Despite extensive efforts, an efficacious HIV vaccine remains elusive. HIV Envelope (Env) is the target of all known 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. However, mice are the most cost effective and widely used vaccine model and mouse immunizations with NLTs have generally failed to induce tier-2 nAbs. Here, we explored if DNA-encoded NLTs would fold properly in vivo and induce an informed humoral response. We observed DNA encoding a BG505 NLT induces autologous tier-2 nAbs in mice, identified murine monoclonal neutralizing antibodies, mapped the responses to a new murine neutralizing Env C3/V5 epitope and determined the structures of Env-nAbs complexes. 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.
