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Structure-guided design and immunological characterization of immunogens presenting the HIV-1 gp120 V3 loop on a CTB scaffold |
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| Authors: | Maxim Totrov Xunqing Jiang Sandra Cohen Aidy Salomon Michael S. Seaman Miroslaw K. Gorny Shan Lu Susan Zolla-Pazner |
| Affiliation: | a Molsoft LLC, 3366 N Torrey Pines Ct., La Jolla, CA 92037, USA b New York Veterans Affairs Medical Center, New York, NY 10010, USA c Departments of Biochemistry, Pharmacology and Pathology, NYU Langone School of Medicine, New York, NY 10016, USA d Public Health Research Institute Center, University of Medicine and Dentistry of New Jersey, Newark, NJ 07103, USA e Beth Israel Deaconess Medical Center, Department of Medicine, Division of Viral Pathogenesis, Harvard Medical School, Boston, MA, USA f University of Massachusetts Medical School, Worcester, MA 01605, USA |
| Abstract: | 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. |
| Keywords: | Immunogen design HIV-1 gp120 V3 loop Cholera toxin B subunit Neutralizing antibody 447-52D HIV vaccine |
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