We propose unconventional, unique and exceptionally novel methods to uncover the structure of broadly neutralizeable epitopes in the variable loops of gp120. This work challenges the standard paradigm that the variable loops of gp120 are too dynamic and variable to have conserved epitopes useful in a vaccine. We were able to devise a novel computational de-noising approach to the sequence and structural variability in these loops and have a high likelihood of identifying the first broadly neutralizing antibodies targeting epitopes in V1, V2 V4 and/or V5. We are confident of attaining this significant outcome based on our preliminary results with the V3 loop. The research group and the proposed research is uniquely suited to the stated goals of the HIT-IT initiative, rather than a conventional research grant (R01) application. This is because we have a proven track record of this kind of innovation targeting the V3 loop, and because the research addresses a problem that is both crucial to an HIV vaccine and simultaneously thought currently to be too challenging to address.

Public Health Relevance

All prior failed HIV vaccines have targeted sequence conserved and non-gp120 determinants in the virus. This is primarily because the dynamic; sequence variable surface loops of gp120 are considered too challenging to dissect for hidden broadly neutralizing antibody epitopes. This research proposes a highly innovative tactic to meet this challenge and produce the first structure-based design of immunogens mimicking broadly neutralizing epitopes in the variable loops V1; V2; V4 and V5.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
3R01AI084119-04S1
Application #
8733248
Study Section
Program Officer
Malaspina, Angela
Project Start
2014-01-29
Project End
2016-01-28
Budget Start
2014-01-29
Budget End
2016-01-28
Support Year
4
Fiscal Year
2014
Total Cost
$623,565
Indirect Cost
$255,680
Name
New York University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Pan, Ruimin; Gorny, Miroslaw K; Zolla-Pazner, Susan et al. (2015) The V1V2 Region of HIV-1 gp120 Forms a Five-Stranded Beta Barrel. J Virol 89:8003-10
Shmelkov, Evgeny; Grigoryan, Arsen; Krachmarov, Chavdar et al. (2014) Sequence-conserved and antibody-accessible sites in the V1V2 domain of HIV-1 gp120 envelope protein. AIDS Res Hum Retroviruses 30:927-31
Shmelkov, Evgeny; Nadas, Arthur; Cardozo, Timothy (2014) Could vaccination with AIDSVAX immunogens have resulted in antibody-dependent enhancement of HIV infection in human subjects? Hum Vaccin Immunother 10:3013-6
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Gorny, Miroslaw K; Pan, Ruimin; Williams, Constance et al. (2012) Functional and immunochemical cross-reactivity of V2-specific monoclonal antibodies from HIV-1-infected individuals. Virology 427:198-207
Karasavvas, Nicos; Billings, Erik; Rao, Mangala et al. (2012) The Thai Phase III HIV Type 1 Vaccine trial (RV144) regimen induces antibodies that target conserved regions within the V2 loop of gp120. AIDS Res Hum Retroviruses 28:1444-57
Agarwal, Alpna; Hioe, Catarina E; Swetnam, James et al. (2011) Quantitative assessment of masking of neutralization epitopes in HIV-1. Vaccine 29:6736-41
Spurrier, Brett; Sampson, Jared M; Totrov, Maxim et al. (2011) Structural analysis of human and macaque mAbs 2909 and 2.5B: implications for the configuration of the quaternary neutralizing epitope of HIV-1 gp120. Structure 19:691-9

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