Besold Katrin, Frankenberg Nadine, Pepperl-Klindworth Sandra, Kuball Jürgen, Theobald Matthias, Hahn Gabriele, Plachter Bodo
Institute of Virology, Johannes Gutenberg-Universität, Mainz, Germany.
Department of Hematology and Oncology, Johannes Gutenberg-Universität, Mainz, Germany.
J Gen Virol. 2007 May;88(Pt 5):1429-1439. doi: 10.1099/vir.0.82686-0.
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 pp65NLV was presented by MHC class I in cells infected with a gpUS2-11-competent virus. Presentation of pp65NLV was still detectable at 96 h post-infection, although at low levels. Partial suppression of pp65NLV 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 IE1TMY. Remarkably, infected cells could restore pp65NLV 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.
人巨细胞病毒（HCMV）感染的免疫控制可由CD8 + 细胞毒性T淋巴细胞（CTL）介导。抗病毒CTL的过继转移可提供针对HCMV再激活和疾病的保护。被膜蛋白pp65和立即早期1蛋白（IE1）被认为是主要的CTL靶标，尽管在生产性感染期间病毒免疫逃逸蛋白gpUS2 - 11可抑制主要组织相容性复合体（MHC）I类限制性抗原呈递。因此，面对免疫逃逸，感染细胞如何用抗原肽进行标记尚不清楚。我们在此表明，免疫显性肽pp65NLV在感染了具有gpUS2 - 11功能的病毒的细胞中由MHC I类呈递。尽管水平较低，但在感染后96小时仍可检测到pp65NLV的呈递。pp65NLV呈递的部分抑制取决于感染菌株表达gpUS2 - 11的能力。HCMV感染细胞（编码gpUS2 - 11）中的MHC I类限制性抗原呈递对pp65衍生的肽具有特异性，因为感染的成纤维细胞不呈递IE1衍生的九肽IE1TMY。值得注意的是，尽管表达了gpUS2 - 11，但在酸性去除MHC I类后，感染细胞可以恢复pp65NLV肽的呈递。这种恢复被证明依赖于蛋白酶体功能。与IE1相反，在面对gpUS2 - 11介导的免疫逃逸时，pp65肽在感染后的早期和晚期加载到MHC I类分子上并转运到细胞表面。因此，pp65是仅不完全受gpUS2 - 11介导的免疫逃逸影响的HCMV蛋白的第一个例子。
