Measles virus (MV) strain CAM/RB which was adapted to growth in

Measles virus (MV) strain CAM/RB which was adapted to growth in the BMS-740808 brain of newborn rodents is highly neurovirulent. and 550S→P) and K29 (535E→G). When the corresponding recombinant viruses were tested in brains of newborn rodents we found that the mutations mediating antibody escape did not confer differential neurovirulence. In contrast however replacement of two different amino acids at positions 195G→R and 200S→N which had been described for the escape mutant set caused the change in neurovirulence. Thus antibody escape and neurovirulence appear not to be associated with the same structural alterations of the MV H protein. Among the morbilliviruses measles virus (MV) is associated with an intermediate capacity to cause neurological complications. These include the acute postinfectious measles encephalitis which develops 2 to 4 weeks after infection or the late complications measles SAP155 inclusion body encephalitis in immunocompromised patients and subacute BMS-740808 sclerosing panencephalitis (SSPE) which develops months to years after the initial infection based on a persistent MV infection (reviewed in reference 3). In late stages of SSPE massive amounts of MV antigen can be detected in inclusion bodies in various neural cell types (1). SSPE is characterized by a restriction of the viral envelope protein expression as a consequence of mutational transcriptional and translational alterations (1 5 An additional constraint is exerted by the high concentration of antiviral antibodies present in the cerebrospinal fluid of SSPE patients. Tissue culture experiments demonstrated that virus-neutralizing antibodies downregulate not only viral gene expression but also transcription and can completely suppress viral replication (2 39 Similar results have been obtained in vivo using Lewis rats (22 38 Suckling rodents have successfully been used as animal models (predominantly mice and rats) for different forms of MV-induced encephalitis (21 23 38 Transgenic mice which express CD46 one of the MV BMS-740808 receptors (7 27 have also been used to induce MV-induced encephalitis (15 26 31 However for development of the acute encephalitis following infection of suckling rats with the rodent-adapted MV strain CAM/RB or mice with the HNT (hamster neurotropic) strain the transgenic expression of receptors such as CD46 appears not to be necessary (23 24 32 35 After intracerebral infection with CAM/RB (RB indicates passage in rat brain) 1 to 14-day-old Lewis rats develop a lethal acute measles encephalitis whereas older animals develop a subacute measles encephalitis (23). Antiviral antibodies may lead to a restriction of the viral gene expression but also to the selection of escape variants. When monoclonal antibodies (MAbs) are used experimentally to select escape variants resulting viruses with altered hemagglutinin (H) protein structures might induce differential pathogenicity in animals. This was observed with escape variants selected in the presence of the MAbs L77 Nc32 K71 and K29 recognizing four different epitopes on MV H (20). Variant CAM/RB viruses escaping the MAbs L77 and Nc32 were neurovirulent whereas viruses escaping the MAbs K29 and K71 appeared to have lost neurovirulence. The H genes of these BMS-740808 viruses have been sequenced elsewhere (20). However because of the number of amino acid changes in this gene and the possibility that changes in other genes also affect the specific BMS-740808 phenotype the molecular BMS-740808 basis of the antibody escape and neurovirulence could not be unequivocally determined in earlier experiments. The generation of recombinant MVs has opened the way to make definitive linkages between mutations introduced experimentally into the viral genome and specific phenotypes (30). We therefore assessed using recombinant MVs the influence of directed mutations in the H gene on antibody escape and neurovirulence. After intracerebral injection into suckling C57BL/6 mice a recombinant virus expressing the H gene of CAM/RB (EdtagCAMH) induced neurological disease and MV antigen was found in neurons and neuronal processes of the hippocampus frontal and olfactory cortices and neostriatum (9). However the neurovirulence of EdtagCAMH was partially reduced compared to that of the.