MECHANISMS OF VIRUS-INDUCED ELASTIC ARTERITIS

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We have developed a novel small animal model of virus induced elastic arteritis that will allow us to define fundamental mechanisms of vascular injury and the role of virus infection and the immune system in controlling or promoting chronic vascular pathology [Nature Medicine, 1997, 3(12):1346-1353]. Little is known about mechanisms that initiate inflammatory lesions of large elastic arteries, and the mechanisms underlying vasculitis are incompletely defined. Recently, attention has been paid to herpesviruses and activated lymphocytes as possible causes or cofactors in vascular injury. Mechanistic studies in a tractable model system have not been performed to determine how herpesvirus infection and the immune system interact to generate or control vascular pathology. We discovered that a newly characterized murine gamma-herpesvirus (gammaHV68) causes striking elastic arteritis in normal mice, and that interferon-gamma (IFNgamma) unresponsive mice and B cell deficient mice are much more susceptible than normal mice to induction of arteritis by gammaHV68. Further analysis revealed (i) a novel tropism of gammaHV68 for vascular smooth muscle cells, (ii) that productive replication is occurring in arteritic lesions, (iii) that IFNgamma acts primarily at the level of somatic cells, and (iv) the pathology of arteritic lesions in IFN-unresponsive and B cell deficient mice are strikingly different. To provide molecular tools for analysis of viral contributions to chronic arteritis we sequenced the genome of gammaHV68 (119,450 bp), demonstrating that gammaHV68 is closely related to the human gamma- herpesviruses Epstein-Barr virus and Kaposi's sarcoma herpesvirus. We have recently isolated mutant and marker rescue gammaHV68, and identified candidate latency-associated gammaHV68 genes. The availability of genetic tools for analysis of the host immune response arid the role of specific viral genes, will allow us to define mechanisms of gammaHV68 induced arteritis as follows. Aim 1. Determine the contribution of latent and productive gammaHV68 infection to chronic arteritis. Aim 2. Determine the mechanism by which IFNgamma regulates arteritis. Aim 3. Determine the mechanism by which B cells regulate arteritis.