Abstract

Passive immunotherapy with potent antibodies could find application in a number of aspects of HIV-1 infection, including the prevention of infection after accidental exposure to the virus, the interruption of transmission of virus from mother to child, and the reduction of viral load in combination with anti-retroviral drugs. Three human monoclonal antibodies (b12, 2G12 and 2F5) and an immunoadhesin (CD4-IgG2) show promise as potential immunotherapeutics by their ability to neutralize a wide range of primary isolates of HIV-1.
Our aim i s to evaluate the anti-viral efficacy of these antibodies, singly and in combination, in vivo in the hu-PBL-SCID mouse model.
The specific aims of this proposal are: (1) To determine the in vitro neutralization properties of a number of antibodies, individually and in combination, for a chosen set of primary isolates (2) To determine the ability of antibodies alone and in combination to protect hu-PBL-SCID mice against challenge with primary isolates. (3) To determine the properties of in vitro selected neutralization escape mutants of primary viruses in the mouse model and the ability of antibodies of protect against these viruses (4) To attempt to generate escape mutants in vivo. The emerging results should assist in the design of immunotherapeutic strategies using neutralizing antibodies and illuminate areas of potential concern such as neutralization escape.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059727-05
Application #
6389819
Study Section
Special Emphasis Panel (ZHL1-CSR-F (S1))
Program Officer
Bradac, James A
Project Start
1997-09-30
Project End
2002-08-31
Budget Start
2001-09-01
Budget End
2002-08-31
Support Year
5
Fiscal Year
2001
Total Cost
$555,600
Indirect Cost

  Institution

Name
Scripps Research Institute
Department
Type
DUNS #
781613492
City
La Jolla
State
CA
Country
United States
Zip Code
92037

  Publications

Venturini, Sara; Allicotti, Gina; Zhao, Yindong et al. (2006) Identification of peptides from human pathogens able to cross-activate an HIV-1-gag-specific CD4+ T cell clone. Eur J Immunol 36:27-36
Venturini, Sara; Mosier, Donald E; Burton, Dennis R et al. (2002) Characterization of human immunodeficiency virus type 1 (HIV-1) Gag- and Gag peptide-specific CD4(+) T-cell clones from an HIV-1-seronegative donor following in vitro immunization. J Virol 76:6987-99
Parren, P W; Marx, P A; Hessell, A J et al. (2001) Antibody protects macaques against vaginal challenge with a pathogenic R5 simian/human immunodeficiency virus at serum levels giving complete neutralization in vitro. J Virol 75:8340-7
Burton, D R; Saphire, E O; Parren, P W (2001) A model for neutralization of viruses based on antibody coating of the virion surface. Curr Top Microbiol Immunol 260:109-43
Poignard, P; Saphire, E O; Parren, P W et al. (2001) gp120: Biologic aspects of structural features. Annu Rev Immunol 19:253-74
Moore, J P; Parren, P W; Burton, D R (2001) Genetic subtypes, humoral immunity, and human immunodeficiency virus type 1 vaccine development. J Virol 75:5721-9
Parren, P W; Burton, D R (2001) The antiviral activity of antibodies in vitro and in vivo. Adv Immunol 77:195-262
Mosier, D E (2000) Human xenograft models for virus infection. Virology 271:215-9
Sanna, P P; Burton, D R (2000) Role of antibodies in controlling viral disease: lessons from experiments of nature and gene knockouts. J Virol 74:9813-7
Poignard, P; Sabbe, R; Picchio, G R et al. (1999) Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo. Immunity 10:431-8

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