Back to Search
Start Over
Computational analysis of anti-HIV-1 antibody neutralization panel data to identify potential functional epitope residues.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2013 Jun 25; Vol. 110 (26), pp. 10598-603. Date of Electronic Publication: 2013 Jun 10. - Publication Year :
- 2013
-
Abstract
- Advances in single-cell antibody cloning methods have led to the identification of a variety of broadly neutralizing anti-HIV-1 antibodies. We developed a computational tool (Antibody Database) to help identify critical residues on the HIV-1 envelope protein whose natural variation affects antibody activity. Our simplifying assumption was that, for a given antibody, a significant portion of the dispersion of neutralization activity across a panel of HIV-1 strains is due to the amino acid identity or glycosylation state at a small number of specific sites, each acting independently. A model of an antibody's neutralization IC50 was developed in which each site contributes a term to the logarithm of the modeled IC50. The analysis program attempts to determine the set of rules that minimizes the sum of the residuals between observed and modeled IC50 values. The predictive quality of the identified rules may be assessed in part by whether there is support for rules within individual viral clades. As a test case, we analyzed antibody 8ANC195, an anti-glycoprotein gp120 antibody of unknown specificity. The model for this antibody indicated that several glycosylation sites were critical for neutralization. We evaluated this prediction by measuring neutralization potencies of 8ANC195 against HIV-1 in vitro and in an antibody therapy experiment in humanized mice. These experiments confirmed that 8ANC195 represents a distinct class of glycan-dependent anti-HIV-1 antibody and validated the utility of computational analysis of neutralization panel data.
- Subjects :
- Amino Acid Sequence
Animals
Computational Biology methods
Epitope Mapping methods
Epitopes chemistry
Epitopes genetics
HIV Antigens chemistry
HIV Antigens genetics
HIV Envelope Protein gp120 chemistry
HIV Envelope Protein gp120 genetics
HIV Envelope Protein gp120 immunology
HIV-1 genetics
Humans
Mice
Mice, Inbred NOD
Mice, Knockout
Models, Immunological
Models, Molecular
Molecular Sequence Data
Neutralization Tests
env Gene Products, Human Immunodeficiency Virus chemistry
env Gene Products, Human Immunodeficiency Virus genetics
Antibodies, Neutralizing metabolism
Epitopes physiology
HIV Antibodies immunology
HIV Antigens immunology
HIV-1 immunology
env Gene Products, Human Immunodeficiency Virus immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1091-6490
- Volume :
- 110
- Issue :
- 26
- Database :
- MEDLINE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 23754383
- Full Text :
- https://doi.org/10.1073/pnas.1309215110