A novel transmembrane domain mediating retention of a highly motile herpesvirus glycoprotein in the endoplasmic reticulum.

Gene m164 of murine cytomegalovirus belongs to the large group of 'private' genes that show no homology to those of other cytomegalovirus species and are thought to represent 'host adaptation' genes involved in virus-host interaction. Previous interest in the m164 gene product was based on the presence of an immunodominant CD8 T-cell epitope presented at the surface of infected cells, despite interference by viral immune-evasion proteins. Here, we provide data to reveal that the m164 gene product shows unusual features in its cell biology.

Subdominant CD8 T-cell epitopes account for protection against cytomegalovirus independent of immunodomination.

Cytomegalovirus (CMV) infection continues to be a complication in recipients of hematopoietic stem cell transplantation (HSCT). Preexisting donor immunity is recognized as a favorable prognostic factor for the reconstitution of protective antiviral immunity mediated primarily by CD8 T cells. Furthermore, adoptive transfer of CMV-specific memory CD8 T (CD8-T(M)) cells is a therapeutic option for preventing CMV disease in HSCT recipients.

Epitope-specific in vivo protection against cytomegalovirus disease by CD8 T cells in the murine model of preemptive immunotherapy.

Preclinical research in murine models as well as subsequent clinical trials have concordantly revealed a high protective potential of antiviral CD8 T cells, of donor-derived ex vivo memory CD8 T cells in particular, in the immunotherapy of cytomegalovirus (CMV) infection in immunocompromised recipients. Although it is generally held view that the observed beneficial effect of the transferred cells is viral epitope-specific, involving the recognition of MHC class-I presented peptides by cognate T cell receptors, this assumption awaits formal proof, at least with regard to the in vivo function of the CD8 T cells. This question is particularly evident for CMV, since the function of viral immune evasion proteins interferes with the MHC class-I pathway of peptide presentation.

CD8 T cells control cytomegalovirus latency by epitope-specific sensing of transcriptional reactivation.

During murine cytomegalovirus (mCMV) latency in the lungs, most of the viral genomes are transcriptionally silent at the major immediate-early locus, but rare and stochastic episodes of desilencing lead to the expression of IE1 transcripts. This low-frequency but perpetual expression is accompanied by an activation of lung-resident effector-memory CD8 T cells specific for the antigenic peptide 168-YPHFMPTNL-176, which is derived from the IE1 protein. These molecular and immunological findings were combined in the "silencing/desilencing and immune sensing hypothesis" of cytomegalovirus latency and reactivation.

Cytomegalovirus encodes a positive regulator of antigen presentation.

Murine cytomegalovirus encodes three regulators of antigen presentation to antiviral CD8 T cells. According to current paradigms, all three regulators are committed to the inhibition of the presentation of antigenic peptides. Whereas m152/gp40 catalyzes the retention of peptide-loaded major histocompatibility complex (MHC) class I molecules in a cis-Golgi compartment, m06/gp48 binds stably to class I molecules and directs them into the cellular cargo-sorting pathway of lysosomal degradation.