MURINE LEUKEMIA VIRUS-INDUCED NEURODEGENERATION OF RATS - ENHANCEMENTOF NEUROPATHOGENICITY CORRELATES WITH ENHANCED VIRAL TROPISM FOR MACROPHAGES, MICROGLIA, AND BRAIN VASCULAR CELLS

A highly neuropathogenic retrovirus, NT40, was generated by serially p assaging an infectious molecular clone of Friend murine leukemia virus , FB29, through F344 Fisher rats. NT40 induced severe neurological sig ns such as reflex abnormalities and ataxia within 4-6 weeks following neonatal inoculation. FB29 led to only very mild neurological dysfunct ions with longer incubation periods. Pathological alterations were cha racterized by mild (FB29) to extensive (NT40) noninflammatory spongifo rm degeneration, mainly of brain-stem areas. Infectious center assays revealed that viral titers in brain tissues of NT40-infected rats were 100-fold higher than those of FB29-infected animals. Employing immuno histochemistry, in situ hybridization, and flow cytometry, NT40 was fo und to infect many endothelial cells of brain blood vessels and microg lia, whereas FB29 infected only microglia and those to a lower extent However, when isolated from adult diseased rats, microglial cells turn ed out in both cases to be nonproductively infected with either FB29 o r NT40. Of peripheral organs, we found enhanced levels of NT40 in peri toneal macrophages but not in spleen, thymus, or serum when compared t o FB29. Altogether these data suggest that an expanded cellular tropis m within the CNS and elevated viral titers in macrophages and microgli a correlated with enhancement of neuropathogenicity. (C) 1995 Academic Press, Inc.