How the Virus Outsmarts the Host: Function and Structure of Cytomegalovirus MHC‐I‐Like Molecules in the Evasion of Natural Killer Cell Surveillance

Revilleza, Maria Jamela; Wang, Rui; Mans, Janet; Hong, Manqing; Natarajan, Kannan; Margulies, David H.

doi:10.1155/2011/724607

Cited by 36 publications

(33 citation statements)

References 98 publications

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“…Although these three proteins are only 11-15% identical in the amino acid sequences of their extracellular domains, they may be aligned sensibly when predictions regarding secondary structure are taken into account (19,43). We speculate that the host stress response leading to expression of an NKG2D ligand was an early step in the coevolution of the host NKG2D ligands and the viral evasins.…”

Section: Resultsmentioning

confidence: 94%

Structural basis of mouse cytomegalovirus m152/gp40 interaction with RAE1γ reveals a paradigm for MHC/MHC interaction in immune evasion

Wang¹,

Natarajan²,

Revilleza³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) cells are activated by engagement of the NKG2D receptor with ligands on target cells stressed by infection or tumorigenesis. Several human and rodent cytomegalovirus (CMV) immunoevasins down-regulate surface expression of NKG2D ligands. The mouse CMV MHC class I (MHC-I)-like m152/gp40 glycoprotein down-regulates retinoic acid early inducible-1 (RAE1) NKG2D ligands as well as host MHC-I. Here we describe the crystal structure of an m152/RAE1γ complex and confirm the intermolecular contacts by mutagenesis. m152 interacts in a pincer-like manner with two sites on the α1 and α2 helices of RAE1 reminiscent of the NKG2D interaction with RAE1. This structure of an MHC-I-like immunoevasin/MHC-I-like ligand complex explains the binding specificity of m152 for RAE1 and allows modeling of the interaction of m152 with classical MHC-I and of related viral immunoevasins.immune recognition | virus evasion | X-ray diffraction C ytomegaloviruses (CMV), members of the β-herpesvirus family, pathogenic in immunosuppressed or immunodeficient hosts (1), may lie dormant for many years but can cause considerable morbidity and mortality with neonatal or HIV infection or during organ transplantation (2). The large size of the CMV dsDNA genomes (as large as 250 kb), allows these viruses to dedicate many genes to viral fitness; a number of these genes thwart the host inflammatory, innate, and adaptive immune responses. Human and mouse studies emphasize the importance of natural killer (NK) and CD8 + T cells in the antiviral response, underscoring the complementary roles of innate and adaptive immunity. Of particular importance to NK-mediated immunity is NKG2D, a C-type lectin-like homodimeric glycoprotein that mediates NK cell activation on ligation by host molecules expressed at the cell surface as a result of cellular or genotoxic stress (3, 4). Human NKG2D ligands include MICA, MICB, and members of the ULBP family (4, 5), and studies suggest a complex relationship between the expression of NKG2D ligands on tumor cells, the effectiveness of immunosurveillance, and clinical prognosis (6, 7). Murine NKG2D recognizes RAE1 family members (RAE1α-ε), H60 (H60a-c), and the murine UL16-binding protein-like transcript 1 (MULT1) (8-10). Remarkably, these NKG2D ligands are related to MHC class I (MHC-I)-like molecules (11,12), and several are targets of MHC-I-like immunoevasins (3). In particular, mouse CMV (MCMV) m152/gp40 (hereafter referred to as "m152") has a dual role, downregulating cell-surface expression of RAE1 family members [but not MULT1 or H60 (13), the targets of MCMV proteins m145 and m155, respectively (14, 15)] as well as host MHC-I molecules (16)(17)(18)(19). A virus-encoded Fc receptor, m138, also controls MULT1, H60 (3), and RAE1ε (20). In vivo, MCMV deletions lacking m145, m152, m155, or m138 are defective in viral control of surface expression of MULT1, RAE1, and H60.To explore the mechanism by which MCMV MHC-I-like immunoevasins interact with and down-regulate their respective NKG2D ligands, we examined th...

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Section: Resultsmentioning

confidence: 94%

Structural basis of mouse cytomegalovirus m152/gp40 interaction with RAE1γ reveals a paradigm for MHC/MHC interaction in immune evasion

Wang¹,

Natarajan²,

Revilleza³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Cytomegaloviruses (CMV) and other viruses from the herpes family have large genomes that encode for a series of immuno-evasive mechanisms, targetting key molecular steps necessary for a successful immune response [23]–[25]. Particularly important for the evasion of NK cell surveillance are MHC-I like molecules that can engage inhibitory NK cell receptors, like the mouse CMV (MCMV) encoded glycoprotein m157 binding to Ly49 receptors [26], [27], and the human CMV (HCMV) UL18 engaging the inhibitory leukocyte immunoglobulin-like receptor LIR–1 [28].…”

Section: Introductionmentioning

confidence: 99%

Virus Encoded MHC-Like Decoys Diversify the Inhibitory KIR Repertoire

2013

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Natural killer (NK) cells are circulating lymphocytes that play an important role in the control of viral infections and tumors. Their functions are regulated by several activating and inhibitory receptors. A subset of these receptors in human NK cells are the killer immunoglobulin-like receptors (KIRs), which interact with the highly polymorphic MHC class I molecules. One important function of NK cells is to detect cells that have down-regulated MHC expression (missing-self). Because MHC molecules have non polymorphic regions, their expression could have been monitored with a limited set of monomorphic receptors. Surprisingly, the KIR family has a remarkable genetic diversity, the function of which remains poorly understood. The mouse cytomegalovirus (MCMV) is able to evade NK cell responses by coding “decoy” molecules that mimic MHC class I. This interaction was suggested to have driven the evolution of novel NK cell receptors. Inspired by the MCMV system, we develop an agent-based model of a host population infected with viruses that are able to evolve MHC down-regulation and decoy molecules. Our simulations show that specific recognition of MHC class I molecules by inhibitory KIRs provides excellent protection against viruses evolving decoys, and that the diversity of inhibitory KIRs will subsequently evolve as a result of the required discrimination between host MHC molecules and decoy molecules.

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“…Latency is regulated by a variety of specific genes in the virus genome. However, CMV is thought to persist also due to its many ways of evading the host immune defenses [4, 5]. Several viral proteins, such as interleukin 10 homolog and others, create an immunosuppressive environment around infected cells that avoids elimination of the latently infected cell by the immune system [6].…”

Section: CMV Pathologymentioning

confidence: 99%

Evaluation of T Cell Immunity against Human Cytomegalovirus: Impact on Patient Management and Risk Assessment of Vertical Transmission

Freer

Quaranta

Pistello

2016

Journal of Immunology Research

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Cytomegalovirus (CMV) is one of the most common infectious agents, infecting the general population at an early age without causing morbidity most of the time. However, on particular occasions, it may represent a serious risk, as active infection is associated with rejection and disease after solid organ transplantation or fetal transmission during pregnancy. Several methods for CMV diagnosis are available on the market, but because infection is so common, careful selection is needed to discriminate primary infection from reactivation. This review focuses on methods based on CMV-specific T cell reactivity to help monitor the consequences of CMV infection/reactivation in specific categories of patients. This review makes an attempt at discussing the pros and cons of the methods available.

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How the Virus Outsmarts the Host: Function and Structure of Cytomegalovirus MHC‐I‐Like Molecules in the Evasion of Natural Killer Cell Surveillance

Cited by 36 publications

References 98 publications

Structural basis of mouse cytomegalovirus m152/gp40 interaction with RAE1γ reveals a paradigm for MHC/MHC interaction in immune evasion

Structural basis of mouse cytomegalovirus m152/gp40 interaction with RAE1γ reveals a paradigm for MHC/MHC interaction in immune evasion

Virus Encoded MHC-Like Decoys Diversify the Inhibitory KIR Repertoire

Evaluation of T Cell Immunity against Human Cytomegalovirus: Impact on Patient Management and Risk Assessment of Vertical Transmission

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