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Prolonged exposure of the HIV-1 gp41 membrane proximal region with L669S substitution.

Publication ,  Journal Article
Shen, X; Dennison, SM; Liu, P; Gao, F; Jaeger, F; Montefiori, DC; Verkoczy, L; Haynes, BF; Alam, SM; Tomaras, GD
Published in: Proc Natl Acad Sci U S A
March 30, 2010

The conserved membrane-proximal external region (MPER) of HIV-1 envelope is a target for the rare broadly neutralizing 2F5, Z13, and 4E10 monoclonal antibodies (mAbs). One strategy to elicit such antibodies is to design an immunogen with increased exposure of the 2F5 and 4E10 mAb epitopes. In this study we characterize a single leucine to serine substitution at position 669 (L669S) in the gp41 Env MPER that confers >250-fold more neutralization sensitivity to 2F5 and 4E10 mAbs than does the wild-type gp41 sequence. On synthetic liposomes, increased solvent exposure of MPER tryptophan residues and stable docking of 2F5 and 4E10 mAbs to mutant MPER peptide liposomes indicate more favorable membrane orientation of MPER neutralizing epitopes with L669S substitution. The time during which virus is sensitive to 2F5 mAb-mediated neutralization is approximately 3-fold longer when the mutation is present. These data suggest that a major contribution to the L669S mutant virus phenotype of enhanced susceptibility to MPER mAbs is prolonged exposure of the MPER neutralizing epitope during viral entry.

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Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 30, 2010

Volume

107

Issue

13

Start / End Page

5972 / 5977

Location

United States

Related Subject Headings

  • Surface Plasmon Resonance
  • Molecular Sequence Data
  • Kinetics
  • In Vitro Techniques
  • Humans
  • HIV-1
  • HIV Envelope Protein gp41
  • HIV Antibodies
  • Binding Sites
  • Antibodies, Neutralizing
 

Citation

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Shen, X., Dennison, S. M., Liu, P., Gao, F., Jaeger, F., Montefiori, D. C., … Tomaras, G. D. (2010). Prolonged exposure of the HIV-1 gp41 membrane proximal region with L669S substitution. Proc Natl Acad Sci U S A, 107(13), 5972–5977. https://doi.org/10.1073/pnas.0912381107
Shen, Xiaoying, S Moses Dennison, Pinghuang Liu, Feng Gao, Frederick Jaeger, David C. Montefiori, Laurent Verkoczy, Barton F. Haynes, S Munir Alam, and Georgia D. Tomaras. “Prolonged exposure of the HIV-1 gp41 membrane proximal region with L669S substitution.Proc Natl Acad Sci U S A 107, no. 13 (March 30, 2010): 5972–77. https://doi.org/10.1073/pnas.0912381107.
Shen X, Dennison SM, Liu P, Gao F, Jaeger F, Montefiori DC, et al. Prolonged exposure of the HIV-1 gp41 membrane proximal region with L669S substitution. Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5972–7.
Shen, Xiaoying, et al. “Prolonged exposure of the HIV-1 gp41 membrane proximal region with L669S substitution.Proc Natl Acad Sci U S A, vol. 107, no. 13, Mar. 2010, pp. 5972–77. Pubmed, doi:10.1073/pnas.0912381107.
Shen X, Dennison SM, Liu P, Gao F, Jaeger F, Montefiori DC, Verkoczy L, Haynes BF, Alam SM, Tomaras GD. Prolonged exposure of the HIV-1 gp41 membrane proximal region with L669S substitution. Proc Natl Acad Sci U S A. 2010 Mar 30;107(13):5972–5977.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

EISSN

1091-6490

Publication Date

March 30, 2010

Volume

107

Issue

13

Start / End Page

5972 / 5977

Location

United States

Related Subject Headings

  • Surface Plasmon Resonance
  • Molecular Sequence Data
  • Kinetics
  • In Vitro Techniques
  • Humans
  • HIV-1
  • HIV Envelope Protein gp41
  • HIV Antibodies
  • Binding Sites
  • Antibodies, Neutralizing