Protecting and pathogenic antibody responses to Dengue virus
Research area: Immune Regulation
Group leaders: Antonio Lanzavecchia
Status: In progress
Antibodies can protect against homologous dengue virus (DENV) infection, but can also precipitate severe dengue by promoting heterotypic virus entry via Fcg receptors (FcgR). We previously reported that human monoclonal antibodies to the domain III (DIII) of the envelope (E) protein potently neutralize DENV infection and are either serotype specific or cross-reactive with two or three but never with all four DENV serotypes. In contrast, DI/DII-specific antibodies have lower neutralizing activity but completely cross-react with the four DENV serotypes. Furthermore we confirmed that all antibodies enhance infection at sub-neutralizing concentrations. The three most potent and broadly neutralizing antibodies were engineered to prevent FcgR binding and found to be devoid of enhancing activity and effective as post-exposure therapy in a mouse model of lethal DENV infection. Based on our findings we hypothesize that the potently neutralizing DIII-specific antibodies protect form homologous but not from heterologous challenge, while the poorly neutralizing DI/II-specific antibodies are the primary culprits for enhancing heterologous infection. We continue the studies on the human antibody response to DENV in collaboration with Federica Sallusto and Luca Varani, IRB and with colleagues based in Ho Chi Minh City, Paris, Berkeley and Chapel Hill.
This work was done in collaboration with Federica Sallusto and Luca Varani, IRB, Bellinzona; Cameron Simmons, Hospital for Tropical Diseases, Ho Chi Minh City (VN); Felix Rey, Institute Pasteur, Paris (FR); Mike Diamond, Washington University School of Medicine, St. Louis, MO (US); Eva Harris, University of California, Berkeley, CA (US); and Aravinda de Silva, University of North Carolina, Chapel Hill, NC (US).