A crucial missing component of current HIV vaccine candidates is an ability to elicit broadly neutralizing antibodies. In the proposed studies we combine vaccine design, next generation sequencing (NGS) bioinformatics, structural biology and mechanistic studies to overcome an important roadblock in HIV vaccine development, that of eliciting antibodies that recognize native conformations of gp41. The membrane proximal external region (MPER) of gp41 is a particularly desirable vaccine target as it is recognized by numerous broadly neutralizing antibodies, the most potent of which is 10E8. However, how antibodies are elicited to the MPER is virtually unknown. Meanwhile, preliminary data suggest that the 10E8 epitope involves interactions between subunits of the trimeric envelope spike. The structure and function of the MPER in its native conformations is also incompletely understood. We propose to immunize mice with three trimeric presentations of the MPER on stabilized native spikes, on liposomes and on nanoparticles. We will identify novel MPER antibodies to epitopes overlapping with 10E8 from immunized mice and from African donors. We will use NGS/bioinformatics analyses to deeply probe the B cell repertoires of the mice and humans to identify germline V-regions of MPER-specific antibodies. We will attempt to manipulate MPER specific B cell responses in mice through antigen modification. In collaboration we will study the EM structure of stabilized envelope spikes in complex with 10E8, while using a battery of assays to define the mechanism of neutralization by 10E8.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI114401-01
Application #
8790381
Study Section
HIV/AIDS Vaccines Study Section (VACC)
Program Officer
Schultz, Alan M
Project Start
2014-06-15
Project End
2019-05-31
Budget Start
2014-06-15
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
$565,076
Indirect Cost
$266,883
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Lahiri, Cecile D; Reed-Walker, Kedria; Sheth, Anandi N et al. (2016) Cerebrospinal fluid concentrations of tenofovir and emtricitabine in the setting of HIV-1 protease inhibitor-based regimens. J Clin Pharmacol 56:492-6
Lee, Jeong Hyun; Leaman, Daniel P; Kim, Arthur S et al. (2015) Antibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike. Nat Commun 6:8167
Kim, Arthur S; Leaman, Daniel P; Zwick, Michael B (2014) Antibody to gp41 MPER alters functional properties of HIV-1 Env without complete neutralization. PLoS Pathog 10:e1004271
Falkowska, Emilia; Le, Khoa M; Ramos, Alejandra et al. (2014) Broadly neutralizing HIV antibodies define a glycan-dependent epitope on the prefusion conformation of gp41 on cleaved envelope trimers. Immunity 40:657-68