The vaccine-induced immune responses that, alone or in combination, will provide optimal protection for a large population of individuals against infection by HIV are still unknown. Nevertheless, many regard the induction of broadly neutralizing antibodies as one of the highest priorities of HIV vaccine research. The identification of monoclonal antibodies with broadly neutralizing properties (bnMAbs) is important to define neutralizing epitopes on the virus that should be targeted by an antibody-based vaccine, to facilitate the solution of a key structure in vaccine design, namely the functional envelope trimer to which only neutralizing antibodies bind with high affinity, and finally to help define conditions for antibody-mediated protection in animal models. Until very recently, only a handful of bnMAbs had been generated and this has undoubtedly restricted progress in immunogen development and structure determination. However recently the field has been energized as (a) potent and broad neutralization has been shown in the sera of a subset of infected individuals, (b) novel bnMAbs have been isolated that show considerably greater potency than the previously described bnMAbs but with comparable or better breadth (c) newer technologies successfully applied to novel bnMAb isolation are expected to yield many more such antibodies.
The specific aims of the application are: 1. To use recently identified potent trimer-specific bnMAbs PG9 and PG16 to evaluate Env molecules in various forms as immunogens and as source material for structural determination. 2. To map the neutralization specificities in the sera of HIV-1 infected individuals with broad and potent neutralizing activity (including """"""""elite neutralizers""""""""). Initial progress on this aim has been very encouraging in suggesting novel epitopes recognized by multiple individuals. 3. To molecularly characterize novel broadly neutralizing human monoclonal antibodies isolated from donors investigated in Aim 2. The significance of this project is that it will increase our understanding of broadly neutralizing HIV epitopes, it will provide insight into how individuals naturally develop broadly neutralizing responses and it may lead directly to the design of immunogens able to elicit such responses.

Public Health Relevance

An optimal HIV vaccine will likely elicit broadly neutralizing antibodies. This application seeks to understand broad neutralization at the molecular level to permit the design of such a vaccine.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
Project #
Application #
Study Section
AIDS Immunology and Pathogenesis Study Section (AIP)
Program Officer
Salzwedel, Karl D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Scripps Research Institute
La Jolla
United States
Zip Code
van Gils, Marit J; van den Kerkhof, Tom L G M; Ozorowski, Gabriel et al. (2016) An HIV-1 antibody from an elite neutralizer implicates the fusion peptide as a site of vulnerability. Nat Microbiol 2:16199
Deruaz, Maud; Moldt, Brian; Le, Khoa M et al. (2016) Protection of Humanized Mice From Repeated Intravaginal HIV Challenge by Passive Immunization: A Model for Studying the Efficacy of Neutralizing Antibodies In Vivo. J Infect Dis 214:612-6
Sok, Devin; Pauthner, Matthias; Briney, Bryan et al. (2016) A Prominent Site of Antibody Vulnerability on HIV Envelope Incorporates a Motif Associated with CCR5 Binding and Its Camouflaging Glycans. Immunity 45:31-45
Doores, Katie J; Kong, Leopold; Krumm, Stefanie A et al. (2015) Two classes of broadly neutralizing antibodies within a single lineage directed to the high-mannose patch of HIV envelope. J Virol 89:1105-18
McCoy, Laura E; Falkowska, Emilia; Doores, Katie J et al. (2015) Incomplete Neutralization and Deviation from Sigmoidal Neutralization Curves for HIV Broadly Neutralizing Monoclonal Antibodies. PLoS Pathog 11:e1005110
Wang, Shenshen; Mata-Fink, Jordi; Kriegsman, Barry et al. (2015) Manipulating the selection forces during affinity maturation to generate cross-reactive HIV antibodies. Cell 160:785-797
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
Sok, Devin; Doores, Katie J; Briney, Bryan et al. (2014) Promiscuous glycan site recognition by antibodies to the high-mannose patch of gp120 broadens neutralization of HIV. Sci Transl Med 6:236ra63
Moldt, Brian; Saye-Francisco, Karen; Schultz, Niccole et al. (2014) Simplifying the synthesis of SIgA: combination of dIgA and rhSC using affinity chromatography. Methods 65:127-32
Garces, Fernando; Sok, Devin; Kong, Leopold et al. (2014) Structural evolution of glycan recognition by a family of potent HIV antibodies. Cell 159:69-79

Showing the most recent 10 out of 138 publications