Infections with Kaposi's sarcoma-associated herpesvirus (KSHV) account for over 44,000 new cases of Kaposi sarcoma (KS) annually and antiviral drugs currently available are not effective against KSHV-associated malignancies. Passive and/or active immunization against KSHV would thus be beneficial for people at risk for KS due to immunosuppression or living in areas of high KSHV prevalence. The aim of this project is to develop human neutralizing antibodies against Kaposi sarcoma-associated herpesvirus (KSHV) by immunizing a new engineered mouse strain (the “Mighty Mouse”) with KSHV glycoprotein gpK8.1. The “Mighty Mouse” produces human antibodies and replicates the antibody-generating capacity of human beings. As KSHV is highly species-specific and unable to replicate in non-primate hosts, we will test the presence of neutralizing antibodies by infecting KSHV-immunized Mighty mice with MHV-68 variants where envelope glycoprotein gp150 has been replaced by the equivalent KSHV protein gpK8.1. Monoclonal anti KSHV-antibodies will then be produced by the hybridoma technique and tested for their in vivo neutralizing activity in Mighty mice infected with the “KSHV-ized” MHV-68 virus.