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Conditional antibody expression to avoid central B cell deletion in humanized HIV-1 vaccine mouse models.

Publication ,  Journal Article
Tian, M; McGovern, K; Cheng, H-L; Waddicor, P; Rieble, L; Dao, M; Chen, Y; Kimble, MT; Cantor, E; Manfredonia, N; Judson, R; Cain, DW ...
Published in: Proc Natl Acad Sci U S A
April 7, 2020

HIV-1 vaccine development aims to elicit broadly neutralizing antibodies (bnAbs) against diverse viral strains. In some HIV-1-infected individuals, bnAbs evolved from precursor antibodies through affinity maturation. To induce bnAbs, a vaccine must mediate a similar antibody maturation process. One way to test a vaccine is to immunize mouse models that express human bnAb precursors and assess whether the vaccine can convert precursor antibodies into bnAbs. A major problem with such mouse models is that bnAb expression often hinders B cell development. Such developmental blocks may be attributed to the unusual properties of bnAb variable regions, such as poly-reactivity and long antigen-binding loops, which are usually under negative selection during primary B cell development. To address this problem, we devised a method to circumvent such B cell developmental blocks 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 the VRC26UCA led to developmental arrest of B cell progenitors in bone marrow; poly-reactivity of the VRC26UCA and poor pairing of the VRC26UCA heavy chain with the mouse surrogate light chain may contribute to this phenotype. The conditional expression strategy bypassed the impediment to VRC26UCA B cell development, enabling the expression of VRC26UCA in mature B cells. This approach should be generally applicable for expressing other bnAbs that are under negative selection during B cell development.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

April 7, 2020

Volume

117

Issue

14

Start / End Page

7929 / 7940

Location

United States

Related Subject Headings

  • env Gene Products, Human Immunodeficiency Virus
  • Mice
  • Lymphocyte Activation
  • Humans
  • HIV-1
  • HIV Seropositivity
  • HIV Infections
  • HIV Antibodies
  • Disease Models, Animal
  • B-Lymphocytes
 

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Tian, M., McGovern, K., Cheng, H.-L., Waddicor, P., Rieble, L., Dao, M., … Alt, F. W. (2020). Conditional antibody expression to avoid central B cell deletion in humanized HIV-1 vaccine mouse models. Proc Natl Acad Sci U S A, 117(14), 7929–7940. https://doi.org/10.1073/pnas.1921996117
Tian, Ming, Kelly McGovern, Hwei-Ling Cheng, Peyton Waddicor, Lisa Rieble, Mai Dao, Yiwei Chen, et al. “Conditional antibody expression to avoid central B cell deletion in humanized HIV-1 vaccine mouse models.Proc Natl Acad Sci U S A 117, no. 14 (April 7, 2020): 7929–40. https://doi.org/10.1073/pnas.1921996117.
Tian M, McGovern K, Cheng H-L, Waddicor P, Rieble L, Dao M, et al. Conditional antibody expression to avoid central B cell deletion in humanized HIV-1 vaccine mouse models. Proc Natl Acad Sci U S A. 2020 Apr 7;117(14):7929–40.
Tian, Ming, et al. “Conditional antibody expression to avoid central B cell deletion in humanized HIV-1 vaccine mouse models.Proc Natl Acad Sci U S A, vol. 117, no. 14, Apr. 2020, pp. 7929–40. Pubmed, doi:10.1073/pnas.1921996117.
Tian M, McGovern K, Cheng H-L, Waddicor P, Rieble L, Dao M, Chen Y, Kimble MT, Cantor E, Manfredonia N, Judson R, Chapdelaine-Williams A, Cain DW, Haynes BF, Alt FW. Conditional antibody expression to avoid central B cell deletion in humanized HIV-1 vaccine mouse models. Proc Natl Acad Sci U S A. 2020 Apr 7;117(14):7929–7940.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

April 7, 2020

Volume

117

Issue

14

Start / End Page

7929 / 7940

Location

United States

Related Subject Headings

  • env Gene Products, Human Immunodeficiency Virus
  • Mice
  • Lymphocyte Activation
  • Humans
  • HIV-1
  • HIV Seropositivity
  • HIV Infections
  • HIV Antibodies
  • Disease Models, Animal
  • B-Lymphocytes