Cytomegalovirus memory inflation and immune protection

Cytomegalovirus (CMV) infection induces powerful and sustained T-cell responses against a few selected immunodominant antigenic epitopes. This immune response was named memory inflation, because it does not contract in the long term, and may even expand over months and years of virus latency. It is by now understood that memory inflation does not occur at the expense of the naïve T-cell pool, but rather as a competitive selection process within the effector pool, where viral antigens with higher avidity of TCR binding and with earlier expression patterns outcompete those that are expressed later and bind TCRs less efficiently. It is also understood that inflationary epitopes require processing by the constitutive proteasome in non-hematopoietic cells, and this likely implies that memory inflation is fuelled by direct low-level antigenic expression in latently infected cells. This review proposes that these conditions make inflationary epitopes the optimal candidates for adoptive immunotherapy of CMV disease in the immunocompromised host. At present, functional target CMV epitopes have been defined only for the most common HLA haplotypes. Mapping the uncharacterized inflationary epitopes in less frequent HLAs may, thus, be a strategy for the identification of optimal immunotherapeutic targets in patients with uncommon haplotypes.