scholarly journals Murine Cytomegalovirus Perturbs Endosomal Trafficking of Major Histocompatibility Complex Class I Molecules in the Early Phase of Infection

2010 ◽  
Vol 84 (21) ◽  
pp. 11101-11112 ◽  
Author(s):  
Maja Ilić Tomaš ◽  
Natalia Kučić ◽  
Hana Mahmutefendić ◽  
Gordana Blagojević ◽  
Pero Lučin
Keyword(s):  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Early Phase ◽  
Secretory Pathway ◽  
Murine Cytomegalovirus ◽  
Endosomal Trafficking ◽  
Complex Class ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Infected Cells

ABSTRACT Murine cytomegalovirus (MCMV) functions interfere with protein trafficking in the secretory pathway. In this report we used Δm138-MCMV, a recombinant virus with a deleted viral Fc receptor, to demonstrate that MCMV also perturbs endosomal trafficking in the early phase of infection. This perturbation had a striking impact on cell surface-resident major histocompatibility complex class I (MHC-I) molecules due to the complementary effect of MCMV immunoevasins, which block their egress from the secretory pathway. In infected cells, constitutively endocytosed cell surface-resident MHC-I molecules were arrested and retained in early endosomal antigen 1 (EEA1)-positive and lysobisphosphatidic acid (LBPA)-negative perinuclear endosomes together with clathrin-dependent cargo (transferrin receptor, Lamp1, and epidermal growth factor receptor). Their progression from these endosomes into recycling and degradative routes was inhibited. This arrest was associated with a reduction of the intracellular content of Rab7 and Rab11, small GTPases that are essential for the maturation of recycling and endolysosomal domains of early endosomes. The reduced recycling of MHC-I in Δm138-MCMV-infected cells was accompanied by their accelerated loss from the cell surface. The MCMV function that affects cell surface-resident MHC-I was activated in later stages of the early phase of viral replication, after the expression of known immunoevasins. MCMV without the three immunoevasins (the m04, m06, and m152 proteins) encoded a function that affects endosomal trafficking. This function, however, was not sufficient to reduce the cell surface expression of MHC-I in the absence of the transport block in the secretory pathway.

scholarly journals Varicella-Zoster Virus Retains Major Histocompatibility Complex Class I Proteins in the Golgi Compartment of Infected Cells

2001 ◽  
Vol 75 (10) ◽  
pp. 4878-4888 ◽  
Author(s):  
Allison Abendroth ◽  
Ines Lin ◽  
Barry Slobedman ◽  
Hidde Ploegh ◽  
Ann M. Arvin
Keyword(s):  
Major Histocompatibility Complex ◽  
T Lymphocytes ◽  
Cell Surface ◽  
Major Histocompatibility Complex Class ◽  
Complex Class ◽  
Mhc I ◽  
Varicella Zoster ◽  
Histocompatibility Complex ◽  
Golgi Compartment ◽  
Infected Cells

ABSTRACT We sought to examine the effects of varicella-zoster virus (VZV) infection on the expression of major histocompatibility complex class I (MHC I) molecules by human fibroblasts and T lymphocytes. By flow cytometry, VZV infection reduced the cell surface expression of MHC I molecules on fibroblasts significantly, yet the expression of transferrin receptor was not affected. Importantly, when human fetal thymus/liver implants in SCID-hu mice were inoculated with VZV, cell surface MHC I expression was downregulated specifically on VZV-infected human CD3+ T lymphocytes, a prominent target that sustains VZV viremia. The stage in the MHC I assembly process that was disrupted by VZV in fibroblasts was examined in pulse-chase and immunoprecipitation experiments in the presence of endoglycosidase H. MHC I complexes continued to be assembled in VZV-infected cells and were not retained in the endoplasmic reticulum. In contrast, immunofluorescence and confocal microscopy showed that VZV infection resulted in an accumulation of MHC I molecules which colocalized to the Golgi compartment. Inhibition of late viral gene expression by treatment of infected fibroblasts with phosphonoacetic acid did not influence the modulation of MHC I expression, nor did transfection of cells with plasmids expressing immediate early viral proteins. However, cells transfected with a plasmid carrying the early geneORF66 did result in a significant downregulation of MHC I expression, suggesting that this gene encodes a protein with an immunomodulatory function. Thus, VZV downregulates MHC I expression by impairing the transport of MHC I molecules from the Golgi compartment to the cell surface; this effect may enable the virus to evade CD8+ T-cell immune recognition during VZV pathogenesis, including the critical phase of T-lymphocyte-associated viremia.

scholarly journals Pol-Specific CD8+ T Cells Recognize Simian Immunodeficiency Virus-Infected Cells Prior to Nef-Mediated Major Histocompatibility Complex Class I Downregulation

2007 ◽  
Vol 81 (21) ◽  
pp. 11703-11712 ◽  
Author(s):  
Jonah B. Sacha ◽  
Chungwon Chung ◽  
Jason Reed ◽  
Anna K. Jonas ◽  
Alexander T. Bean ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
T Cell ◽  
Major Histocompatibility Complex Class ◽  
T Cell Epitopes ◽  
Complex Class ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Infected Cells

ABSTRACT Effective, vaccine-induced CD8+ T-cell responses should recognize infected cells early enough to prevent production of progeny virions. We have recently shown that Gag-specific CD8+ T cells recognize simian immunodeficiency virus-infected cells at 2 h postinfection, whereas Env-specific CD8+ T cells do not recognize infected cells until much later in infection. However, it remains unknown when other proteins present in the viral particle are presented to CD8+ T cells after infection. To address this issue, we explored CD8+ T-cell recognition of epitopes derived from two other relatively large virion proteins, Pol and Nef. Surprisingly, infected cells efficiently presented CD8+ T-cell epitopes from virion-derived Pol proteins within 2 h of infection. In contrast, Nef-specific CD8+ T cells did not recognize infected cells until 12 h postinfection. Additionally, we show that SIVmac239 Nef downregulated surface major histocompatibility complex class I (MHC-I) molecules beginning at 12 h postinfection, concomitant with presentation of Nef-derived CD8+ T-cell epitopes. Finally, Pol-specific CD8+ T cells eliminated infected cells as early as 6 h postinfection, well before MHC-I downregulation, suggesting a previously underappreciated antiviral role for Pol-specific CD8+ T cells.

scholarly journals High Viremia Is Associated with High Levels of In Vivo Major Histocompatibility Complex Class I Downregulation in Rhesus Macaques Infected with Simian Immunodeficiency Virus SIVmac239

2010 ◽  
Vol 84 (10) ◽  
pp. 5443-5447 ◽  
Author(s):  
Thomas C. Friedrich ◽  
Shari M. Piaskowski ◽  
Enrique J. León ◽  
Jessica R. Furlott ◽  
Nicholas J. Maness ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Ex Vivo ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Infected Cells

ABSTRACT Human and simian immunodeficiency viruses (HIV and SIV) downregulate major histocompatibility complex class I (MHC-I) molecules from the surface of infected cells. Although this activity is conserved across viral isolates, its importance in AIDS pathogenesis is not clear. We therefore developed an assay to detect the level of MHC-I expression of SIV-infected cells directly ex vivo. Here we show that the extent of MHC-I downregulation is greatest in SIVmac239-infected macaques that never effectively control virus replication. Our results suggest that a high level of MHC-I downregulation is a hallmark of fast disease progression in SIV infection.

scholarly journals GRP78, a Coreceptor for Coxsackievirus A9, Interacts with Major Histocompatibility Complex Class I Molecules Which Mediate Virus Internalization

2002 ◽  
Vol 76 (2) ◽  
pp. 633-643 ◽  
Author(s):  
Kathy Triantafilou ◽  
Didier Fradelizi ◽  
Keith Wilson ◽  
Martha Triantafilou
Keyword(s):  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Major Histocompatibility Complex Class ◽  
Class I ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Class I Mhc ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Coxsackievirus A9

ABSTRACT It is becoming apparent that over the years cell infection by virus seems to have evolved into a multistep process in which many viruses employ distinct cell surface molecules for their attachment and cell entry. In this study the attachment and entry pathway of coxsackievirus A9 (CAV-9), a member of the Picornaviridae family, was investigated. It has been known that, although integrin αvβ3 is utilized as a receptor, its presence alone is insufficient for CAV-9 infection and that CAV-9 also requires a 70-kDa major histocompatibility complex class I (MHC-I)-associated protein (MAP-70) as a coreceptor molecule. We document by protein isolation and peptide sequencing that the 70-kDa protein is GRP78, a member of the heat shock protein 70 family of stress proteins. Furthermore we show by using fluorescence resonance energy transfer (FRET) that GRP78 is also expressed on the cell surface and associates with MHC-I molecules. In addition CAV-9 infection of permissive cells requires GRP78 and also MHC-I molecules, which are essential for virus internalization. The identification of GRP78 as a coreceptor for CAV-9 and the revelation of GRP78 and MHC-I associations have provided new insights into the life cycle of CAV-9, which utilizes integrin αvβ3 and GRP78 as receptor molecules whereas MHC-I molecules serve as the internalization pathway of this virus to mammalian cells.

scholarly journals Mtv-1 Superantigen Trafficks Independently of Major Histocompatibility Complex Class II Directly to the B-Cell Surface by the Exocytic Pathway

1998 ◽  
Vol 72 (4) ◽  
pp. 2577-2588 ◽  
Author(s):  
Michael E. Grigg ◽  
Christopher W. McMahon ◽  
Stanislaw Morkowski ◽  
Alexander Y. Rudensky ◽  
Ann M. Pullen
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Major Histocompatibility Complex Class ◽  
Secretory Pathway ◽  
Sodium Dodecyl ◽  
Class Ii ◽  
Complex Class ◽  
Major Histocompatibility ◽  
Histocompatibility Complex

ABSTRACT Presentation of the Mtv-1 superantigen (vSag1) to specific Vβ-bearing T cells requires association with major histocompatibility complex class II molecules. The intracellular route by which vSag1 trafficks to the cell surface and the site of vSag1-class II complex assembly in antigen-presenting B lymphocytes have not been determined. Here, we show that vSag1 trafficks independently of class II to the plasma membrane by the exocytic secretory pathway. At the surface of B cells, vSag1 associates primarily with mature peptide-bound class II αβ dimers, which are stable in sodium dodecyl sulfate. vSag1 is unstable on the cell surface in the absence of class II, and reagents that alter the surface expression of vSag1 and the conformation of class II molecules affect vSag1 stimulation of superantigen reactive T cells.

scholarly journals CD4 and Major Histocompatibility Complex Class I Downregulation by the Human Immunodeficiency Virus Type 1 Nef Protein in Pediatric AIDS Progression

2003 ◽  
Vol 77 (21) ◽  
pp. 11536-11545 ◽  
Author(s):  
Nicoletta Casartelli ◽  
Gigliola Di Matteo ◽  
Marina Potestà ◽  
Paolo Rossi ◽  
Margherita Doria
Keyword(s):  
Human Immunodeficiency Virus ◽  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Major Histocompatibility Complex Class ◽  
Complex Class ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) nef gene is a crucial determinant in AIDS disease progression. Although several in vitro activities have been attributed to the Nef protein, identifying the one critical for in vivo pathogenicity remains elusive. In this study, we examined a large number of nef alleles derived at various time points from 13 perinatally infected children showing different progression rates: six nonprogressors (NPs), three slow progressors (SPs), and four rapid progressors (RPs). The patient-derived nef alleles were analyzed for their steady-state expression of a Nef protein, for their relative ability to downregulate cell surface expression of CD4 and major histocompatibility complex class I (MHC-I) and for their capacity to bind the clathrin adaptor AP-1 complex. We found that NP-derived nef alleles, compared to nef alleles isolated from SPs and RPs, had reduced CD4 and MHC-I downregulation activities. In contrast, SP- and RP-derived nef alleles did not differ and efficiently downregulated both CD4 and MHC-I. AP-1 binding was a conserved function of primary nef alleles not correlated with clinical progression. Defective Nef proteins from NPs, rather than sharing common specific changes in their sequences, accumulated various amino acid substitutions, mainly located outside the conserved domains previously associated with Nef biological properties. Our data indicate that Nef-mediated downregulation of cell surface CD4 and MHC-I significantly contributes to the expression of the pathogenic potential of HIV-1.

scholarly journals Two Functional Variants of AP-1 Complexes Composed of either γ2 or γ1 Subunits Are Independently Required for Major Histocompatibility Complex Class I Downregulation by HIV-1 Nef

2020 ◽  
Vol 94 (7) ◽  
Author(s):  
Lucas A. Tavares ◽  
Julianne V. de Carvalho ◽  
Cristina S. Costa ◽  
Roberta M. Silveira ◽  
Andreia N. de Carvalho ◽  
...  
Keyword(s):  
T Cells ◽  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Major Histocompatibility Complex Class ◽  
Adaptor Protein ◽  
Class I ◽  
Complex Class ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Hiv 1

ABSTRACT The HIV-1 accessory protein Nef downregulates the cell surface expression of major histocompatibility complex class I (MHC-I) molecules to facilitate virus spreading. The Nef-induced downregulation of MHC-I molecules such as HLA-A requires the clathrin adaptor protein 1 (AP-1) complex. The cooperative interaction of Nef, AP-1, and the cytosolic tail (CT) of HLA-A leads to a redirection of HLA-A targeting from the trans-Golgi network (TGN) to lysosomes for degradation. Although the γ-adaptin subunit of AP-1 has two distinct isoforms (γ1 and γ2), which may form two AP-1 complex variants, so far, only the importance of AP-1γ1 in MHC-I downregulation by Nef has been investigated. Here, we report that the AP-1γ2 isoform also participates in this process. We found that AP-1γ2 forms a complex with Nef and HLA-A2_CT and that this interaction depends on the Y320 residue in HLA-A2_CT and Nef expression. Moreover, Nef targets AP-1γ1 and AP-1γ2 to different compartments in T cells, and the depletion of either AP-1 variant impairs the Nef-mediated reduction of total endogenous HLA-A levels and rescues HLA-A levels on the cell surface. Finally, immunofluorescence and immunoelectron microscopy analyses reveal that the depletion of γ2 in T cells compromises both the Nef-mediated retention of HLA-A molecules in the TGN and targeting to multivesicular bodies/late endosomes. Altogether, these results show that in addition to AP-1γ1, Nef also requires the AP-1γ2 variant for efficient MHC-I downregulation. IMPORTANCE HIV-1 Nef mediates evasion of the host immune system by inhibiting MHC-I surface presentation of viral antigens. To achieve this goal, Nef modifies the intracellular trafficking of MHC-I molecules in several ways. Despite being the subject of intense study, the molecular details underlying these modifications are not yet fully understood. Adaptor protein 1 (AP-1) plays an essential role in the Nef-mediated downregulation of MHC-I molecules such as HLA-A in different cell types. However, AP-1 has two functionally distinct variants composed of either γ1 or γ2 subunit isoforms. Because previous studies on the role of AP-1 in MHC-I downregulation by Nef focused on AP-1γ1, an important open question is the participation of AP-1γ2 in this process. Here, we show that AP-1γ2 is also essential for Nef-mediated depletion of surface HLA-A molecules in T cells. Our results indicate that Nef hijacks AP-1γ2 to modify HLA-A intracellular transport, redirecting these proteins to lysosomes for degradation.

scholarly journals Major histocompatibility complex class I-restricted protection against murine cytomegalovirus requires missing-self recognition by the natural killer cell inhibitory Ly49 receptors

2019 ◽  
Author(s):  
Bijal A. Parikh ◽  
Michael D. Bern ◽  
Sytse J. Piersma ◽  
Liping Yang ◽  
Diana L. Beckman ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Major Histocompatibility Complex Class ◽  
Nk Cells ◽  
Natural Killer ◽  
Murine Cytomegalovirus ◽  
Complex Class ◽  
Mhc I ◽  
Histocompatibility Complex ◽  
Missing Self

AbstractViruses have evolved strategies that highlight critical, intertwined host immune mechanisms. As postulated by the missing-self hypothesis, natural killer (NK) cells and major histocompatibility complex class I (MHC-I)-restricted cytotoxic T lymphocytes (CTLs) have opposing requirements for ubiquitously expressed MHC-I molecules. Since NK cell MHC-I-specific Ly49 inhibitory receptors prevent killing of cells with normal MHC-I, viruses evading CTLs by down-regulating MHC-I should be vulnerable to NK cells. However, definitive integrated in vivo evidence for this interplay has been lacking, in part due to receptor polymorphism and a proposed second function of Ly49 receptors in licensing NK cells via self-MHC-I. Here we generated mice lacking specific Ly49 inhibitory receptors to show their essential role in licensing and controlling murine cytomegalovirus (MCMV) infection in vivo in an MHC-restricted manner. When MCMV cannot down-regulate MHC-I, NK cells cannot control infection that instead is mediated by CTLs, as predicted by the missing-self hypothesis.

scholarly journals Major histocompatibility complex class I molecules are down-regulated at the cell surface by the K5 protein encoded by Kaposi’s sarcoma-associated herpesvirus/human herpesvirus-8

2001 ◽  
Vol 82 (5) ◽  
pp. 1175-1180 ◽  
Author(s):  
Muzammel Haque ◽  
Keiji Ueda ◽  
Kazushi Nakano ◽  
Yuko Hirata ◽  
Carlo Parravicini ◽  
...  
Keyword(s):  
Major Histocompatibility Complex ◽  
Cell Surface ◽  
Kaposi's Sarcoma ◽  
Human Herpesvirus ◽  
Kaposi’S Sarcoma ◽  
Human Herpesvirus 8 ◽  
Complex Class ◽  
Mhc I ◽  
Herpesvirus 8 ◽  
Histocompatibility Complex

The expression of major histocompatibility complex class I (MHC-I) molecules at the cell surface was down-regulated in BC-3 cells infected with Kaposi’s sarcoma-associated herpesvirus (KSHV)/human herpesvirus-8 at early times after treatment with 12-O-tetradecanoylphorbol acetate (TPA), and in HeLa cells transfected with the K5 gene of KSHV. However, an immunoprecipitation study on these cells with anti-MHC-I monoclonal antibody revealed that there was no significant reduction in the synthesis of MHC-I molecules. A pulse–chase analysis followed by endoglycosidase H digestion also demonstrated the stability and transport of MHC-I molecules from the endoplasmic reticulum to at least the medial-Golgi. K5 antigen was clearly detected by immunohistological examination of samples from Kaposi’s sarcoma, primary effusion lymphoma and Castleman’s disease. These results suggest that the down-regulation of MHC-I molecules by K5 gene expression during reactivation may be important for evading immunological surveillance in the host.

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