NATURAL VARIANTS OF CYTOTOXIC EPITOPES ARE T-CELL RECEPTOR ANTAGONISTS FOR ANTIVIRAL CYTOTOXIC T-CELLS

IT has been suggested that mutations within immunodominant cytotoxic T -lymphocyte (CTL) epitopes may be exploited by viruses to evade protec tive immune responses critical for clearance(1-4). Viral escape could originate from passive mechanisms, such as mutations within crucial CT L epitopes, either affecting major histocompatibility complex binding or T-cell antigen receptor (TCR) recognition. Additionally, it has rec ently been shown that substitutions of TCR contact sites can yield ana logue peptides that can still interact with the T-cell receptor but be unable to deliver a full stimulatory signal, thus inducing anergy(5) or acting as an antagonist for the TCR(6-8). We report here that hepat itis B virus isolates derived from two chronically infected patients d isplay variant epitopes that act as natural TCR antagonists with the c apacity to inhibit the CTL response to the wild-type epitope. During n atural infection, TCR antagonist mutations of CTL epitopes could contr ibute to the development of viral persistence, especially if the antiv iral CTL response is monospecific or the epitope is strongly immunodom inant.