Multimeric scaffolds displaying the HIV-1 Envelope mper induce mper-specific antibodies and cross-neutralizing antibodies when Co-Immunized with gp160 DNA

Shelly J. Krebs, Sean P. McBurney, Dina N. Kovarik, Chelsea D. Waddell, J. Pablo Jaworski, William F. Sutton, Michelle M. Gomes, Maria Trovato, Garret Waagmeester, Susan J. Barnett, Piergiuseppe DeBerardinis, Nancy L. Haigwood

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    Abstract

    Developing a vaccine that overcomes the diversity of HIV-1 is likely to require a strategy that directs antibody (Ab) responses toward conserved regions of the viral Envelope (Env). However, the generation of neutralizing Abs (NAbs) targeting these regions through vaccination has proven to be difficult. One conserved region of particular interest is the membrane proximal external region (MPER) of Env located within the gp41 ectodomain. In order to direct the immune response to this region, the MPER and gp41 ectodomain were expressed separately as N-terminal fusions to the E2 protein of Geobacillus stearothermophilus. The E2 protein acts as a scaffold by self-assembling into 60-mer particles, displaying up to 60 copies of the fused target on the surface. Rabbits were immunized with E2 particles displaying MPER and/or the gp41 ectodomain in conjunction with DNA encoding full-length gp160. Only vaccines including E2 particles displaying MPER elicited MPERspecific Ab responses. NAbs were elicited after two immunizations that largely targeted the V3 loop. To overcome V3 immunodominance in the DNA component, E2 particles displaying MPER were used in conjunction with gp160 DNA lacking hypervariable regions V2, V3, or combined V1V2V3. All rabbits had HIV binding Ab responses and NAbs following the second vaccination. Using HIV-2/HIV-1 MPER chimeric viruses as targets, NAbs were detected in 12/16 rabbits after three immunizations. Low levels of NAbs specific for Tier 1 and 2 viruses were observedin all groups. This study provides evidence that co-immunizing E2 particles displaying MPER and gp160 DNA can focus Ab responses toward conserved regions of Env.

    Original languageEnglish (US)
    Article numbere0113463
    JournalPloS one
    Volume9
    Issue number12
    DOIs
    StatePublished - Dec 2014

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    ASJC Scopus subject areas

    • Biochemistry, Genetics and Molecular Biology(all)
    • Agricultural and Biological Sciences(all)
    • General

    Cite this

    Krebs, S. J., McBurney, S. P., Kovarik, D. N., Waddell, C. D., Jaworski, J. P., Sutton, W. F., Gomes, M. M., Trovato, M., Waagmeester, G., Barnett, S. J., DeBerardinis, P., & Haigwood, N. L. (2014). Multimeric scaffolds displaying the HIV-1 Envelope mper induce mper-specific antibodies and cross-neutralizing antibodies when Co-Immunized with gp160 DNA. PloS one, 9(12), [e0113463]. https://doi.org/10.1371/journal.pone.0113463