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Author Notes:

Correspondence to Ashley T. Haase, M.D., Department of Microbiology and Immunology, University of Minnesota, 689-23rd Avenue S.E., Campus Delivery Code 2821A, Minneapolis, MN 55455-1507, USA. Tel: +1 612-624-4442; fax: +1 612-626-0623; haase001@umn.edu

J.E.V., M.S.M., R.P.J., D.R.B., and A.T.H. designed the experiments.

J.E.V. designed and produced protein immunogens, carried out mouse and rabbit immunization experiments, evaluated serum and CVF Ig by ELISA and western blot, prepared figures and helped to write the manuscript.

M.S.M. incorporated protein into liposomes for immunizations, prepared figures and helped to write the manuscript.

K.A.R. and F.V. performed the rhesus macaque experiments.

L.D. evaluated serum and CVF levels of antibodies by quantitative western blotting.

L.S. performed the neutralization assays.

J.E.R. generated the rhesus version of monoclonal antibody 4.9C for the passive immunization experiments.

E.A.F. helped with protein production and purification.

R.A. helped prepare figures.

All the authors analyzed the data and helped write the manuscript.

We thank Jon Warren and Akiko Iwasaki for helpful discussion.

Conflicts of Interest and Source of Funding: The authors declare no conflicts of interest.

Subjects:

Research Funding:

This work was supported by National Institutes of Health Grants R01 AI102625 and P30 AI036214.

The 4.9C antibody used in the passive immunization studies was produced by the NIH Nonhuman Primate Reagent Resource funded by NIH grant OD010976 and NIAID contract HHSN272200130031C.

Portions of this work were facilitated by the Protein Expression and Proteomics Core of the University of California, San Diego, Center for AIDS Research (CFAR).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Immunology
  • Infectious Diseases
  • Virology
  • mucosal concentration
  • SIV VACCINE
  • trimeric gp41 antibodies
  • SIMIAN IMMUNODEFICIENCY VIRUS
  • ATTENUATED SIV
  • TRANSMEMBRANE PROTEIN
  • CONTROL REPLICATION
  • IMMUNE-RESPONSES
  • MACAQUES
  • LIVE
  • INFECTION
  • TYPE-1
  • SIVMAC239-DELTA-NEF

Reproducing SIVnef vaccine correlates of protection: trimeric gp41 antibody concentrated at mucosal front lines

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Journal Title:

AIDS

Volume:

Volume 30, Number 16

Publisher:

, Pages 2427-2438

Type of Work:

Article | Post-print: After Peer Review

Abstract:

Vaccination with SIV mac239 δnef provides robust protection against subsequent challenge with wild-type simian immunodeficiency virus (SIV), but safety issues have precluded designing an HIV-1 vaccine based on a live-attenuated virus concept. Safe immunogens and adjuvants that could reproduce identified immune correlates of SIV mac239 δnef protection therefore offer an alternative path for development of an HIV vaccine. Here we describe SIV envelope trimeric gp41 (gp41t) immunogens based on a protective correlate of antibodies to gp41t concentrated on the path of virus entry by the neonatal Fc receptor (FcRn) in cervical vaginal epithelium. We developed a gp41t immunogen-monophosphoryl lipid A adjuvant liposomal nanoparticle for intramuscular (i.m.) immunization and a gp41t-Fc immunogen for intranasal immunization for pilot studies in mice, rabbits, and rhesus macaques. Repeated immunizations to mimic persistent antigen exposure in infection elicited gp41t antibodies in rhesus macaques that were detectable in FcRn cervical vaginal epithelium, thus recapitulating one key feature of SIV mac239 δnef vaccinated and protected animals. Although this strategy did not reproduce the system of local production of antibody in SIV mac239 δnef-vaccinated animals, passive immunization experiments supported the concept that sufficiently high levels of antibody can be concentrated by the FcRn at mucosal frontlines, thus setting the stage for assessing protection against vaginal challenge by gp41t immunization.

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© 2016 Wolters Kluwer Health, Inc. All rights reserved.

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