Conditional Antibody Expression to Avoid Central B Cell Deletion in a Humanized HIV-1 Vaccine Mouse Models
Conditional Antibody Expression to Avoid Central B Cell Deletion in a Humanized HIV-1 Vaccine Mouse Models
Abstract HIV-1 vaccine development aims to elicit broadly neutralizing antibodies (bnAbs) against diverse viral strains. In some HIV-1 infected individuals, bnAbs evolve from precursor antibodies through affinity maturation. To induce bnAbs, a vaccine must mediate a similar process of antibody maturation. One way to test vaccination strategies is to immunize mouse models that express human bnAb precursors. Such immunization experiments can assess whether the vaccine can convert precursor antibody into bnAb. A major problem with such mouse models is that bnAb expression often hinders B cell development in the bone marrow. Such developmental blocks may be attributed to unusual properties of bnAb variable regions, such as poly-reactivity and long antigen-binding loops, which are often under negative selection during primary B cell development. To address this problem, we devised a method to circumvent B cell developmental block by expressing bnAbs conditionally in mature B cells. We validated this method by expressing the unmutated common ancestor (UCA) of the human VRC26 bnAb in transgenic mice. Constitutive expression of combined immunoglobulin heavy and light chains of VRC26UCA led to developmental arrest of B cell progenitors in the bone marrow; poly-reactivity of VRC26UCA and poor pairing of VRC26UCA IgH chain with mouse surrogate light chain may contribute to the phenotype. The conditional expression strategy circumvented this developmental impediment, allowing the VRC26UCA to be expressed in mature peripheral B cells. This method should be generally applicable for expressing other antibodies that are under negative selection during B cell development. Significance statementMouse models can provide fast and cost-effective systems to test HIV-1 vaccine candidates at the pre-clinical stage. To serve this purpose, mouse models are engineered to express the precursors of human bnAbs against diverse HIV-1 strains. Immunization of such mouse models can evaluate the ability of vaccines to mature the precursor antibodies into bnAbs. However, due to unusual properties of bnAbs, mouse models expressing their precursors often have B cell developmental defects. In this study, we devised and validated a strategy to address this problem. This method could also facilitate the expression of other clinically relevant antibodies in mature B cells in transgenic mice; immunization of such mice could be used to generate novel antibodies with desirable properties.
Cain Derek W.、Dao Mai、Chen Yiwei、Kimble Michael T.、Cantor Elizabeth、Judson Rachael、Alt Frederick W.、Manfredonia Nicole、Cheng Hwei-Ling、Waddicor Peyton、Tian Ming、Haynes Barton F.、Rieble Lisa、McGovern Kelly、Chapdelaine-Williams Aimee
Department of Medicine, Duke Human Vaccine Institute, Duke School of MedicineProgram in Cellular and Molecular Medicine, Boston Children?ˉs Hospital, Department of Genetics, Harvard Medical School, Howard Hughes Medical InstituteProgram in Cellular and Molecular Medicine, Boston Children?ˉs Hospital, Department of Genetics, Harvard Medical School, Howard Hughes Medical InstituteProgram in Cellular and Molecular Medicine, Boston Children?ˉs Hospital, Department of Genetics, Harvard Medical School, Howard Hughes Medical InstituteProgram in Cellular and Molecular Medicine, Boston Children?ˉs Hospital, Department of Genetics, Harvard Medical School, Howard Hughes Medical InstituteProgram in Cellular and Molecular Medicine, Boston Children?ˉs Hospital, Department of Genetics, Harvard Medical School, Howard Hughes Medical InstituteProgram in Cellular and Molecular Medicine, Boston Children?ˉs Hospital, Department of Genetics, Harvard Medical School, Howard Hughes Medical InstituteProgram in Cellular and Molecular Medicine, Boston Children?ˉs Hospital, Department of Genetics, Harvard Medical School, Howard Hughes Medical InstituteProgram in Cellular and Molecular Medicine, Boston Children?ˉs Hospital, Department of Genetics, Harvard Medical School, Howard Hughes Medical InstituteProgram in Cellular and Molecular Medicine, Boston Children?ˉs Hospital, Department of Genetics, Harvard Medical School, Howard Hughes Medical InstituteProgram in Cellular and Molecular Medicine, Boston Children?ˉs Hospital, Department of Genetics, Harvard Medical School, Howard Hughes Medical InstituteDepartment of Medicine, Duke Human Vaccine Institute, Duke School of Medicine||Department of Immunology, Duke University School of MedicineProgram in Cellular and Molecular Medicine, Boston Children?ˉs Hospital, Department of Genetics, Harvard Medical School, Howard Hughes Medical InstituteProgram in Cellular and Molecular Medicine, Boston Children?ˉs Hospital, Department of Genetics, Harvard Medical School, Howard Hughes Medical InstituteProgram in Cellular and Molecular Medicine, Boston Children?ˉs Hospital, Department of Genetics, Harvard Medical School, Howard Hughes Medical Institute
医学研究方法基础医学生物科学研究方法、生物科学研究技术
HIV-1immunoglobulinmouse model
Cain Derek W.,Dao Mai,Chen Yiwei,Kimble Michael T.,Cantor Elizabeth,Judson Rachael,Alt Frederick W.,Manfredonia Nicole,Cheng Hwei-Ling,Waddicor Peyton,Tian Ming,Haynes Barton F.,Rieble Lisa,McGovern Kelly,Chapdelaine-Williams Aimee.Conditional Antibody Expression to Avoid Central B Cell Deletion in a Humanized HIV-1 Vaccine Mouse Models[EB/OL].(2025-03-28)[2025-05-17].https://www.biorxiv.org/content/10.1101/2020.01.03.894279.点此复制
评论