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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.
Affiliation
  • 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 in En | MEDLINE | ID: mdl-37436900
ABSTRACT
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.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: HIV Infections / HIV-1 / HIV Seropositivity Limits: Humans Language: En Journal: Cell Rep Year: 2023 Document type: Article Affiliation country:
Fulltext
Add to My VHL
Print
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PubMed Links
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: HIV Infections / HIV-1 / HIV Seropositivity Limits: Humans Language: En Journal: Cell Rep Year: 2023 Document type: Article Affiliation country: