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Published March 27, 2023 | Submitted
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CD4-binding site immunogens elicit heterologous anti-HIV-1 neutralizing antibodies in transgenic and wildtype animals


Passive transfer of broadly neutralizing anti-HIV-1 antibodies (bNAbs) protects against infection, and therefore eliciting bNAbs by vaccination is a major goal of HIV-1 vaccine efforts. bNAbs that target the CD4-binding site (CD4bs) on HIV-1 Env are among the most broadly active, but to date, responses elicited against this epitope in vaccinated animals have lacked potency and breadth. We hypothesized that CD4bs bNAbs resembling the antibody IOMA might be easier to elicit than other CD4bs antibodies that exhibit higher somatic mutation rates, a difficult-to-achieve mechanism to accommodate Env's N276_(gp120) N-glycan, and rare 5-residue light chain complementarity determining region 3s (CDRL3s). As an initial test of this idea, we developed IOMA germline-targeting Env immunogens and evaluated a sequential immunization regimen in transgenic mice expressing germline-reverted IOMA. These mice developed CD4bs epitope-specific responses with heterologous neutralization, and cloned antibodies overcame neutralization roadblocks including accommodating the N276_(gp120) glycan, with some neutralizing selected HIV-1 strains more potently than IOMA. The immunization regimen also elicited CD4bs-specific responses in animals containing polyclonal antibody repertoires. Thus, germline-targeting of IOMA-class antibody precursors represents a potential vaccine strategy to induce CD4bs bNAbs.

Additional Information

The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. We thank J. Moore (Weill Cornell Medical College), R.W. Sanders and M.J. van Gils (Amsterdam UMC) for SOSIP expression plasmids; M. Silva, M. B. Melo and D. J. Irvine (MIT) for providing SMNP adjuvant; Lotta von Boehmer (Stanford University) for discussion; J. Vielmetter, P. Hoffman, and the Protein Expression Center in the Beckman Institute at Caltech for expression assistance; T. Eisenreich and S. Tittley for animal husbandry and K. Gordon and K. Chosphel for fluorescence-activated cell sorting at Rockefeller University. Electron microscopy was performed in the Caltech Cryo-EM Center with assistance from S. Chen and A. Malyutin. This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) Grants HIVRAD P01 AI100148 (to P.J.B. and M.C.N.), HIVRAD P01 AI138212 (to L.S., A.T.M., and M.N.), and R21 AI127249 (to A.T.M.), the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) grant INV-002143 (P.J.B., M.C.N., and M.A.M.), a Bill and Melinda Gates Foundation grant # OPP1146996 (to M.S.S.), the Intramural Research Program of the NIAID (to M.A.M. and Y.N.), and NIH P50 AI150464 (P.J.B.). A.T.D. and M.E.A. were supported by NSF Graduate Research Fellowships. M.C.N. is an HHMI investigator. Under the grant conditions of the Bill and Melinda Gates Foundation Collaboration, a Creative Commons Attribution 4.0 Generic License has already been assigned to the Author Accepted Manuscript version that might arise from this submission. The authors have declared no competing interest.

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August 20, 2023
December 13, 2023