The Pathogenesis of Avirulent Semliki Forest Virus Infections in Athymic Nude Mice

Abstract

SUMMARYThe course and outcome of intraperitoneally induced infections with the avirulent strain A7(74 ) of Semliki Forest virus have been studied in athymic 'nude' (nu/nu) mice, their heterozygous (nu/+) littermates and conventional Swiss A2G mice. The main distinguishing characteristics of the infection in the nu/nu mice were the persistence of virus in the brain after an initial phase of incomplete virus clearance and the apparent establishment of a secondary phase of virus replication in the brain which was associated with a falling neutralizing antibody response. This secondary phase of virus replication persisted until at least the 28th day after inoculation. In addition the typical histological lesions of encephalitis induced by this virus were rare and focal demyelination, which occurred at a light microscopy level in up to 26 % of nu/+ and Swiss A2G mice, was not observed. It is suggested that in immunocompetent mice the development of lesions including demyelination may be a result of an immunopathological response to virus infection which is related to the presence of thymus derived lymphocytes.

Evaluation of cancer virotherapy with attenuated replicative Semliki forest virus in different rodent tumor models

“…We did not analyze the tissues beyond 1 week p.i., but it is likely that the virus is cleared and becomes undetectable by immunohistochemistry at later time points. Namely, other groups have reported a transient decline in CNS virus titers in infected nude mice, 22,24 although viral RNA could still be detected by in situ hybridization. The decline in virus antigen observed in the present study correlates with peaking of virus-specific IgM and the leakiness of the bloodbrain-barrier that occurs during infection with avirulent SFV.…”

“…Although not analyzed in the present study, the A7(74) CNS titers have been shown to be restricted also in nude and SCID mice (several magnitudes lower than in WT SFV), indicating that the restriction of A7(74) replication is not mediated by cells of the adaptive immune system. 22,24 The efficacy of the virotherapy in the nude mouse model is demonstrated in Figure 1. However, as opposed to the SCID mouse tumor model data in our previous study, 15 only the intratumoral administration route was effective.…”

“…The decline in virus antigen observed in the present study correlates with peaking of virus-specific IgM and the leakiness of the bloodbrain-barrier that occurs during infection with avirulent SFV. 21,22,[24][25][26] We therefore believe that virus-specific IgM may have inhibited virus replication below the detection limit due to temporary access of serum components to the CNS. Although not analyzed in the present study, the A7(74) CNS titers have been shown to be restricted also in nude and SCID mice (several magnitudes lower than in WT SFV), indicating that the restriction of A7(74) replication is not mediated by cells of the adaptive immune system.…”

Persistence of Virulent Semliki Forest Virus in Mouse Brain Following Co-inoculation with Defective Interfering Particles

“…Protected mice (169 in total) were observed for up to 9 months after infection and all but one remained clinically normal. The only other reports of persistent infections with SFV in vertebrate hosts were obtained when the immunological status of the animal had been altered either by prior passive immunization (Seamer et al, 1971) or by using athymic nude mice (Jagelman et al, 1978;Bradish et al, 1979). However, as the persistent infections which we have found were established in immunologically normal mice we conclude that they result directly from the inoculation of DI virus.…”

“…(athymic nude mice: Jagelman et al, 1978;Bradish et al, 1979) or has undergone passive immunotherapy (Seamer et al, 1971). Thus, SFV provides a system to test for the possible effects of DI virus on the establishment of persistence in vivo.…”