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Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity.

Publication ,  Journal Article
Veillette, M; Désormeaux, A; Medjahed, H; Gharsallah, N-E; Coutu, M; Baalwa, J; Guan, Y; Lewis, G; Ferrari, G; Hahn, BH; Haynes, BF; Finzi, A ...
Published in: J Virol
March 2014

UNLABELLED: Anti-HIV-1 envelope glycoprotein (Env) antibodies without broadly neutralizing activity correlated with protection in the RV144 clinical trial, stimulating interest in other protective mechanisms involving antibodies, such as antibody-dependent cell-mediated cytotoxicity (ADCC). Env epitopes targeted by many antibodies effective at mediating ADCC are poorly exposed on the unliganded Env trimer. Here we investigated the mechanism of exposure of ADCC epitopes on Env and showed that binding of Env and CD4 within the same HIV-1-infected cell effectively exposes these epitopes. Env capacity to transit to the CD4-bound conformation is required for ADCC epitope exposure. Importantly, cell surface CD4 downregulation by Nef and Vpu accessory proteins and Vpu-mediated BST-2 antagonism modulate exposure of ADCC-mediating epitopes and reduce the susceptibility of infected cells to this effector function in vitro. Significantly, Env conformational changes induced by cell surface CD4 are conserved among Env from HIV-1 and HIV-2/SIVmac lineages. Altogether, our observations describe a highly conserved mechanism required to expose ADCC epitopes that might help explain the evolutionary advantage of downregulation of cell surface CD4 by the HIV-1 Vpu and Nef proteins. IMPORTANCE: HIV-1 envelope epitopes targeted by many antibodies effective at mediating antibody-dependent cell-mediated cytotoxicity (ADCC) are poorly exposed on the unliganded envelope trimer. Here we investigated the mechanism of exposure of these epitopes and found that envelope interaction with the HIV-1 CD4 receptor is required to expose some of these epitopes. Moreover, our results suggest that HIV-1 CD4 downregulation might help avoid the killing of HIV-1-infected cells by this immune mechanism.

Duke Scholars

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Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

March 2014

Volume

88

Issue

5

Start / End Page

2633 / 2644

Location

United States

Related Subject Headings

  • nef Gene Products, Human Immunodeficiency Virus
  • env Gene Products, Human Immunodeficiency Virus
  • Virology
  • Viral Regulatory and Accessory Proteins
  • Protein Multimerization
  • Protein Interaction Domains and Motifs
  • Protein Conformation
  • Protein Binding
  • Models, Molecular
  • Humans
 

Citation

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Veillette, M., Désormeaux, A., Medjahed, H., Gharsallah, N.-E., Coutu, M., Baalwa, J., … Finzi, A. (2014). Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity. J Virol, 88(5), 2633–2644. https://doi.org/10.1128/JVI.03230-13
Veillette, Maxime, Anik Désormeaux, Halima Medjahed, Nour-Elhouda Gharsallah, Mathieu Coutu, Joshua Baalwa, Yongjun Guan, et al. “Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity.J Virol 88, no. 5 (March 2014): 2633–44. https://doi.org/10.1128/JVI.03230-13.
Veillette M, Désormeaux A, Medjahed H, Gharsallah N-E, Coutu M, Baalwa J, et al. Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity. J Virol. 2014 Mar;88(5):2633–44.
Veillette, Maxime, et al. “Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity.J Virol, vol. 88, no. 5, Mar. 2014, pp. 2633–44. Pubmed, doi:10.1128/JVI.03230-13.
Veillette M, Désormeaux A, Medjahed H, Gharsallah N-E, Coutu M, Baalwa J, Guan Y, Lewis G, Ferrari G, Hahn BH, Haynes BF, Robinson JE, Kaufmann DE, Bonsignori M, Sodroski J, Finzi A. Interaction with cellular CD4 exposes HIV-1 envelope epitopes targeted by antibody-dependent cell-mediated cytotoxicity. J Virol. 2014 Mar;88(5):2633–2644.

Published In

J Virol

DOI

EISSN

1098-5514

Publication Date

March 2014

Volume

88

Issue

5

Start / End Page

2633 / 2644

Location

United States

Related Subject Headings

  • nef Gene Products, Human Immunodeficiency Virus
  • env Gene Products, Human Immunodeficiency Virus
  • Virology
  • Viral Regulatory and Accessory Proteins
  • Protein Multimerization
  • Protein Interaction Domains and Motifs
  • Protein Conformation
  • Protein Binding
  • Models, Molecular
  • Humans