Virus-gastheer interacties: survival of the smartest

De virologie mag zich in een grote belangstelling verheugen. Influenzavirussen waren rond. De recente introductie van vaccinatie tegen humaan papillomavirus, HPV, de veroorzaker van baarmoederhalskanker, heeft veel discussie opgeleverd. HIV blijft een probleem en de dreigingen van SARS-Coronavirus en bioterroristische aanslagen met pokkenvirus, maar ook de varkenspest en mond- en klauwzeerepidemieën liggen nog vers in het geheugen

Proteasomal Degradation of Proinsulin Requires Derlin-2, HRD1 and p97

Nephrolog

Herpesviruses and immunity: The art of evasion

Herpesviruses have evolved several effective strategies to counter the host immune response. Chief among these is inhibition of the host MHC class I antigen processing and presentation pathway, thereby reducing the presentation of virus-derived epitopes on the surface of the infected cell. This review summarizes the mechanisms used by herpesviruses to achieve this goal, including shut-down of MHC class I molecule synthesis, blockage of proteasome-mediated peptide generation and prevention of TAP-mediated peptide transport. Furthermore, herpesvirus proteins can retain MHC class I molecules in the endoplasmic reticulum, or direct their retrograde translocation from the endoplasmic reticulum or endocytosis from the plasma membrane, with subsequent degradation. The resulting down-regulation of cell surface MHC class! peptide complexes thwarts the ability of cytotoxic T lymphocytes to recognize and eliminate virus-infected cells. The subversion of the natural killer cell response by herpesvirus proteins and microRNAs is also discussed. (C) 2010 Elsevier B.V. All rights reserved.Molecular basis of virus replication, viral pathogenesis and antiviral strategie

Exploiting human herpesvirus immune evasion for therapeutic gain: potential and pitfalls

Herpesviruses stand out for their capacity to establish lifelong infections of immunocompetent hosts, generally without causing overt symptoms. Herpesviruses are equipped with sophisticated immune evasion strategies, allowing these viruses to persist for life despite the presence of a strong antiviral immune response. Although viral evasion tactics appear to target virtually any stage of the innate and adaptive host immune response, detailed knowledge is now available on the molecular mechanisms underlying herpesvirus obstruction of MHC class I-restricted antigen presentation to T cells. This opens the way for clinical application. Here, we review and discuss recent efforts to exploit human herpesvirus MHC class I evasion strategies for the rational design of novel strategies for vaccine development, cancer treatment, transplant protection and gene therapy.Immunology and Cell Biology advance online publication, 8 February 2011; doi:10.1038/icb.2010.129.Molecular basis of virus replication, viral pathogenesis and antiviral strategie

Immune Evasion by Epstein-Barr Virus

Therapeutic cell differentiatio

CD8(+) T Cell Responses against TAP-Inhibited Cells Are Readily Detected in the Human Population

Target cell recognition by CTLs depends on the presentation of peptides by HLA class I molecules. Tumors and herpes viruses have adopted strategies to greatly hamper this peptide presentation at the important bottleneck, the peptide transporter TAP. Previously, we described the existence of a CD8(+) CTL subpopulation that selectively recognizes such TAP-deficient cells in mouse models. In this study, we show that the human counterpart of this CTL subset is readily detectable in healthy subjects. Autologous PBMC cultures were initiated with dendritic cells rendered TAP-impaired by gene transfer of the viral evasion molecule UL49.5. Strikingly, specific reactivity to B-LCLs expressing one of the other viral TAP-inhibitors (US6, ICP47, or BNLF2a) was already observed after three rounds of stimulation. These short-term T cell cultures and isolated CD8(+) CTL clones derived thereof did not recognize the normal B-LCL, indicating that the cognate peptide-epitopes emerge at the cell surface upon an inhibition in the MHC class I processing pathway. A diverse set of TCRs was used by the clones, and the cellular reactivity was TCR-dependent and HLA class I-restricted, implying the involvement of a broad antigenic peptide repertoire. Our data indicate that the human CD8(+) T cell pool comprises a diverse reactivity to target cells with impairments in the intracellular processing pathway, and these might be exploited for cancers that are associated with such defects and for infections with immune-evading herpes viruses. The Journal of Immunology, 2010, 185: 6508-6517.Experimental cancer immunology and therap

The "Bridge" in the Epstein-Barr Virus Alkaline Exonuclease Protein BGLF5 Contributes to Shutoff Activity during Productive Infection

Molecular basis of virus replication, viral pathogenesis and antiviral strategie

Endogenous HLA class II epitopes that are immunogenic in vivo show distinct behavior toward HLA-DM and its natural inhibitor HLA-DO

Immunobiology of allogeneic stem cell transplantation and immunotherapy of hematological disease

Epstein-Barr virus isolates retain their capacity to evade T cell immunity through BNLF2a despite extensive sequence variation

The Epstein-Barr virus (EBV)-encoded immune evasion protein BNLF2a inhibits the transporter associated with antigen processing (TAP), thereby downregulating HLA class I expression at the cell surface. As a consequence, recognition of EBV-infected cells by cytotoxic T cells is impaired. Here, we show that sequence polymorphism of the BNLF2a protein is observed with natural EBV isolates, with evidence for positive selection. Despite these mutations, the BNLF2a variants efficiently reduce cell surface HLA class I levels. This conservation of BNLF2a function during evolution of EBV implies an important role for the viral TAP inhibitor in preventing T cell recognition during viral infection

Multiple E2 ubiquitin-conjugating enzymes regulate human cytomegalovirus US2-mediated immunoreceptor downregulation

Transplantation and autoimmunit