Abstract

The proposed research aims to characterize human antibody responses to the HIV-1 virus at the molecular level, and to generate human monoclonal antibodies for clinical evaluation in combatting HIV infection. The latter includes passive immunization as a potential treatment for AIDS and prophylaxis in pregnant women to prevent transmission of the virus to offspring. Panels of antibodies against HIV-1 envelope proteins will be generated by establishing Fab libraries from appropriate donors on the surface of M13 phage and selection of specific Fabs by antigen panning. Fabs will be characterized in terms of in vitro neutralizing ability, antigen affinity, epitope recognized and nucleic acid sequence. Fabs will be linked to Fc genetically for the production of glycosylated whole IgG antibodies in eukaryotic cells. A cocktail of antibodies for therapeutic application will be assembled based on exceptional neutralizing ability, reactivity with multiple viral strains, recognition of different epitopes on the viral envelope and possible synergistic effects. The research will provide opportunities to explore the mechanism(s) responsible for virus neutralization and some of the rules governing antibody recognition of viral antigens.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI033292-01
Application #
3148372
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Project Start
1992-07-01
Project End
1995-06-30
Budget Start
1992-07-01
Budget End
1993-06-30
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

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
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
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
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
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

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