Sequential immunization of macaques elicits heterologous neutralizing antibodies targeting the V3-glycan patch of HIV-1 Env.

Autor: Escolano A; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA., Gristick HB; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Gautam R; Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., DeLaitsch AT; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Abernathy ME; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Yang Z; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Wang H; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Hoffmann MAG; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Nishimura Y; Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Wang Z; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA., Koranda N; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Kakutani LM; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Gao H; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Gnanapragasam PNP; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Raina H; Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Gazumyan A; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA., Cipolla M; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA., Oliveira TY; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA., Ramos V; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA., Irvine DJ; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., Silva M; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139, USA., West AP Jr; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Keeffe JR; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Barnes CO; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA., Seaman MS; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA., Nussenzweig MC; Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.; Howard Hughes Medical Institute, The Rockefeller University, New York, NY 10065, USA., Martin MA; Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Bjorkman PJ; Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125, USA.
Jazyk: angličtina
Zdroj: Science translational medicine [Sci Transl Med] 2021 Nov 24; Vol. 13 (621), pp. eabk1533. Date of Electronic Publication: 2021 Nov 24.
DOI: 10.1126/scitranslmed.abk1533
Abstrakt: Broadly neutralizing antibodies (bNAbs) against HIV-1 develop after prolonged virus and antibody coevolution. Previous studies showed that sequential immunization with a V3-glycan patch germline-targeting HIV-1 envelope trimer (Env) followed by variant Envs can reproduce this process in mice carrying V3-glycan bNAb precursor B cells. However, eliciting bNAbs in animals with polyclonal antibody repertoires is more difficult. We used a V3-glycan immunogen multimerized on virus-like particles (VLPs), followed by boosting with increasingly native-like Env-VLPs, to elicit heterologous neutralizing antibodies in nonhuman primates (NHPs). Structures of antibody/Env complexes after prime and boost vaccinations demonstrated target epitope recognition with apparent maturation to accommodate glycans. However, we also observed increasing off-target antibodies with boosting. Eight vaccinated NHPs were subsequently challenged with simian-human immunodeficiency virus (SHIV), and seven of eight animals became infected. The single NHP that remained uninfected after viral challenge exhibited one of the lowest neutralization titers against the challenge virus. These results demonstrate that more potent heterologous neutralization resulting from sequential immunization is necessary for protection in this animal model. Thus, improved prime-boost regimens to increase bNAb potency and stimulate other immune protection mechanisms are essential for developing anti–HIV-1 vaccines.
Databáze: MEDLINE