EFFICIENT REPLICATION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 AND MEASLES-VIRUS IN A HUMAN-TO-MOUSE GRAFT-VERSUS-HOST DISEASE-MODEL PERMITS IMMUNIZATION RESEARCH

An acute graft versus host disease (GVHD) murine model was developed t o study the pathogenic and protective mechanisms against viruses that replicate in cells of the human immune system. The model allowed effic ient replication of lymphotropic, macrophage and amphitropic strains o f human immunodeficiency virus type 1 (HIV-1) and measles virus (MV). Cytopathic lymphotropic strains of HIV-1 and a wild-type MV strain rep licated in a 'burst'-like manner, whereas a non-cytopathic lymphotropi c HIV-1 strain and all macrophage-tropic HIV-1 strains caused persiste nt infection of the graft. The replication kinetics of infection with these viruses were highly reproducible and were very similar to those observed in natural infection of humans. Infection with these viruses, with the exception of HIV-1(SF2), led to a significant delay and abro gation of the GvHD, indicating a direct immunosuppressive effect. Inte restingly, infection with the lymphotropic HIV-1(SF2) strain was rapid ly and spontaneously abrogated. The model was also shown to be suitabl e for the evaluation of passive immunization strategies. Administratio n of a combination of antibodies against the HIV-1 V3 loop and the HIV -1 CD4 binding sites prevented subsequent infection with HIV-1(IIIB). In contrast, administration of CD4 binding site specific human monoclo nal antibody at a concentration that would neutralize the virus in vit ro enhanced in vivo infection with HTV-1(IIIB). The model also allowed evaluation of in vivo immunization studies. Immunization with a live attenuated measles vaccine resulted in protection from a wild-type MV challenge, whereas immunization with a subunit candidate vaccine appea red to give partial protection.