Lack of MHC class I complex expression has no effect on spread and control of cytomegalovirus infection in vivo (original) (raw)
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Inhibition of the MHC Class II Antigen Presentation Pathway by Human Cytomegalovirus
Human cytomegalovirus (HCMV) causes serious diseasc in immunocompromised individuals. Normally. anti-HCMV immune response controls virus replication following reactivation from latency. However. HCMV, like other large herpesviruses. encodes immune cvasion proteins that allow the virus to replicate. for a time or in specific tissues, and produce viral progeny in the face of robust host immunity. HCMV glycoproteins US2. US3. US6 and US 11 all inhibit different stages of the MHC class I antigen presentation pathway and can reduce recognition by CDS + T lymphocytes. Here. we discuss two novel in-hibitors of the MHC class II antigen presentation pathway. HCMV glycoproteins US2 and US3. Both US2 and US3 can inhibit presentation of exogenous protein antigens to CD4-T lymphocytes in in vitro assays. US2 causes degradation ofMHC class" molecules: HLA-DR-Si and HLA-DM-Si. as well as class I heavy chain (HC). but does not affect DR-~ or DM-~ chains. Mutant forms of US2 have been constructed that can bind to DR-Si and class I HC but do not cause their degradation. separating the binding step from other processes that precede degradation. We also found evidence that US2-induced degradation of class I and" proteins involves a cellular component. other than Secnl. that is limiting in quantity. Unlike US2, US3 binds newly synthesized class " Si/~ complexes. reducing the association with the invariant chain (Ii) and causing mislocalization of class" complexes in cells. US3 expression reduces accumulation of class" complexes in peptide-loading compartments and loading of peptides. Since US2 and US3 are expressed solely within HCMV-infected cells. it appears that these viral proteins have evolved to inhibit presentation of endogenous. intracellular viral antigens to anti-HCMV CD4' T cells. This is different from how the MHC class" pathway is normally viewed. as a pathway for presentation of exogenous. extracellular proteins. The existence of these proteins indicates the importance of class II-mediated presentation of endogenous antigens in signalling virus infection to CD4 + T cel".
Medical Microbiology and Immunology, 2012
Medical interest in cytomegalovirus (CMV) is based on lifelong neurological sequelae, such as sensorineural hearing loss and mental retardation, resulting from congenital infection of the fetus in utero, as well as on CMV disease with multiple organ manifestations and graft loss in recipients of hematopoietic cell transplantation or solid organ transplantation. CMV infection of transplantation recipients occurs consequent to reactivation of virus harbored in a latent state in the transplanted donor cells and tissues, or in the tissues of the transplantation recipient herself or himself. Hence, CMV infection is a paradigm for a viral infection that causes disease primarily in the immunocompromised host, while infection of the immunocompetent host is associated with only mild and nonspecific symptoms so that it usually goes unnoticed. Thus, CMV is kept under strict immune surveillance. These medical facts are in apparent conflict with the notion that CMVs in general, human CMV as well as animal CMVs, are masters of 'immune evasion', which during virus-host co-speciation have convergently evolved sophisticated mechanisms to avoid their recognition by innate and adaptive immunity of their respective host species, with viral genes apparently dedicated to serve just this purpose (Reddehase in Nat Rev Immunol 2:831-844, 2002). With focus on viral interference with antigen presentation to CD8 T cells in the preclinical model of murine CMV infection, we try here to shed some more light on the in vivo balance between host immune surveillance of CMV infection and viral 'immune evasion' strategies.
Human cytomegalovirus US3 modulates destruction of MHC class I molecules
Molecular Immunology, 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-mediated MHC class I downregulation, the fate of class I molecules was examined in US3/US11-expressing cells and virus infection studies. Co-expression of US3 and US11 resulted in a decrease of surface expression of class I molecules. However, the class I molecules in US3/US11 cells were mostly retained in the ER with an attenuated rate of proteasome destruction. Analysis of class I levels from virusinfected cells using HCMV variants either expressing US3 or US11 revealed efficient surface class I down-regulation upon expression of both viral proteins. Cells infected with both US3 and US11 expressing viruses demonstrate enhanced retention of MHC class I complexes within the ER. Collectively, the data suggests a paradigm where HCMV-induced surface class I downregulation occurs by diverse mechanisms dependent on the expression of specific US genes. These results validate the commitment of HCMV to limiting the surface expression of class I levels during infection.
Immunologic Research, 2009
The mouse cytomegalovirus (CMV), a β-herpesvirus, exploits its large (~230 kb) double-stranded DNA genome for both essential and non-essential functions. Among the non-essential functions are those that offer the virus selective advantage in eluding both the innate and adaptive immune responses of the host. Several non-essential genes of MCMV are thought to encode MHC-I-like genes and to function as immunoevasins. To understand further the evolution and function of these viral MHC-I (MHC-Iv) molecules, X-ray structures of several of them have been determined, confirming the overall MHC-I-like structure, but also elucidating features unique to this family. Future efforts promise to clarify the nature of the molecular ligands of these molecules, their evolution in the context of the adapting immune response of the murine host, and by analogy the evolution of the host response to human CMV as well.
Here, we show that the HCMV protein US2 causes degradation of two essential proteins in the MHC class II antigen presentation pathway: HLA-DR-α and DM-α. This was unexpected, as US2 has been shown to cause degradation of MHC class I (refs. 5,6), which has only limited homology with class II proteins. Expression of US2 in cells reduced or abolished their ability to present antigen to CD4 + T lymphocytes. Thus, US2 may allow HCMV-infected macrophages to remain relatively 'invisible' to CD4 + T cells, a property that would be important after virus reactivation.
Different Aspects Concerning Viral Infection and the Role of MHC Molecules in Viral Prevention
The Open Microbiology Journal, 2021
Major Histocompatibility Complex (MHC) molecules play a crucial role in inducing an adaptive immune response. T-cell epitopes require compatible MHC molecules to form MHC-peptide Complexes (pMHC) that activate the T-cell Receptors (TCR) of T-lymphocyte clones. MHCs are polymorphic molecules with wide varieties of gene alleles. There are two classes of MHC molecules, class I and II. Both classes have three classical loci HLA-A, -B, and –C are present in class I and HLA-DP, -DQ, and -DR in class II. To induce a compatible T-lymphocyte clone, the Tcell epitope requires the association of the compatible MHC molecule to form pMHC. Each MHC variant possesses a different groove that is capable of binding a different range of antigenic epitopes. Without the compatible MHC molecule, a T cell clone cannot be activated by a particular viral epitope. With the aim of preventing viral transmission, the efficiency of a viral vaccine is related to the existence of specific MHC alleles in the indivi...
The Journal of general virology, 2001
Liver and intestinal epithelial cells are a major target of infection by cytomegaloviruses (CMV), causing severe disease in affected organs of immunocompromised patients. CMV downregulates major histocompatibility complex class I (MHC-I) molecule expression in fibroblasts in order to avoid lysis by CD8(+) cytotoxic T lymphocytes. However, MHC-I expression in human cytomegalovirus (HCMV)-infected hepatic tissue was reported to be increased. As it is unclear at present whether HCMV affects MHC-I expression in epithelial cells, new cell culture models for HCMV infection of differentiated hepatobiliary cell lines were established. HCMV immediate early gene expression was achieved in 60 to 95% of cells. Progression of the HCMV replication cycle differed from prototypic infection of fibroblasts, since structural early and late proteins were produced at low levels and HCMV progeny yielded much lower titres in hepatobiliary cells. In contrast, HCMV glycoproteins, gpUS2, gpUS3, gpUS6 and gpU...
The Journal of Immunology, 2005
Clinical and low passage strains of human CMV (HCMV) encode an additional MHC class I-related molecule UL142, in addition to the previously described UL18. The UL142 open reading frame is encoded within the ULb region which is missing from a number of common high passage laboratory strains. Cells expressing UL142 following transfection, and fibroblasts infected with a recombinant adenovirus-expressing UL142, were used to screen both polyclonal NK cells and NK cell clones, in a completely autologous system. Analysis of 100 NK cell clones derived from five donors, revealed 23 clones that were inhibited by fibroblasts expressing UL142 alone. Small-interfering RNA-mediated knockdown of UL142 mRNA expression in HCMV-infected cells resulted in increased sensitivity to lysis. From these data we conclude that UL142 is a novel HCMV-encoded MHC class I-related molecule which inhibits NK cell killing in a clonally dependent manner. The Journal of Immunology, 2005, 175: 7457-7465.