Neurologic disease induced by polytropic murine retroviruses

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Neurologic disease induced by polytropic murine retroviruses: neurovirulence

determined by efficiency of spread to microglial cells

Several murine leukemia viruses (MuLV) induce neurologic disease in

susceptible mice. To identify features of central nervous system (CNS)

infection that correlate with neurovirulence, we compared two neurovirulent

MuLV, Fr98 and Fr98/SE, with a nonneurovirulent MuLV, Fr54. All three

viruses utilize the polytropic receptor and are coisogenic, each containing

a different envelope gene within a common genetic background. Both Fr98 and

Fr98/SE induce a clinical neurologic disease characterized by

hyperexcitability and ataxia yet differ in incubation period, 16 to 30 and

30 to 60 days, respectively. Fr54 infects the CNS but fails to induce

clinical signs of neurologic disease. In this study, we compared the

histopathology, regional virus distribution, and cell tropism in the brain,

as well as the relative CNS viral burdens. All three viruses induced similar

histopathologic effects, characterized by intense reactive astrogliosis and

microglial activation associated with minimal vacuolar degeneration. The

infected target cells for each virus consisted primarily of endothelial and

microglial cells, with rare oligodendrocytes. Infection localized

predominantly in white matter tracts of the cerebellum, internal capsule,

and corpus callosum. The only feature that correlated with relative

neurovirulence was viral burden as measured by both viral CA protein

expression in cerebellar homogenates and quantification of infected cells.

Interestingly, Fr54 (nonneurovirulent) and Fr98/SE (slow disease) had

similar viral burdens at 3 weeks postinoculation, suggesting that they

entered the brain with comparable efficiencies. However, spread of Fr98/SE

within the brain thereafter exceeded that of Fr54, reaching levels of viral

burden comparable to that seen for Fr98 (rapid disease) at 3 weeks. These

results suggest that the determinants of neurovirulence in the envelope gene

may influence the efficiency of virus spread within the brain and that a

critical number of infected cells may be required for induction of clinical

neurologic disease. J. Virol., Jul 1997, 5287-5294, Vol 71, No. 7, SJ

on, KJ Hasenkrug, B Chesebro and JL Portis,Laboratory of Persistent

Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy

and Infectious Diseases, National Institutes of Health, Hamilton, Montana

59840, USA.

http://jvi.asm.org/cgi/content/abstract/71/7/5287