That the hemagglutinin (HA) of reovirus, encoded in the S1 gene, determines the central nervous system (CNS) cell tropism of reovirus type 1 and 3 was shown using recombinant clones containing nine genes from one serotype and the S1 gene from the other. Clone 1.HA3 contains nine genes from type 1 and the S1 gene from type 3; 3.HA1 is the reciprocal clone. Type 3 and 1.HA3 cause a fatal encephalitis in newborn mice with neuronal destruction but no ependymal cell damage, whereas type 1 and 3.HA1 cause a nonfatal ependymal infection but no neuronal damage. Immunofluorescent studies showed no viral antigen in ependymal cells of mice infected with type 3 or 1.HA3 or in neuronal cells of mice infected with type 1 or 3.HA1. With type 3 or clones containing the type 3 HA, maximal brain titers were 10(10) plaque-forming units; maximal titers were 10(8) plaque-forming units for type 1 or clones containing the type 1 HA. This pattern of reovirus virulence for CNS probably relates to the specific interaction of viral HA with neuronal or ependymal surface receptors.

Reovirus type 3 inoculated intracerebrally or subcutaneously into newborn mice induced an acute necrotizing and uniformly fatal encephalitis. Subsequently, between the eighth and tenth day of age, reovirus type 3 infection changed to a nonlethal infection. This pattern of virulence was directly correlated with the ability of the virus to replicate in the brain and histologically was accompanied by a gradual diminution in the intensity and extent of encephalitis such that histological abnormalities were absent in the brains of virus-injected adult animals. Some animals injected at ages 10 to 18 days developed brainstem and diencephalic lesions, indicating a nonuniform resistance of neurons to viral infection with aging. Neither a changing immune response pattern nor a modification or loss of viral receptors appears to explain either the susceptibility of newborn or the resistance of adult animals to reovirus type 3 encephalitis. Splenic mononuclear cells from mice younger (but not older) than 7 days also permitted reovirus type 3 replication in vitro. Thus, the age dependent resistance to reovirus type 3 encephalitis appears related to an intrinsic resistance to viral replication by neuronal cells, a resistance that may occur simultaneously in nonneuronal cell populations.

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A xenogeneic antiserum raised to antireovirus immunoglobulin was used to define an idiotypic determinant present on antibodies to reovirus type 3 hemagglutinin. The same idiotype was identified on nonimmune lymphoid cells and on neuronal cells that specifically bind the hemagglutinin of type 3 reovirus. This idiotypic determinant, called Id3, is shared by (a) a monoclonal antibody to the neutralization site of hemagglutinin from type 3 reovirus; (b) BALB/c serum antibodies to the hemagglutinin of reovirus type 3; (c) R1.1, a murine thymoma cell line that binds reovirus type 3; (d) primary cultures of murine neuronal cells. The presence of an idiotype shared by antihemagglutinin antibodies and by structures on nonlymphoid cells suggests a general relationship between disparate receptors that recognize a common determinant. Furthermore, this suggests a novel approach for the study of viral receptor interactions and for analysis of mechanisms of autoimmune responses.