HIV-1 gp41 contains highly conserved regions that are attractive targets for vaccine design. One such region is the membrane-proximal external region (MPER) of gp41, and the human monoclonal antibodies (mAbs) that bind to it, 2F5, 4E10 and Z13, neutralize primary isolates of HIV-1 from different clades. In addition, the N-heptad repeat (NHR) region of gp41 is a target of fusion inhibitor drugs and neutralizing mAbs. (In our preliminary studies, we have identified an affinity-improved version of Z13 (Z13e1), as well as rabbit mAbs and a human HIV-1 neutralizing mAb that were elicited against the NHR region of gp41.) Eliciting broadly neutralizing Abs against gp41 has been difficult due in part to heterogeneity in gp41 structure and a poor understanding of the specific structure and presentation of the neutralizing epitopes on HIV-1 gp41. We have designed a series of gp41 mimetics that specifically present the neutralizing epitopes of the MPER and NHR region of gp41. These gp41 mimetics will be used to immunize rabbits, and the serum neutralizing Ab titers measured to determine the best MPER and NHR lead immunogens (Aim 1). In order to gain more specific knowledge about the immunogenicity of the neutralizing epitopes, rabbit mAbs that were elicited to these epitopes will be rescued by phage display and tested individually for neutralizing activity (Aim 2). The mAb panels will be used to probe the gp41 mimetics, and then modifications will be introduced so as to favorably display the neutralizing epitopes and occlude the non-neutralizing ones (Aim 3). In addition, in a collaborative effort, structures of the mAb Z13e1 and two HIV-1 neutralizing mAbs against the NHR region (rabbit and human) will be determined (Aim 4). In these ways, antibody access to the MPER and NHR region of gp41 will be precisely evaluated, which in turn should lead to improved gp41-based immunogens that will elicit more potent neutralizing Abs against HIV-1.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI069993-03
Application #
7642332
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Bradac, James A
Project Start
2007-07-15
Project End
2012-06-30
Budget Start
2009-07-01
Budget End
2010-06-30
Support Year
3
Fiscal Year
2009
Total Cost
$464,749
Indirect Cost
Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037
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Nelson, Josh D; Kinkead, Heather; Brunel, Florence M et al. (2008) Antibody elicited against the gp41 N-heptad repeat (NHR) coiled-coil can neutralize HIV-1 with modest potency but non-neutralizing antibodies also bind to NHR mimetics. Virology 377:170-83
Scherer, Erin M; Zwick, Michael B; Teyton, Luc et al. (2007) Difficulties in eliciting broadly neutralizing anti-HIV antibodies are not explained by cardiolipin autoreactivity. AIDS 21:2131-9

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