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Identification of an HIV-1 clade A envelope that exhibits broad antigenicity and neutralization sensitivity and elicits antibodies targeting three distinct epitopes

Academic Article
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Overview

authors

  • Hoffenberg, S.
  • Powell, R.
  • Carpov, A.
  • Wagner, D.
  • Wilson, A.
  • Pond, S. K.
  • Lindsay, R.
  • Arendt, H.
  • DeStefano, J.
  • Phogat, S.
  • Poignard, Pascal
  • Fling, S. P.
  • Simek, M.
  • LaBranche, C.
  • Montefiori, D.
  • Wrin, T.
  • Phung, P.
  • Burton, Dennis
  • Koff, W.
  • King, C. R.
  • Parks, C. L.
  • Caulfield, M. J.

publication date

  • May 2013

journal

  • Journal of Virology  Journal

abstract

  • Broadly neutralizing antibodies (bNAbs) PG9 and PG16 were isolated from an International AIDS Vaccine Initiative (IAVI) Protocol G subject infected with human immunodeficiency virus type 1 (HIV-1) clade A. Both antibodies are highly potent and neutralize greater than 70% of viruses tested. We sought to begin immunogen design based on viral sequences from this patient; however, pseudoviruses prepared with 19 envelope sequences from this subject were resistant to neutralization by PG9 and PG16. Therefore, we used a bioinformatics approach to identify closely related viruses that were potentially sensitive to PG9 and PG16. A most-recent common ancestor (MRCA) sequence for the viral envelope (Env) was determined and aligned with 99 subtype A gp160 sequences from the Los Alamos HIV database. Virus BG505.W6M.ENV.C2 (BG505) was found to have the highest degree of homology (73%) to the MRCA sequence. Pseudoviruses prepared with this Env were sensitive to neutralization with a broad panel of bNAbs, including PG9 and PG16. When expressed by 293T cells as soluble gp120, the BG505 monomer bound well to both PG9 and PG16. We further showed that a point mutation (L111A) enabled more efficient production of a stable gp120 monomer that preserves the major neutralization epitopes. Finally, we showed that an adjuvanted formulation of this gp120 protein elicited neutralizing antibodies in rabbits (following a gp120 DNA vaccine prime) and that the antisera competed with bNAbs from 3 classes of nonoverlapping epitopes. Thus, the BG505 Env protein warrants further investigation as an HIV vaccine candidate, as a stand-alone protein, or as a component of a vaccine vector.

subject areas

  • Antibodies, Neutralizing
  • Computational Biology
  • Epitopes
  • Female
  • Genotype
  • HIV Antibodies
  • HIV Envelope Protein gp120
  • HIV Infections
  • HIV-1
  • Humans
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Identity

PubMed Central ID

  • PMC3648150

International Standard Serial Number (ISSN)

  • 0022-538X

Digital Object Identifier (DOI)

  • 10.1128/jvi.02827-12

PubMed ID

  • 23468492
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Additional Document Info

start page

  • 5372

end page

  • 5383

volume

  • 87

issue

  • 10

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