PATHOGENESIS OF DISEASES INDUCED BY NON-ONCOGENIC RETROVIRUSES

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Abstract

The overall goal of this project is to understand how retroviruses adversely affect the central nervous system and the nature of the role of macrophages in disease pathogenesis. We are utilizing the mouse as an animal model and are investigating two types of neurovirulent viruses that cause different brain diseases. We have studied the host and viral factors which control neuroinvasiveness (the capacity of these viruses to enter the brain), and the determinants of neurovirulence (induction of brain disease) after these viruses have entered the brain. Our work on neuroinvasiveness has uncovered a viral protein that has been known to exist for many years, but its function in the virus life cycle is unknown. We are interested in understanding the function of this protein since it appears to be an accessory protein of the virus that promotes virus dissemination in the host. A fragment of this protein has been found to be incorporated into virions. Our work on neurovirulence has focused on the role of the viral envelope protein and its interaction with microglial cells (brain macrophages). Although these viruses interfere with normal neuronal function and in some cases actually result in neuronal death, they do not infect the neurons they damage. Instead, it is infection of microglial cells (fixed tissue macrophages of the central nervous system) that is responsible for the neurovirulence of these viruses. Furthermore, neurovirulence has been mapped to the viral envelope protein (coat protein of the virus) and we are interested in understanding the nature of the interaction between this protein and microglial cells which appears to play such an important role in disease pathogenesis. This year we have found that increased expression in the brain of two beta-chemokines, MIP-1 alpha and MIP-1 beta is associated, both spatially and temporally, with the induction of virus-induced neurodegeneration. Furthermore, upregulation of these genes is dependent on the amino acid sequence of the viral envelope protein. This is particularly interesting because these chemokines are also upregulated in the brains of patients with AIDS Dementia. Although increased expression of the cytokines TNF alpha and beta are also upregulated in the brains of infected mice, this appears to be a late event likely representing a response to the neuronal damage.