The pathogenic mechanisms underlying lentivirus infection of the CNS are important to understand. A key determinant for lentivirus replication is cellular activation. Recently, we discovered that visna virus activates mitogen-activated protein kinase (MAPK) as early as 15 minutes post-infection, and sustains MAPK activation throughout the course of viral infection in vitro.MAPK is typically activated only transiently except in cancerous cells. Chronic activation of MAPK in cells of the CNS has been linked to inflammatory, demyelinating, and degenerative CNS diseases such as Alzheimer's disease and multiple sclerosis and may, in fact, be a common pathway that underlies the neurological changes of many CNS diseases, including HIV-associated dementia. In this application, we propose to define the viral protein/cellular protein interactions critical for induction and sustained activation of MAPK, evaluate the contribution of MAPK activation to CNS disease, and define the function of the Tat protein in the development of lentivirus-induced CNS disease. Our hypothesis is that visna virus initiates an intracellular signaling cascade, consisting minimally of specific sequentially activated and temporally regulated protein kinases, at least one of which, MAPK, is absolutely required for virus replication. The function of the visna virus transactivating protein, Tat, may also rely on interactions with cellular transcription factors and/or other kinases activated by MAPK that facilitate transcription of viral genes as well as a select subset of cellular genes.
The specific aims will identify critical virus/cell interactions occurring at multiple stages of viral replication - integration, transcriptional activation, assembly and virus maturation.
In Aim 1, the mechanisms of action of the visna virus Tat protein will be identified. In particular, the Tat-associated kinase and other relevant proteins involved in transactivation of viral and cellular genes will be identified.
In Aim 2, the mechanism of visna virus induction of rapid and sustained activation of MAPK will be examined.
In Aim 3, the stages of visna virus replication regulated by MAPK activation will be determined.
In Aim 4, we will examine in vivo whether there is a correlation between MAPK activation and the development of inflammatory and demyelinating changes in the CNS of sheep infected with visna virus.
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