0000000000123965
AUTHOR
Katrin Besold
showing 9 related works from this author
Human cytomegalovirus US3 modulates destruction of MHC class I molecules
2012
Human cytomegalovirus (HCMV), a member of the Herpesviridae family, is proficient at establishing lifelong persistence within the host in part due to immune modulating genes that limit immune recognition. HCMV encodes at least five glycoproteins within its unique short (US) genomic region that interfere with MHC class I antigen presentation, thus hindering viral clearance by cytotoxic T lymphocytes (CTL). Specifically, US3 retains class I within the endoplasmic reticulum (ER), while US2 and US11 induce class I heavy chain destruction. A cooperative effect on class I down-regulation during stable expression of HCMV US2 and US3 has been established. To address the impact of US3 on US11-mediat…
Strong and sustained effector function of memory- versus naïve-derived T cells upon T-cell receptor RNA transfer: Implications for cellular therapy
2012
Current protocols used to select CMV-specific T cells for adoptive immunotherapy focus on virus-specific memory T cells from seropositive donors. However, this strategy is not feasible in patients undergoing allogeneic haematopoietic stem-cell transplantation (HSCT) from CMV-seronegative donors. Here, we redirected T cells of CMV-seronegative donors with a human genetically engineered TCR recognizing an HLA-A*0201-binding peptide epitope of CMVpp65. To facilitate clinical translation of this approach, we used a non-viral expression system based on in vitro transcribed RNA and electroporation. Although memory and naive-derived T-cell subsets were both efficiently transfected by TCR-RNA, memo…
CD8 T cell-evasive functions of human cytomegalovirus display pervasive MHC allele specificity, complementarity, and cooperativity.
2014
Abstract Immunoevasive proteins (“evasins”) of human CMV (HCMV) modulate stability and localization of MHC class I (MHC I) molecules, and their supply of antigenic peptides. However, it is largely unknown to what extent these evasins interfere with recognition by virus-specific CD8 T cells. We analyzed the recognition of HCMV-infected cells by a panel of CD8 T cells restricted through one of nine different MHC I allotypes. We employed a set of HCMV mutants deleted for three or all four of the MHC I modulatory genes US2, US3, US6, and US11. We found that different HCMV evasins exhibited different allotype-specific patterns of interference with CD8 T cell recognition of infected cells. In con…
Exogenous introduction of an immunodominant peptide from the non-structural IE1 protein of human cytomegalovirus into the MHC class I presentation pa…
2008
Exogenous introduction of particle-associated proteins of human cytomegalovirus (HCMV) into the major histocompatibility complex (MHC) class I presentation pathway by subviral dense bodies (DB) is an effective way to sensitize cells against CD8 T-cell (CTL) recognition and killing. Consequently, these particles have been proposed as a platform for vaccine development. We have developed a strategy to refine the antigenic composition of DB. For proof of principle, an HCMV recombinant (RV-VM3) was generated that encoded the immunodominant CTL determinant IE1TMY from the IE1 protein in fusion with the major constituent of DB, the tegument protein pp65. To generate RV-VM3, a bacterial artificial…
Suppression of CD8+ T cell recognition in the immediate-early phase of human cytomegalovirus infection.
2012
Human cytomegalovirus (HCMV) interferes with MHC class I-restricted antigen presentation and thereby reduces recognition by CD8+ T-cells. This interference is mediated primarily by endoplasmic reticulum-resident glycoproteins that are encoded in the US2–11 region of the viral genome. Such a suppression of recognition would be of particular importance immediately after infection, because several immunodominant viral antigens are already present in the cell in this phase. However, which of the evasion proteins gpUS2–11 interfere(s) with antigen presentation to CD8+ T-cells at this time of infection is not known. Here we address this question, using recombinant viruses (RV) that express only o…
Processing and MHC class I presentation of human cytomegalovirus pp65-derived peptides persist despite gpUS2–11-mediated immune evasion
2007
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 pp65NLVwas presented by MHC class I in cells infected…
Polyethylenimine is a strong inhibitor of human papillomavirus and cytomegalovirus infection.
2012
ABSTRACT Polyethylenimines are cationic polymers with potential as delivery vectors in gene therapy and with proven antimicrobial activity. However, the antiviral activity of polyethylenimines has not been addressed in detail thus far. We have studied the inhibitory effects of a linear 25-kDa polyethylenimine on infections with human papillomaviruses and human cytomegaloviruses. Preincubation of cells with polyethylenimine blocked primary attachment of both viruses to cells, resulting in a significant reduction of infection. In addition, the dissemination of human cytomegalovirus in culture cells was efficiently reduced by recurrent administration of polyethylenimine. Polyethylenimine conce…
Human cytomegalovirus pp71 stimulates major histocompatibility complex class i presentation of IE1-derived peptides at immediate early times of infec…
2013
ABSTRACT Suppression of major histocompatibility complex (MHC) class I-mediated presentation of human cytomegalovirus (HCMV) peptides is an important mechanism to avoid CD8 T lymphocyte recognition and killing of infected cells. Of particular interest is how MHC class I presentation of essential regulatory immediate early (IE) proteins of HCMV can be effectively compromised at times when known viral immunoevasins are not abundantly expressed. The tegument protein pp71 had been suggested to be involved in MHC class I downregulation. Intriguingly, this polypeptide is also critically engaged in the initial derepression of the major IE gene locus, leading to enhanced expression of IE proteins I…
Cytomegalovirus Interleukin-10 Expression in Infected Cells Does Not Impair MHC Class I Restricted Peptide Presentation on Bystanding Antigen-Present…
2006
Human cytomegalovirus (HCMV) has evolved strategies to counteract its surveillance by the immune system. Mitigation of antiviral immune responses is considered critical for establishment of viral latency and for spread. Recently, a gene encoding an interleukin-10 homologue (cmvIL-10) has been discovered in the HCMV genome. Using recombinant cmvIL-10, several mostly immunosuppressive functions of the molecule have been described. However, the role of cmvIL-10 in the context of viral infection was not addressed. To be able to analyze this issue, we generated cmvIL- 10-negative viral mutants. Using these mutants, we tested whether the expression of cmvIL-10 by infected cells would render bysta…