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A chimeric HIV-1 envelope glycoprotein trimer with an embedded granulocyte-macrophage colony-stimulating factor (GM-CSF) domain induces enhanced antibody and T cell responses.

TitleA chimeric HIV-1 envelope glycoprotein trimer with an embedded granulocyte-macrophage colony-stimulating factor (GM-CSF) domain induces enhanced antibody and T cell responses.
Publication TypeJournal Article
Year of Publication2011
Authorsvan Montfort T, Melchers M, Isik G, Menis S, Huang P-S, Matthews K, Michael E, Berkhout B, Schief WR, Moore JP, Sanders RW
JournalJ Biol Chem
Volume286
Issue25
Pagination22250-61
Date Published2011 Jun 24
ISSN1083-351X
KeywordsAmino Acid Sequence, Animals, Antibodies, Neutralizing, Antibody Specificity, Granulocyte-Macrophage Colony-Stimulating Factor, HEK293 Cells, HIV Envelope Protein gp120, HIV-1, Humans, Mice, Models, Molecular, Molecular Sequence Data, Protein Engineering, Protein Multimerization, Protein Structure, Quaternary, Protein Structure, Tertiary, Recombinant Fusion Proteins, T-Lymphocytes, Helper-Inducer, Viral Vaccines
Abstract

An effective HIV-1 vaccine should ideally induce strong humoral and cellular immune responses that provide sterilizing immunity over a prolonged period. Current HIV-1 vaccines have failed in inducing such immunity. The viral envelope glycoprotein complex (Env) can be targeted by neutralizing antibodies to block infection, but several Env properties limit the ability to induce an antibody response of sufficient quantity and quality. We hypothesized that Env immunogenicity could be improved by embedding an immunostimulatory protein domain within its sequence. A stabilized Env trimer was therefore engineered with the granulocyte-macrophage colony-stimulating factor (GM-CSF) inserted into the V1V2 domain of gp120. Probing with neutralizing antibodies showed that both the Env and GM-CSF components of the chimeric protein were folded correctly. Furthermore, the embedded GM-CSF domain was functional as a cytokine in vitro. Mouse immunization studies demonstrated that chimeric Env(GM-CSF) enhanced Env-specific antibody and T cell responses compared with wild-type Env. Collectively, these results show that targeting and activation of immune cells using engineered cytokine domains within the protein can improve the immunogenicity of Env subunit vaccines.

DOI10.1074/jbc.M111.229625
Alternate JournalJ. Biol. Chem.
PubMed ID21515681
PubMed Central IDPMC3121371
Grant ListAI36082 / AI / NIAID NIH HHS / United States
AI45463 / AI / NIAID NIH HHS / United States

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