PhD ceremony Ms. N.V. Ayala Núñez: Dengue virus cell entry. Unraveling the role of antibodies, maturation status, and antiviral drugs

Antibody-dependent enhancement (ADE) is thought to play a critical role in the exacerbation of dengue virus-induced disease during a heterologous re-infection. Pre-existing cross-reactive anti-dengue antibodies are generally believed to bind to the newly infecting DENV and target the antibody-virus complexes to Fc-receptor expressing cells, cells that are highly permissive to DENV infection. Intriguingly, instead of neutralizing viral infection, these cross-reactive antibodies have been shown to facilitate successful viral entry at sub-neutralizing antibody concentrations, thereby promoting viral infection and consequently disease. The mechanism by which antibodies influence viral infection is poorly understood. The work presented in this thesis provides a detailed insight into the internalisation route and endocytic trafficking of DENV in macrophages in the absence and presence of enhancing concentrations of antibody. Also, we analysed which antibodies stimulate the infectivity of immature DENV particles. Furthermore, given the clinical importance of ADE, we also aimed to identify anti-dengue compounds that interfere with DENV infection in the presence of antibodies.