On the mechanism of neurotropism of vesicular stomatitis virus in newborn hamsters. studies with temperature-sensitive mutants

Ontario Cancer Institute and the Department of Medical Biophysics, University of Toronto, 500 Sherbourne Street, Toronto, Ontario, Canada M4X 1K9 The virulence of temperature-sensitive mutants of vesicular stomatitis virus (VSV) injected subcutaneously into newborn hamsters was positively correlated with their tendency to generate revertants and with their leakiness in cultured hamster embryo fibroblasts maintained at 37 °C, the measured body temperature of the animals under our experimental conditions. The complementation group of the mutants seemed important only in that it tended to determine reversion frequency and leakiness. One non-reverting group I mutant (T1026), however, was much less virulent than would be expected from its extreme eakiness at body temperature. The disease produced by the less virulent mutants was characterized by neurological symptoms and led to delayed death, unlike the rapid death produced by virulent mutants. Infectious virus could be found in higher titres in the brains than in peripheral organs of such animals (with ratios as high as 10 8 ). This neurotropism was not correlated with the complementation group of themutant but was shown to be the consequence of survival for more than 3 days after injection. Age was not responsible for the effect. Animals injected at birth with T1026 were completely resistant to subcutaneous superinfection with the highly virulent wild-type virus HR at 3 to 4 days, though non-T1026-protected animals were completely sensitive. When HR was injected intracerebrally at 3 to 4 days, the T1026-protected animals allowed replication to high titres in the brain but not in peripheral organs, whereas non-T1026-protected animals allowed replication to high titres in both brain and in peripheral organs. We suggest from these results that the observed neurotropism is produced by a resistance mechanism operative in peripheral organs but not in the brain; this resistance develops rapidly in newborn animals on exposure to virus and clears virus from the peripheral organs leaving it in the brain. It is possible that our effect represents a controlled and accelerated induction of the classical peripheral resistance of animals to various viruses which normally develops with age. Received 4 April 1975; accepted 31 July 1975.