The design of an immunogen able to elicit broadly neutralizing antibodies is a major, but so far elusive, goal of HIV vaccine research. The existence of such antibodies is indicated by the description of rare broadly neutralizing HIV sera and a handful of broadly neutralizing human monoclonal antibodies (bnMAbs) isolated from HIV infected individuals. To understand how to better induce broadly neutralizing HIV antibodies it is important to identify the appropriate B cell precursors and to stimulate them with effective antigens. For this reason we propose to develop mouse strains carrying B cells with "germline" versions of bnMAbs and to follow their responses to test immunogens. This approach renders visible the responses of the very B cells that we wish to recruit into the HIV antibody response and should allow rapid screening of vaccine candidates for the ability to elicit neutralizing antibodies in a context in which the appropriate precursors are present in high frequency. Failure of response in this context would not be ascribable to a deficiency in appropriate B cells unless such B cells are eliminated by immune tolerance, an outcome that can be experimentally excluded.
The specific aims of the proposal are (1) to generate transgenic (knockin) mice carrying B cells expressing germline versions of the bnMAbs b12, 2G12 and 2F5 and (2) To investigate antibody responses in the transgenic mice to a wide variety of immunogens using a number of immunization strategies. The project is a close collaboration between a laboratory (Nemazee) with expertise in B cells, including knockin mice, and one (Burton) with expertise in antibodies and HIV. It is expected to generate valuable reagents and animals for the proposed UO1 consortium.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AI078224-05
Application #
8225294
Study Section
Special Emphasis Panel (ZAI1-KS-I (J3))
Program Officer
Ferguson, Stacy E
Project Start
2008-03-15
Project End
2013-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
5
Fiscal Year
2012
Total Cost
$702,711
Indirect Cost
$331,887
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
Doyle-Cooper, Colleen; Hudson, Krystalyn E; Cooper, Anthony B et al. (2013) Immune tolerance negatively regulates B cells in knock-in mice expressing broadly neutralizing HIV antibody 4E10. J Immunol 191:3186-91
Doores, Katie J; Huber, Michael; Le, Khoa M et al. (2013) 2G12-expressing B cell lines may aid in HIV carbohydrate vaccine design strategies. J Virol 87:2234-41
Ota, Takayuki; Doyle-Cooper, Colleen; Cooper, Anthony B et al. (2013) B cells from knock-in mice expressing broadly neutralizing HIV antibody b12 carry an innocuous B cell receptor responsive to HIV vaccine candidates. J Immunol 191:3179-85
Doores, Katie J; Fulton, Zara; Huber, Michael et al. (2010) Antibody 2G12 recognizes di-mannose equivalently in domain- and nondomain-exchanged forms but only binds the HIV-1 glycan shield if domain exchanged. J Virol 84:10690-9
Huber, Michael; Le, Khoa M; Doores, Katie J et al. (2010) Very few substitutions in a germ line antibody are required to initiate significant domain exchange. J Virol 84:10700-7