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Select humans and animals control persistent viral infections via adaptive immune responses that include production of neutralizing antibodies. The precise genetic basis for the control remains enigmatic. Here, we report positional cloning of the gene responsible for production of retrovirus-neutralizing antibodies in mice of the I/LnJ strain. It encodes the beta subunit of the non-classical major histocompatibility complex class II (MHC-II)-like molecule H2-O, a negative regulator of antigen presentation. The recessive and functionally null I/LnJH2-Oballele supported the production of virus-neutralizing antibodies independently of the classical MHC haplotype. Subsequent bioinformatics and functional analyses of the human H2-Ob homolog, HLA-DOB, revealed both loss- and gain-of-function alleles, which could affect the ability of their carriers to control infections with human hepatitis B (HBV) and C (HCV) viruses. Thus, understanding of the previously unappreciated role of H2-O (HLA-DO) in immunity to infections may suggest new approaches in achieving neutralizing immunity to viruses.I/LnJ mice are resistant to retroviruses by producing virus-neutralizing antibodiesResistance is conferred by mutant non-classical MHC class II molecule H2-OMutations in several alleles of human HLA-DOB affected antigen presentationWild-type H2-O and HLA-DO serve as negative regulators of anti-viral immunityGenetics affect sensitivity of animals and humans to viral infections. Denzin et al. show that mice from the I/LnJ strain produce neutralizing antibodies against retroviruses due to inactivation of beta subunit of non-classical major histocompatibility complex (MHC) protein H2-O. Mutations found in human orthologous HLA-DO genes may explain resistance or sensitivity to hepatitis B and C viruses.