BRAIN-SPECIFIC AND INTESTINE-SPECIFIC VARIANTS OF REOVIRUS SEROTYPE-3STRAIN DEARING ARE SELECTED DURING CHRONIC INFECTION OF SEVERE COMBINED IMMUNODEFICIENT MICE

`Mutants of mammalian reoviruses, enteric double-stranded-RNA-containi ng viruses that spread systemically after primary replication in intes tinal tissue, have been extensively studied as models of viral pathoge nesis, While reovirus serotype 3 strain Dearing (T3D) causes acute enc ephalitis in newborn mice, adult severe combined immunodeficient (SCID ) mice develop chronic infection with T3D, with some mice living more than 100 days after infection (B. L. Haller, M. L. Barkon, G. P. Vogle r, and H. W. Virgin IV, J, Virol, 69:357-364, 1995). To determine whet her organ-specific reovirus variants are selected during chronic infec tion, we characterized the pathogenetic properties of two variants of T3D isolated 87 days after intraperitoneal infection of adult SCID mic e. A brain-specific variant (T3DvBr) (i) grew to a higher titer than T 3D in SCID mouse brain (but not intestine) after intraperitoneal inocu lation, (ii) killed adult SCID mice faster than T3D, and (iii) grew we ll in neonatal NIH Swiss [NIH(s)] mouse brain tissue after intramuscul ar but not peroral inoculation. An intestine-specific variant (T3DvInt ) (i) grew to a higher titer than T3D in SCID mouse intestine (but not brain) after intraperitoneal inoculation, (ii) killed SCID mice with kinetics equivalent to those of T3D, (iii) was much less virulent than T3D in neonatal NIH(s) mice, (iv) grew better than T3D in intestines after intramuscular or peroral inoculation into neonatal NIH(s) mice, and (v) grew poorly in brain tissue of neonatal NIH(s) mice after intr amuscular inoculation. During prolonged infection of SCID mice, organ specific variants of T3D, which are more efficient than wild-type T3D at one specific stage in reovirus pathogenesis, are selected.