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Vaccine. 2018 Oct 8;36(42):6345-6353. doi: 10.1016/j.vaccine.2018.07.032. Epub 2018 Sep 14.

Design, display and immunogenicity of HIV1 gp120 fragment immunogens on virus-like particles.

Author information

1
Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India.
2
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA.
3
International AIDS Vaccine Initiative, Brooklyn, NY 11226, USA.
4
Department of Surgery, Duke University Medical Center, Durham, NC, USA.
5
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA. Electronic address: mgfinn@gatech.edu.
6
Molecular Biophysics Unit, Indian Institute of Science, Bangalore 560012, India. Electronic address: varadar@mbu.iisc.ernet.in.

Abstract

The broadly neutralizing antibody against HIV-1, b12, binds to the CD4 binding site (CD4bs) on the outer domain (OD) of the gp120 subunit of HIV-1 Env. We have previously reported the design of an E. coli expressed fragment of HIV-1 gp120, b122a, containing about 70% of the b12 epitope with the idea of focusing the immune response to this structure. Since the b122a structure was found to be only partially folded, as assessed by circular dichroism and protease resistance, we attempted to stabilize it by the introduction of additional disulfide bonds. One such mutant, b122a1-b showed increased stability and bound b12 with 30-fold greater affinity as compared to b122a. Various b122a and OD fragment proteins were displayed on the surface of Qβ virus-like particles. Sera raised against these particles in six-month long rabbit immunization studies could neutralize Tier1 viruses across different subtypes with the best results observed with b122a1-b displayed particles. Significantly higher amounts of antibodies directed towards the CD4bs were also elicited by particles displaying b122a1-b. This study highlights the ability of fragment immunogens to focus the antibody response to the conserved CD4bs of HIV-1.

KEYWORDS:

Immune focusing; Nanoparticles; Neutralizing antibodies; Protein stability; Vaccine

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