Recombinant measles viruses expressing altered hemagglutinin (H) genes: Functional separation of mutations determining H antibody escape from neurovirulence

Measles virus (NM strain CAM/RB, which was adapted to growth in the brain o f newborn rodents, is highly neurovirulent. It has been reported earlier th at experimentally selected virus variants escaping from the monoclonal anti bodies (MAbs) Nc32 and L77 to hemagglutinin (H) preserved their neurovirule nce, whereas mutants escaping MAbs K71 and K29 were found to be strongly at tenuated (U. G. Liebert et al., J. Virol. 68:1486-1493, 1994). To investiga te the molecular basis of these findings, we have generated a panel of reco mbinant Ws expressing the H protein from CAM/RB and introduced the amino ac id substitutions thought to be responsible for antibody escape and/or neuro virulence. Using these recombinant viruses, we identified the amino acid ch anges conferring escape from the MAbs L77 (377R -->Q and 378M -->K), Nc32 ( 388G -->S), K71 (492E -->K and 550S -->P), and K29 (535E -->G). When the co rresponding recombinant viruses were tested in brains of newborn rodents, w e found that the mutations mediating antibody escape did not confer differe ntial neurovirulence. In contrast, however, replacement of two different am ino acids, at positions 195G -->R and 200S -->N, which had been described f or the escape mutant set, caused the change in neurovirulence. Thus, antibo dy escape and neurovirulence appear not to be associated with the same stru ctural alterations of the MV H protein.