Characterising viral antibody evasion by conformational masking. . (360G-Wellcome-107653_Z_15_Z)

CM limits the availability of neutralisation targets; nevertheless, it does not prevent the emergence of antibodies against these sites. Rather, CM prevents antibodies from accessing their targets and inactivating virus particles in circulation. However, coordinated unmasking is necessary to enable functional domains to participate in virus entry. This imposes rate-limiting steps on the entry program, and introduces a phase in which the unmasked virus is vulnerable to antibodies. Using robus t in vitro models I will quantify the effect of CM on virus entry kinetics. I will also discover whether drugs that interrupt entry can extend the window of opportunity for antibodies. By limiting entry, CM confers a potential fitness cost; however, in natural infection this is likely offset by the benefits of antibody evasion. Exploiting deep sequencing analysis and phenotypic characterisation, I will perform in vitro and in vivo studies to establish the role of immune selection in maintaining CM. This will provide an important understanding of how immune responses shape viral evolution. Building on my expertise in cutting-edge microscopy, I will use a novel super-resolution virometry assay to directly measure antibody binding to defined model viruses and patient-derived variants; therefore quantifying the molecular consequences of CM.