The functional importance of flavivirus maturation

PhD ceremony: Ms. I.A. Rodenhuis-Zybert, 13.15 uur, Aula Academiegebouw, Broerstraat 5, Groningen

Dissertation: The functional importance of flavivirus maturation

Promotor(s): prof. J.C. Wilschut

Faculty: Medical Sciences

Among flaviviruses that cause disease in humans, infections with mosquito-transmitted four serotypes of Dengue virus (DENV 1-4), West-Nile virus (WNV) are currently of a most global concern. Yet to date, there are no vaccines approved for use against these viruses. Vaccine development for DENV proved to be particularly challenging since antibodies produced during primary infection has been linked to the risk ofdeveloping severe disease upon secondary infection with another serotype.

Flavivirus-specific antibodies are mainly directed against two viral glycoproteins: the main envelope protein E and prM that constitutes the surface of the generally noninfectious, so called immature viruses.Herein we show in vitro and in vivo that in the presence of prM and E antibodies, immature viruses become infectious. In fact, opsonization with the antibodies facilitates, otherwise poor, entry of immature dengue virions into Fc-receptors bearing cells. Furthermore, we have shown that activity of furin, an enzyme residing in the host cell, is critical to elicit infectious phenotype of the immature virus, suggesting viral maturation process upon entry. Thus, we have demonstrated that antibody response of the infected individual can render otherwise non-pathogenic virions infectious and thereby contribute to the development of the severe disease presentation.