Structure-guided Design and Immunological Characterization of Immunogens Presenting the HIV-1 gp120 V3 Loop on a CTB Scaffold
Department of Medicine
AIDS Vaccines; Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; *Cholera Toxin; Drug Design; HIV Antibodies; *HIV Envelope Protein gp120; HIV-1; Immunization; *Peptide Fragments; Rabbits
Immunology and Infectious Disease | Life Sciences | Medicine and Health Sciences | Virology
V3 loop is a major neutralizing determinant of the HIV-1 gp120. Using 3D structures of cholera toxin B subunit (CTB), complete V3 in the gp120 context, and V3 bound to a monoclonal antibody (mAb), we designed two V3-scaffold immunogen constructs (V3-CTB). The full-length V3-CTB presenting the complete V3 in a structural context mimicking gp120 was recognized by the large majority of our panel of 24 mAbs. The short V3-CTB presenting a V3 fragment in the conformation observed in the complex with the 447-52D Fab, exhibited high-affinity binding to this mAb. The immunogens were evaluated in rabbits using DNA-prime/protein-boost protocol. Boosting with the full-length V3-CTB induced high anti-V3 titers in sera that potently neutralize multiple HIV virus strains. The short V3-CTB was ineffective. The results suggest that very narrow antigenic profile of an immunogen is associated with poor Ab response. An immunogen with broader antigenic activity elicits robust Ab response.
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Citation: Virology. 2010 Sep 30;405(2):513-23. Epub 2010 Jul 21. Link to article on publisher's site