This is a renewal application for grant R37 AI36082 Neutralization of primary HIV-1 viruses that was awarded in 2008. The overall goal is a detailed molecular understanding of how neutralizing antibodies, alone and together, inhibit HIV-1 infection of target cells, and how the antigens that they are directed to modulate the antibody response by interacting with dendritic cells and B cells. The work outlined in the proposal will be conducted in Dr. John Moore's laboratory at the Weill Comell Medical College We propose three Specific Aims:
Specific Aim 1 : Mechanism, stoichiometry and kinetic aspects of HIV-1 neutralization by Abs. In this Aim we will use new in vitro neutralization assays to dissect how neutralizing antibodies with different specificities block HIV-1 infection and to quantify the persistent fi-action that survives neutralization. We will use transmembrane-protein mutants to study how differential exposure of epitopes on the Env-glycoprotein complex affect the potency and extent of neutralization.
Specific Aim 2 : Synergy, cooperativity and breadth of HIV-1 neutralization. We will build on our finding of Env-glycoprotein heterogeneity as a source of synergy between neutralizing antibodies. Using new mathematical analyses, we will explore the relationship between synergy and cooperativity and how they affect potency and extent of neutralization of different primary HIV-1 inocula with varying degrees of heterogeneity.
Specific Aim 3 : Induction of immunosuppressive responses by the mannose moieties of gpl20 glycans. We will characterize how gpl20 at high concentrations that may prevail locally after immunization affect the interplay between dendritic cells and lymphocytes, including the secretion of cytokines and B-cell stimulatory factors. The pursuit of these goals will help provide in vitro correlates for which neutralizing antibodies may be most protective in vivo and inform the design of immunogens so that high titers of such antibodies can be induced.

Public Health Relevance

An effective preventive vaccine against HIV-1 infection is important to stop the global AIDS epidemic spreading further. Such a vaccine must induce antibodies that protect against infection by the virus, most probably antibodies that neutralize virus infectivity. In our research program, we will try to determine why some such antibodies are more protective than others, and why they are so difficult to induce by vaccination.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AI036082-22
Application #
8627529
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Li, Yen
Project Start
1994-05-01
Project End
2018-05-31
Budget Start
2014-06-01
Budget End
2015-05-31
Support Year
22
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10065
Behrens, Anna-Janina; Vasiljevic, Snezana; Pritchard, Laura K et al. (2016) Composition and Antigenic Effects of Individual Glycan Sites of a Trimeric HIV-1 Envelope Glycoprotein. Cell Rep 14:2695-706
Klasse, P J (2016) How to assess the binding strength of antibodies elicited by vaccination against HIV and other viruses. Expert Rev Vaccines 15:295-311
Sanders, Rogier W; van Gils, Marit J; Derking, Ronald et al. (2015) HIV-1 VACCINES. HIV-1 neutralizing antibodies induced by native-like envelope trimers. Science 349:aac4223
Derking, Ronald; Ozorowski, Gabriel; Sliepen, Kwinten et al. (2015) Comprehensive antigenic map of a cleaved soluble HIV-1 envelope trimer. PLoS Pathog 11:e1004767
Sliepen, Kwinten; Medina-Ramírez, Max; Yasmeen, Anila et al. (2015) Binding of inferred germline precursors of broadly neutralizing HIV-1 antibodies to native-like envelope trimers. Virology 486:116-20
Klasse, P J (2015) Molecular determinants of the ratio of inert to infectious virus particles. Prog Mol Biol Transl Sci 129:285-326
Guttman, Miklos; Cupo, Albert; Julien, Jean-Philippe et al. (2015) Antibody potency relates to the ability to recognize the closed, pre-fusion form of HIV Env. Nat Commun 6:6144
Alexander, Marina R; Sanders, Rogier W; Moore, John P et al. (2015) Short Communication: Virion Aggregation by Neutralizing and Nonneutralizing Antibodies to the HIV-1 Envelope Glycoprotein. AIDS Res Hum Retroviruses 31:1160-5
Pugach, Pavel; Ozorowski, Gabriel; Cupo, Albert et al. (2015) A native-like SOSIP.664 trimer based on an HIV-1 subtype B env gene. J Virol 89:3380-95
Julien, Jean-Philippe; Lee, Jeong Hyun; Ozorowski, Gabriel et al. (2015) Design and structure of two HIV-1 clade C SOSIP.664 trimers that increase the arsenal of native-like Env immunogens. Proc Natl Acad Sci U S A 112:11947-52

Showing the most recent 10 out of 104 publications