral kinases that are targets of cdk inhibitors. The goals of this proposal are to test the antiviral effects of the drugs in cell models and in an animal model of VZV replication and ultimately describe the mechanisms whereby cdk inhibitor drugs render cells nonpermissive for VZV replication.
The first aim i s to evaluate the ability of cdk inhibitors to block VZV replication in vitro. Roscovitine, purvalanol, and flavopiridol are three cdk inhibitors that cause cell-cycle arrest and will be tested for their ability to block VZV growth in cell culture.
The second aim i s to evaluate the ability of cdk inhibitors to block VZV replication in vivo. Human skin explants and the SCID-hu mouse implanted with human skin or thymus/liver tissues (a source of T cells) will be used to study the effects of cdk inhibitors on VZV replication.
The third aim i s to define the molecular mechanisms of cdk inhibition of VZV replication. The effects of VZV infection on cell cycle regulatory components will be studied and the proteins involved in these interactions will be identified. This proposal is designed to address at the molecular level how cdk inhibitors prevent VZV replication in vitro and in vivo. Understanding precisely how cdk inhibitors block VZV growth is the starting point for development of effective antiviral agents. ? ?
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