Induction of tier-2 neutralizing antibodies in mice with a DNA-encoded HIV envelope native like trimer

Ziyang Xu, Susanne Walker, Megan C. Wise, Neethu Chokkalingam, Mansi Purwar, Alan Moore, Edgar Tello-Ruiz, Yuanhan Wu, Sonali Majumdar, Kylie M. Konrath, Abhijeet Kulkarni, Nicholas J. Tursi, Faraz I. Zaidi, Emma L. Reuschel, Ishaan Patel, April Obeirne, Jianqiu Du, Katherine Schultheis, Lauren Gites, Trevor Smith, Janess Mendoza, Kate E. Broderick, Laurent Humeau, Jesper Pallesen, David B. Weiner and Daniel W. Kulp ()
Additional contact information
Ziyang Xu: The Wistar Institute
Susanne Walker: The Wistar Institute
Megan C. Wise: Inovio Pharmaceuticals
Neethu Chokkalingam: The Wistar Institute
Mansi Purwar: The Wistar Institute
Alan Moore: Indiana University
Edgar Tello-Ruiz: The Wistar Institute
Yuanhan Wu: The Wistar Institute
Sonali Majumdar: The Wistar Institute
Kylie M. Konrath: The Wistar Institute
Abhijeet Kulkarni: The Wistar Institute
Nicholas J. Tursi: The Wistar Institute
Faraz I. Zaidi: The Wistar Institute
Emma L. Reuschel: The Wistar Institute
Ishaan Patel: The Wistar Institute
April Obeirne: The Wistar Institute
Jianqiu Du: Indiana University
Katherine Schultheis: Inovio Pharmaceuticals
Lauren Gites: Inovio Pharmaceuticals
Trevor Smith: Inovio Pharmaceuticals
Janess Mendoza: Inovio Pharmaceuticals
Kate E. Broderick: Inovio Pharmaceuticals
Laurent Humeau: Inovio Pharmaceuticals
Jesper Pallesen: Indiana University
David B. Weiner: The Wistar Institute
Daniel W. Kulp: The Wistar Institute

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract HIV Envelope (Env) is the main vaccine target for induction of neutralizing antibodies. Stabilizing Env into native-like trimer (NLT) conformations is required for recombinant protein immunogens to induce autologous neutralizing antibodies(nAbs) against difficult to neutralize HIV strains (tier-2) in rabbits and non-human primates. Immunizations of mice with NLTs have generally failed to induce tier-2 nAbs. Here, we show that DNA-encoded NLTs fold properly in vivo and induce autologous tier-2 nAbs in mice. DNA-encoded NLTs also uniquely induce both CD4 + and CD8 + T-cell responses as compared to corresponding protein immunizations. Murine neutralizing antibodies are identified with an advanced sequencing technology. The structure of an Env-Ab (C05) complex, as determined by cryo-EM, identifies a previously undescribed neutralizing Env C3/V5 epitope. Beyond potential functional immunity gains, DNA vaccines permit in vivo folding of structured antigens and provide significant cost and speed advantages for enabling rapid evaluation of new HIV vaccines.

Date: 2022
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DOI: 10.1038/s41467-022-28363-z

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