title: Persistence of viremia and production of neutralizing antibodies differentially regulated by polymorphic APOBEC3 and BAFF-R loci in friend virus-infected mice.
abstract: Several host genes control retroviral replication and pathogenesis through the regulation of immune responses to viral antigens. The Rfv3 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 the APOBEC3 and BAFF-R loci, both of which show functional polymorphisms among different strains of mice. The exon 5-lacking product of the APOBEC3 allele expressed in FV-resistant C57BL/6 (B6) mice directly restricts viral replication, and mice lacking the B6-derived APOBEC3 exhibit exaggerated pathology and reduced production of neutralizing antibodies. However, the mechanisms by which the polymorphisms at the APOBEC3 locus affect the production of neutralizing antibodies remain unclear. Here we show that the APOBEC3 genotypes do not directly affect the B-cell repertoire, and mice lacking B6-derived APOBEC3 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-derived APOBEC3 or a lack of the wild-type BAFF-R resulted in slower production of neutralizing antibodies. Indeed, B cells were hyperactivated soon after infection in the APOBEC3- or BAFF-R-deficient mice. In contrast to mice deficient in the B6-derived APOBEC3, which cleared viremia by 4 weeks after FV infection, mice lacking the functional BAFF-R allele exhibited sustained viremia, indicating that the polymorphisms at the BAFF-R locus may better explain the Rfv3-defining phenotype of persistent viremia.
authors.affiliation: Department of Immunology, Kinki University School of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, Osaka 589-8511, Japan.
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Tsuji-Kawahara
authors.forename: Tomomi
authors.initials: T
authors.lastname: Chikaishi
authors.forename: Eri
authors.initials: E
authors.lastname: Takeda
authors.forename: Maiko
authors.initials: M
authors.lastname: Kato
authors.forename: Saori
authors.initials: S
authors.lastname: Kinoshita
authors.forename: Eiji
authors.initials: E
authors.lastname: Kajiwara
authors.forename: Shiki
authors.initials: S
authors.lastname: Takamura
authors.forename: Masaaki
authors.initials: M
authors.lastname: Miyazawa
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood / Q000276:immunology*; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D053265:B-Cell Activation Factor Receptor / Q000235:genetics / Q000276:immunology; D003564:Cytidine Deaminase / Q000235:genetics* / Q000276:immunology; D005622:Friend murine leukemia virus / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011110:Polymorphism, Genetic; D012192:Retroviridae Infections / Q000235:genetics / Q000276:immunology / Q000662:veterinary* / Q000821:virology; D012376:Rodent Diseases / Q000235:genetics* / Q000276:immunology* / Q000821:virology; D014766:Viremia / Q000235:genetics* / Q000276:immunology / Q000821:virology
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D053265:B-Cell Activation Factor Receptor; C486662:Tnfrsf13c protein, mouse; C503504:Apobec3 protein, mouse; D003564:Cytidine Deaminase