ROLE OF IMMUNE-RESPONSES IN PROTECTION AND PATHOGENESIS DURING SEMLIKI FOREST VIRUS ENCEPHALITIS

The course of Semliki Forest virus (SFV) A7(74) infection in immunocom petent BALB/c, athymic nu/nu and severe combined immunodeficient (SCID ) mice was compared. BALB/c mice remained healthy and exhibited transi ent viraemia and infectious virus in the brain from days 2 to 7. Antib odies were detectable by day 5. In comparison, SCID mice displayed a h igh incidence of paralysis and died: the average day of death was day 23. From infection until death, virus was present in blood and brain. No antibodies were detectable. Athymic mice were intermediate with a t ransient viraemia and a persistent (>210 days) sub-clinical central ne rvous system (CNS) infection. These mice produced anti-viral IgM but n ot IgG. The pattern of infection in BALB/c or nu/nu mice could be recr eated in infected SCID mice by transfer of immune serum from BALB/c or nu/nu mice, with the important exception that although BALB/c immune serum could abolish infectivity titres in the CNS, scattered cells pos itive for viral RNA remained. Transfer of serum decreased mortality an d delayed the onset of paralysis. Transfer to infected SCID mice of a non-neutralizing IgG anti-E2 monoclonal antibody did not affect the vi raemia but could also reduce brain virus titres. Irrespective of speci fic immune responses, virus replication in CNS cells was restricted, w as generally non-cytopathic and in the absence of specific immune resp onses could persist. From day 14 lesions of inflammatory, primary demy elination were observed throughout the CNS of BALB/c mice. In contrast , despite prolonged brain virus titres, no demyelinating lesions were observed in infected nu/nu or SCID mice. Lesions could be initiated in the latter by transfer of spleen cells but not antibody. In summary, the focal restricted infection in the CNS of adult mice infected with SFV A7(74) is independent of specific immune responses. IgM antibodies clear the viraemia. IgG antibodies including non-neutralizing antibod ies reduce and clear infectious virus but cells positive for viral RNA remain. These may normally be cleared by T cell responses which are d amaging and give rise to lesions of demyelination.