title: Immunoglobulin somatic hypermutation by APOBEC3/Rfv3 during retroviral infection.
abstract: Somatic hypermutation (SHM) is an integral process in the development of high-affinity antibodies that are important for recovery from viral infections and vaccine-induced protection. Ig SHM occurs predominantly in germinal centers (GC) via the enzymatic activity of activation-induced deaminase (AID). In contrast, the evolutionarily related apolipoprotein B mRNA-editing enzyme, catalytic polypeptide 3 (APOBEC3) proteins are known to restrict retroviruses, including HIV-1. We previously reported that mouse APOBEC3 encodes Recovery from Friend virus 3 (Rfv3), a classical resistance gene in mice that promotes the neutralizing antibody response against retrovirus infection. We now show that APOBEC3/Rfv3 complements AID in driving Ig SHM during retrovirus infection. Analysis of antibody sequences from retrovirus-specific hybridomas and GC B cells from infected mice revealed Ig heavy-chain V genes with significantly increased C-to-T and G-to-A transitions in wild-type as compared with APOBEC3-defective mice. The context of the mutations was consistent with APOBEC3 but not AID mutational activity. These findings help explain the role of APOBEC3/Rfv3 in promoting the neutralizing antibody responses essential for recovery from retroviral infection and highlight APOBEC3-mediated deamination as a previously unidentified mechanism for antibody diversification in vivo.
authors.affiliation: Departments of Medicine andMicrobiology and Immunology, University of Colorado Denver, Aurora, CO 80045; and.
authors.forename: Kalani
authors.initials: K
authors.lastname: Halemano
authors.affiliation: Departments of Medicine and.
authors.forename: Kejun
authors.initials: K
authors.lastname: Guo
authors.affiliation: Departments of Medicine and.
authors.forename: Karl J
authors.initials: KJ
authors.lastname: Heilman
authors.affiliation: Departments of Medicine and.
authors.forename: Bradley S
authors.initials: BS
authors.lastname: Barrett
authors.affiliation: Departments of Medicine and.
authors.forename: Diana S
authors.initials: DS
authors.lastname: Smith
authors.affiliation: Laboratory of Persistent Viral Diseases, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, MT 59840.
authors.forename: Kim J
authors.initials: KJ
authors.lastname: Hasenkrug
authors.affiliation: Departments of Medicine andMicrobiology and Immunology, University of Colorado Denver, Aurora, CO 80045; and mario.santiago@ucdenver.edu.
authors.forename: Mario L
authors.initials: ML
authors.lastname: Santiago
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000235:genetics* / Q000276:immunology; D000914:Antibodies, Viral / Q000235:genetics*; D001402:B-Lymphocytes / Q000276:immunology; D001483:Base Sequence; D003564:Cytidine Deaminase / Q000235:genetics / Q000276:immunology*; D018858:Germinal Center / Q000166:cytology; D051379:Mice; D008969:Molecular Sequence Data; D012192:Retroviridae Infections / Q000235:genetics*; D017422:Sequence Analysis, DNA; D027041:Somatic Hypermutation, Immunoglobulin / Q000235:genetics / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D000098830:AICDA (Activation-Induced Cytidine Deaminase)
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D000098830:AICDA (Activation-Induced Cytidine Deaminase); C503504:Apobec3 protein, mouse; D003564:Cytidine Deaminase
keywords: Friend retrovirus; affinity maturation; antibody repertoire profiling; humoral immunity; restriction factor