Your browser doesn't support javascript.
loading
Improved HIV-1 neutralization breadth and potency of V2-apex antibodies by in silico design.
Holt, Graham T; Gorman, Jason; Wang, Siyu; Lowegard, Anna U; Zhang, Baoshan; Liu, Tracy; Lin, Bob C; Louder, Mark K; Frenkel, Marcel S; McKee, Krisha; O'Dell, Sijy; Rawi, Reda; Shen, Chen-Hsiang; Doria-Rose, Nicole A; Kwong, Peter D; Donald, Bruce R.
Afiliación
  • Holt GT; Department of Computer Science, Duke University, Durham, NC, USA; Program in Computational Biology & Bioinformatics, Duke University, Durham, NC, USA.
  • Gorman J; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Wang S; Program in Computational Biology & Bioinformatics, Duke University, Durham, NC, USA.
  • Lowegard AU; Department of Computer Science, Duke University, Durham, NC, USA; Program in Computational Biology & Bioinformatics, Duke University, Durham, NC, USA.
  • Zhang B; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Liu T; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Lin BC; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Louder MK; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Frenkel MS; Department of Biochemistry, Duke University, Durham, NC, USA.
  • McKee K; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • O'Dell S; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Rawi R; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Shen CH; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Doria-Rose NA; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
  • Kwong PD; Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. Electronic address: pdkwong@nih.gov.
  • Donald BR; Department of Computer Science, Duke University, Durham, NC, USA; Department of Biochemistry, Duke University, Durham, NC, USA; Department of Mathematics, Duke University, Durham, NC, USA; Department of Chemistry, Duke University, Durham, NC, USA. Electronic address: brd+cell22@cs.duke.edu.
Cell Rep ; 42(7): 112711, 2023 07 25.
Article en En | MEDLINE | ID: mdl-37436900
Broadly neutralizing antibodies (bNAbs) against HIV can reduce viral transmission in humans, but an effective therapeutic will require unusually high breadth and potency of neutralization. We employ the OSPREY computational protein design software to engineer variants of two apex-directed bNAbs, PGT145 and PG9RSH, resulting in increases in potency of over 100-fold against some viruses. The top designed variants improve neutralization breadth from 39% to 54% at clinically relevant concentrations (IC80 < 1 µg/mL) and improve median potency (IC80) by up to 4-fold over a cross-clade panel of 208 strains. To investigate the mechanisms of improvement, we determine cryoelectron microscopy structures of each variant in complex with the HIV envelope trimer. Surprisingly, we find the largest increases in breadth to be a result of optimizing side-chain interactions with highly variable epitope residues. These results provide insight into mechanisms of neutralization breadth and inform strategies for antibody design and improvement.
Asunto(s)
Palabras clave
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Infecciones por VIH / VIH-1 / Seropositividad para VIH Límite: Humans Idioma: En Revista: Cell Rep Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Infecciones por VIH / VIH-1 / Seropositividad para VIH Límite: Humans Idioma: En Revista: Cell Rep Año: 2023 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos