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Contemporary HIV-1 consensus Env with AI-assisted redesigned hypervariable loops promote antibody binding.
Bai, Hongjun; Lewitus, Eric; Li, Yifan; Thomas, Paul V; Zemil, Michelle; Merbah, Mélanie; Peterson, Caroline E; Thuraisamy, Thujitha; Rees, Phyllis A; Hajduczki, Agnes; Dussupt, Vincent; Slike, Bonnie; Mendez-Rivera, Letzibeth; Schmid, Annika; Kavusak, Erin; Rao, Mekhala; Smith, Gabriel; Frey, Jessica; Sims, Alicea; Wieczorek, Lindsay; Polonis, Victoria; Krebs, Shelly J; Ake, Julie A; Vasan, Sandhya; Bolton, Diane L; Joyce, M Gordon; Townsley, Samantha; Rolland, Morgane.
Affiliation
  • Bai H; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
  • Lewitus E; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, 20817, USA.
  • Li Y; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
  • Thomas PV; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, 20817, USA.
  • Zemil M; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
  • Merbah M; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, 20817, USA.
  • Peterson CE; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, 20817, USA.
  • Thuraisamy T; Emerging Infectious Disease Branch, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
  • Rees PA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
  • Hajduczki A; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, 20817, USA.
  • Dussupt V; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
  • Slike B; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, 20817, USA.
  • Mendez-Rivera L; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, 20817, USA.
  • Schmid A; Emerging Infectious Disease Branch, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
  • Kavusak E; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
  • Rao M; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, 20817, USA.
  • Smith G; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, 20817, USA.
  • Frey J; Emerging Infectious Disease Branch, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
  • Sims A; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, 20817, USA.
  • Wieczorek L; Emerging Infectious Disease Branch, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
  • Polonis V; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
  • Krebs SJ; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, 20817, USA.
  • Ake JA; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
  • Vasan S; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, 20817, USA.
  • Bolton DL; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
  • Joyce MG; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, 20817, USA.
  • Townsley S; U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, 20910, USA.
  • Rolland M; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, 20817, USA.
Nat Commun ; 15(1): 3924, 2024 May 09.
Article in En | MEDLINE | ID: mdl-38724518
ABSTRACT
An effective HIV-1 vaccine must elicit broadly neutralizing antibodies (bnAbs) against highly diverse Envelope glycoproteins (Env). Since Env with the longest hypervariable (HV) loops is more resistant to the cognate bnAbs than Env with shorter HV loops, we redesigned hypervariable loops for updated Env consensus sequences of subtypes B and C and CRF01_AE. Using modeling with AlphaFold2, we reduced the length of V1, V2, and V5 HV loops while maintaining the integrity of the Env structure and glycan shield, and modified the V4 HV loop. Spacers are designed to limit strain-specific targeting. All updated Env are infectious as pseudoviruses. Preliminary structural characterization suggests that the modified HV loops have a limited impact on Env's conformation. Binding assays show improved binding to modified subtype B and CRF01_AE Env but not to subtype C Env. Neutralization assays show increases in sensitivity to bnAbs, although not always consistently across clades. Strikingly, the HV loop modification renders the resistant CRF01_AE Env sensitive to 10-1074 despite the absence of a glycan at N332.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: HIV Antibodies / HIV-1 / Env Gene Products, Human Immunodeficiency Virus / Antibodies, Neutralizing Limits: Humans Language: En Journal: Nat Commun Year: 2024 Document type: Article
Fulltext
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: HIV Antibodies / HIV-1 / Env Gene Products, Human Immunodeficiency Virus / Antibodies, Neutralizing Limits: Humans Language: En Journal: Nat Commun Year: 2024 Document type: Article