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Antibody-directed evolution reveals a mechanism for enhanced neutralization at the HIV-1 fusion peptide site.
Banach, Bailey B; Pletnev, Sergei; Olia, Adam S; Xu, Kai; Zhang, Baoshan; Rawi, Reda; Bylund, Tatsiana; Doria-Rose, Nicole A; Nguyen, Thuy Duong; Fahad, Ahmed S; Lee, Myungjin; Lin, Bob C; Liu, Tracy; Louder, Mark K; Madan, Bharat; McKee, Krisha; O'Dell, Sijy; Sastry, Mallika; Schön, Arne; Bui, Natalie; Shen, Chen-Hsiang; Wolfe, Jacy R; Chuang, Gwo-Yu; Mascola, John R; Kwong, Peter D; DeKosky, Brandon J.
Affiliation
  • Banach BB; Bioengineering Graduate Program, The University of Kansas, Lawrence, KS, 66045, USA.
  • Pletnev S; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • Olia AS; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • Xu K; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • Zhang B; Department of Veterinary Biosciences, The Ohio State University, Columbus, OH, 43210, USA.
  • Rawi R; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • Bylund T; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • Doria-Rose NA; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • Nguyen TD; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • Fahad AS; Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, 66045, USA.
  • Lee M; Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, 66045, USA.
  • Lin BC; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • Liu T; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • Louder MK; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • Madan B; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • McKee K; Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, 66045, USA.
  • O'Dell S; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • Sastry M; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • Schön A; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • Bui N; Department of Biology, John Hopkins University, Baltimore, MD, 21218, USA.
  • Shen CH; Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, 66045, USA.
  • Wolfe JR; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • Chuang GY; Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, 66045, USA.
  • Mascola JR; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • Kwong PD; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA.
  • DeKosky BJ; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, 20814, USA. pkwong@mail.nih.gov.
Nat Commun ; 14(1): 7593, 2023 Nov 21.
Article in En | MEDLINE | ID: mdl-37989731
ABSTRACT
The HIV-1 fusion peptide (FP) represents a promising vaccine target, but global FP sequence diversity among circulating strains has limited anti-FP antibodies to ~60% neutralization breadth. Here we evolve the FP-targeting antibody VRC34.01 in vitro to enhance FP-neutralization using site saturation mutagenesis and yeast display. Successive rounds of directed evolution by iterative selection of antibodies for binding to resistant HIV-1 strains establish a variant, VRC34.01_mm28, as a best-in-class antibody with 10-fold enhanced potency compared to the template antibody and ~80% breadth on a cross-clade 208-strain neutralization panel. Structural analyses demonstrate that the improved paratope expands the FP binding groove to accommodate diverse FP sequences of different lengths while also recognizing the HIV-1 Env backbone. These data reveal critical antibody features for enhanced neutralization breadth and potency against the FP site of vulnerability and accelerate clinical development of broad HIV-1 FP-targeting vaccines and therapeutics.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: HIV Infections / HIV-1 Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2023 Document type: Article Affiliation country:
Fulltext
Add to My VHL
Print
XML
PubMed Links
Search on Google

Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: HIV Infections / HIV-1 Limits: Humans Language: En Journal: Nat Commun Journal subject: BIOLOGIA / CIENCIA Year: 2023 Document type: Article Affiliation country: