Immune Evasion Proteins Enhance Cytomegalovirus Latency in the Lungs

Institute for Virology, University Medical Center of Johannes Gutenberg University, 55131 Mainz, Germany.
Journal of Virology (Impact Factor: 4.44). 08/2009; 83(19):10293-8. DOI: 10.1128/JVI.01143-09
Source: PubMed


CD8 T cells control cytomegalovirus (CMV) infection in bone marrow transplantation recipients and persist in latently infected
lungs as effector memory cells for continuous sensing of reactivated viral gene expression. Here we have addressed the question
of whether viral immunoevasins, glycoproteins that specifically interfere with antigen presentation to CD8 T cells, have an
impact on viral latency in the murine model. The data show that deletion of immunoevasin genes in murine CMV accelerates the
clearance of productive infection during hematopoietic reconstitution and leads to a reduced latent viral genome load, reduced
latency-associated viral transcription, and a lower incidence of recurrence in lung explants.

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    ABSTRACT: For recognition of infected cells by CD8 T cells, antigenic peptides are presented at the cell surface, bound to major histocompatibility complex class I (MHC-I) molecules. Downmodulation of cell surface MHC-I molecules is regarded as a hallmark function of cytomegalovirus-encoded immunoevasins. The molecular mechanisms by which immunoevasins interfere with the MHC-I pathway suggest, however, that this downmodulation may be secondary to an interruption of turnover replenishment and that hindrance of the vesicular transport of recently generated peptide-MHC (pMHC) complexes to the cell surface is the actual function of immunoevasins. Here we have used the model of murine cytomegalovirus (mCMV) infection to provide experimental evidence for this hypothesis. To quantitate pMHC complexes at the cell surface after infection in the presence and absence of immunoevasins, we generated the recombinant viruses mCMV-SIINFEKL and mCMV-Deltam06m152-SIINFEKL, respectively, expressing the K(b)-presented peptide SIINFEKL with early-phase kinetics in place of an immunodominant peptide of the viral carrier protein gp36.5/m164. The data revealed approximately 10,000 K(b) molecules presenting SIINFEKL in the absence of immunoevasins, which is an occupancy of approximately 10% of all cell surface K(b) molecules, whereas immunoevasins reduced this number to almost the detection limit. To selectively evaluate their effect on preexisting pMHC complexes, cells were exogenously loaded with SIINFEKL peptide shortly after infection with mCMV-SIINFEKA, in which endogenous presentation is prevented by an L174A mutation of the C-terminal MHC-I anchor residue. The data suggest that pMHC complexes present at the cell surface in advance of immunoevasin gene expression are downmodulated due to constitutive turnover in the absence of resupply.
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