Exploiting novel antiviral immune responses

Studies of antiviral humoral immunity are dominated by neutralization. However, within a host viruses spread cell-to-cell, which avoids this activity. Thus, antibodies that bind cell-surface viral antigens and activate antibody-dependent cellular cytotoxicity (ADCC) become critical. Entry glycoproteins are assumed to be optimal targets for both neutralizing and ADCC activity. However, when we developed novel techniques to measure proteome-wide ADCC, we found that entry glycoproteins are poor ADCC targets. Instead, non-structural proteins are dominant targets. Thus, the induction of neutralisation and ADCC requires different strategies. By focusing on entry glycoproteins, current vaccines fail to provide maximal protection against certain viruses. By focusing on non-structural antigens, we generated the first antibodies capable of promoting immunological control of HCMV.

We, therefore, propose that non-structural ADCC is an important component of protection, and provides a novel route to enhance antiviral strategies. However, it also reveals fundamental gaps in our understanding – we do not know what determines ADCC potency. We, therefore, seek to understand the protective capacity of non-structural ADCC in disease, how it can be exploited to enhance next-generation therapeutics, and what determines the induction of robust ADCC, as the basis to systematically exploit ADCC against other and future virus threats.