Persistence of Viremia and Production of Neutralizing Antibodies Differentially Regulated by PolymorphicAPOBEC3andBAFF-RLoci in Friend Virus-Infected Mice

Several host genes control retroviral replication and pathogenesis through the regulation of immune responses to viral antigens. TheRfv3 gene influences the persistence of viremia and production of virus-neutralizing antibodies in mice infected with Friend mouse retrovirus complex (FV). This locus has been mapped within a narrow segment of mouse chromosome 15 harboring theAPOBEC3 andBAFF-R loci, both of which show functional polymorphisms among different strains of mice. The exon 5-lacking product of theAPOBEC3 allele expressed in FV-resistant C57BL/6 (B6) mice directly restricts viral replication, and mice lacking the B6-derivedAPOBEC3 exhibit exaggerated pathology and reduced production of neutralizing antibodies. However, the mechanisms by which the polymorphisms at theAPOBEC3 locus affect the production of neutralizing antibodies remain unclear. Here we show that theAPOBEC3 genotypes do not directly affect the B-cell repertoire, and mice lacking B6-derivedAPOBEC3 still produce FV-neutralizing antibodies in the presence of primed T helper cells. Instead, higher viral loads at a very early stage of FV infection caused by either a lack of the B6-derivedAPOBEC3 or a lack of the wild-typeBAFF-R resulted in slower production of neutralizing antibodies. Indeed, B cells were hyperactivated soon after infection in theAPOBEC3 - orBAFF-R -deficient mice. In contrast to mice deficient in the B6-derivedAPOBEC3 , which cleared viremia by 4 weeks after FV infection, mice lacking the functionalBAFF-R allele exhibited sustained viremia, indicating that the polymorphisms at theBAFF-R locus may better explain theRfv3 -defining phenotype of persistent viremia.