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Article
Daniel Kulp
Wistar Institute
Corresponding Author
ORCiD: https://orcid.org/0000-0002-0527-3804
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This work is licensed under a CC BY 4.0 License. Read Full License
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.
Keywords
HIV Vaccine, HIV Envelope, Autologous Neutralizing Antibodies, Informed Humoral Response, In Vivo Folding, Structured Antigens
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Yes there is potential Competing Interest. M.C.W., D.B.W and D.W.K. have a pending patent with regard to in vivo assembly of trimers using DNA delivery. M.C.W, K.E.B., and L.M.H are employees of Inovio Pharmaceuticals and as such receive salary and benefits including ownership of stock and stock options from the company. D.B.W. has received grant funding, participates in industry collaborations, has received speaking honoraria, and has received fees for consulting, including serving on scientific review committees and board series. Remuneration received by D.B.W. includes direct payments, stock or stock options, and in the interest of disclosure he notes potential conflicts associated with his work with Inovio and possible others.
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- MD39paperfigure20200903v10Supplemantary.pdf
Supplementary Figures
- Rawdatatrimermanuscript.xlsx
Raw data
- Table1.png
Table 1. Detailed characterization of isolated murine BG505.MD39-specific clones in terms of VH, VJ, VD, VK, VK, VJ gene usage, HCDR3 and LCDR3 lengths.
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This preprint is under consideration at a Nature Portfolio Journal. A preprint is a preliminary version of a manuscript that has not completed peer review at a journal. Research Square does not conduct peer review prior to posting preprints. The posting of a preprint on this server should not be interpreted as an endorsement of its validity or suitability for dissemination as established information or for guiding clinical practice.
Nature journals have partnered with Research Square to offer In Review, a journal-integrated preprint deposition service.
Article
Daniel Kulp
Wistar Institute
Corresponding Author
ORCiD: https://orcid.org/0000-0002-0527-3804
Badges
Prescreen
This manuscript passed our Prescreen assessment
Complete author information
Appropriate declaration statements
Potential risks to human health
Prescreen
Peer Review Timeline
CURRENT STATUS: Under Review
Version 1
Posted 15 Mar, 2021
Metrics
Comments: 0
PDF Downloads: ...
HTML Views: ...
License:
This work is licensed under a CC BY 4.0 License. Read Full License
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.
Figure 1
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