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Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies.

Publication ,  Journal Article
Gnanakaran, S; Daniels, MG; Bhattacharya, T; Lapedes, AS; Sethi, A; Li, M; Tang, H; Greene, K; Gao, H; Haynes, BF; Cohen, MS; Shaw, GM ...
Published in: PLoS Comput Biol
October 7, 2010

A steady increase in knowledge of the molecular and antigenic structure of the gp120 and gp41 HIV-1 envelope glycoproteins (Env) is yielding important new insights for vaccine design, but it has been difficult to translate this information to an immunogen that elicits broadly neutralizing antibodies. To help bridge this gap, we used phylogenetically corrected statistical methods to identify amino acid signature patterns in Envs derived from people who have made potently neutralizing antibodies, with the hypothesis that these Envs may share common features that would be useful for incorporation in a vaccine immunogen. Before attempting this, essentially as a control, we explored the utility of our computational methods for defining signatures of complex neutralization phenotypes by analyzing Env sequences from 251 clonal viruses that were differentially sensitive to neutralization by the well-characterized gp120-specific monoclonal antibody, b12. We identified ten b12-neutralization signatures, including seven either in the b12-binding surface of gp120 or in the V2 region of gp120 that have been previously shown to impact b12 sensitivity. A simple algorithm based on the b12 signature pattern was predictive of b12 sensitivity/resistance in an additional blinded panel of 57 viruses. Upon obtaining these reassuring outcomes, we went on to apply these same computational methods to define signature patterns in Env from HIV-1 infected individuals who had potent, broadly neutralizing responses. We analyzed a checkerboard-style neutralization dataset with sera from 69 HIV-1-infected individuals tested against a panel of 25 different Envs. Distinct clusters of sera with high and low neutralization potencies were identified. Six signature positions in Env sequences obtained from the 69 samples were found to be strongly associated with either the high or low potency responses. Five sites were in the CD4-induced coreceptor binding site of gp120, suggesting an important role for this region in the elicitation of broadly neutralizing antibody responses against HIV-1.

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Published In

PLoS Comput Biol

DOI

EISSN

1553-7358

Publication Date

October 7, 2010

Volume

6

Issue

10

Start / End Page

e1000955

Location

United States

Related Subject Headings

  • Sequence Alignment
  • Phylogeny
  • Neutralization Tests
  • Mutation
  • Models, Molecular
  • Logistic Models
  • Humans
  • HIV-1
  • HIV Envelope Protein gp41
  • HIV Envelope Protein gp120
 

Citation

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Gnanakaran, S., Daniels, M. G., Bhattacharya, T., Lapedes, A. S., Sethi, A., Li, M., … Korber, B. (2010). Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies. PLoS Comput Biol, 6(10), e1000955. https://doi.org/10.1371/journal.pcbi.1000955
Gnanakaran, S., Marcus G. Daniels, Tanmoy Bhattacharya, Alan S. Lapedes, Anurag Sethi, Ming Li, Haili Tang, et al. “Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies.PLoS Comput Biol 6, no. 10 (October 7, 2010): e1000955. https://doi.org/10.1371/journal.pcbi.1000955.
Gnanakaran S, Daniels MG, Bhattacharya T, Lapedes AS, Sethi A, Li M, et al. Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies. PLoS Comput Biol. 2010 Oct 7;6(10):e1000955.
Gnanakaran, S., et al. “Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies.PLoS Comput Biol, vol. 6, no. 10, Oct. 2010, p. e1000955. Pubmed, doi:10.1371/journal.pcbi.1000955.
Gnanakaran S, Daniels MG, Bhattacharya T, Lapedes AS, Sethi A, Li M, Tang H, Greene K, Gao H, Haynes BF, Cohen MS, Shaw GM, Seaman MS, Kumar A, Gao F, Montefiori DC, Korber B. Genetic signatures in the envelope glycoproteins of HIV-1 that associate with broadly neutralizing antibodies. PLoS Comput Biol. 2010 Oct 7;6(10):e1000955.

Published In

PLoS Comput Biol

DOI

EISSN

1553-7358

Publication Date

October 7, 2010

Volume

6

Issue

10

Start / End Page

e1000955

Location

United States

Related Subject Headings

  • Sequence Alignment
  • Phylogeny
  • Neutralization Tests
  • Mutation
  • Models, Molecular
  • Logistic Models
  • Humans
  • HIV-1
  • HIV Envelope Protein gp41
  • HIV Envelope Protein gp120