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

• DOI: 10.1038/s41467-022-28363-z
• Publication Date: 2022-02-04T11:14:57Z
• Authors: 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; Daniel W. Kulp
• Keywords: 0301 basic medicine; Enzyme-Linked Immunospot Assay; Science; T-Lymphocytes; HIV Infections; HIV Antibodies; Article; Epitopes; Interferon-gamma; Mice; 03 medical and health sciences; Cell Line, Tumor; Vaccines, DNA; Animals; Humans; Antigens, Viral; AIDS Vaccines; Mice, Inbred BALB C; Q; Cryoelectron Microscopy; Vaccination; env Gene Products, Human Immunodeficiency Virus; Antibodies, Neutralizing; 3. Good health; HEK293 Cells; HIV-1

AbstractHIV 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.