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Processing and MHC class I presentation of human cytomegalovirus pp65-derived peptides persist despite gpUS2–11-mediated immune evasion

Nadine Frankenberg^1,

Jürgen Kuball^2,

Gabriele Hahn^3,

¹ Institute of Virology, Johannes Gutenberg-Universität, Mainz, Germany
² Department of Hematology and Oncology, Johannes Gutenberg-Universität, Mainz, Germany
³ Max von Pettenkofer Institut, Department of Virology, Ludwig-Maximilians-Universität München, Germany

Correspondence
Bodo Plachter
plachter{at}uni-mainz.de

Immune control of human cytomegalovirus (HCMV) infection can be mediated by CD8⁺ cytolytic T lymphocytes (CTL). Adoptive transfer of antiviral CTL confers protection against HCMV reactivation and disease. The tegument protein pp65 and the immediate-early 1 protein (IE1) are recognized to be major CTL targets, even though during productive infection the viral immunoevasion proteins gpUS2–11 act to suppress major histocompatibility complex (MHC) class I-restricted antigen presentation. Thus it was not clear how infected cells could be labelled with antigenic peptides in the face of immunoevasion. We show here that the immunodominant peptide pp65_NLV was presented by MHC class I in cells infected with a gpUS2–11-competent virus. Presentation of pp65_NLV was still detectable at 96 h post-infection, although at low levels. Partial suppression of pp65_NLV presentation was dependent on the ability of the infecting strain to express gpUS2–11. MHC class I-restricted antigen presentation in HCMV-infected cells (encoding gpUS2–11) exhibited specificity for pp65-derived peptides, as infected fibroblasts did not present the IE1-derived nonapeptide IE1_TMY. Remarkably, infected cells could restore pp65_NLV peptide presentation after acid removal of MHC class I despite gpUS2–11 expression. This recovery was shown to be dependent on proteasome functionality. In contrast to IE1, pp65 peptides are loaded on MHC class I molecules to be transported to the cell surface at early and late times after infection in the face of gpUS2–11-mediated immunoevasion. pp65 is therefore the first example of an HCMV protein only incompletely subjected to gpUS2–11-mediated immunoevasion.

Present address: Novartis Pharma AG, Werk Klybeck, Klybeckerstrasse 141, CH-4057 Basel, Switzerland.

Present address: Fred Hutchinson Cancer Research, 1100 Fairview Avenue N., Seattle, WA 98109-1024, USA.

Present address: Bioscientia Hamburg, Papenreye 63, D-22453 Hamburg, Germany.

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