The human herpesvirus-7 (HHV-7) U21 immunoevasin subverts NK-mediated cytoxicity through modulation of MICA and MICB

Herpesviruses have evolved numerous immune evasion strategies to facilitate establishment of lifelong persistent infections. Many herpesviruses encode gene products devoted to preventing viral antigen presentation as a means of escaping detection by cytotoxic T lymphocytes. The human herpesvirus-7 (HHV-7) U21 gene product, for example, is an immunoevasin that binds to class I major histocompatibility complex molecules and redirects them to the lysosomal compartment. Virus infection can also induce the upregulation of surface ligands that activate NK cells. Accordingly, the herpesviruses have evolved a diverse array of mechanisms to prevent NK cell engagement of NK-activating ligands on virus-infected cells. Here we demonstrate that the HHV-7 U21 gene product interferes with NK recognition. U21 can bind to the NK activating ligand ULBP1 and reroute it to the lysosomal compartment. In addition, U21 downregulates the surface expression of the NK activating ligands MICA and MICB, resulting in a reduction in NK-mediated cytotoxicity. These results suggest that this single viral protein may interfere both with CTL-mediated recognition through the downregulation of class I MHC molecules as well as NK-mediated recognition through downregulation of NK activating ligands.     

Natural killer cells regulate murine cytomegalovirus-induced sialadenitis and salivary gland disease

The transmission of herpesviruses depends on viral shedding at mucosal surfaces. The salivary gland represents a major site of persistent viral replication for many viruses, including cytomegalovirus. We established a mouse model of salivary gland dysfunction after acute viral infection and investigated the cellular requirements for the loss of secretion. Murine cytomegalovirus (MCMV) infection severely impaired saliva secretion independently of salivary gland virus levels. Lymphocytes or circulating monocytes/macrophages were not required for secretory dysfunction. Dysfunction occurred before glandular inflammation, suggesting that a soluble mediator initiated the disruption of acinar cell function. Despite genetic differences in innate resistance to MCMV, NK cells protected the host against acinar atrophy and the loss of secretions under conditions of an exceedingly low virus inoculum. NK cells also modulated the type of glandular inflammation after infection, as they prevented an influx of Siglec-F(+) polymorphonuclear leukocytes (PMNs). Therefore, beyond their recognized role in controlling MCMV replication, NK cells preserve organ integrity and function and regulate the innate inflammatory response within the gland.     

Successful control of viruses by NK cells--a balance of opposing forces?

Natural killer (NK) cells play a crucial role in limiting the severity of diseases caused by a range of viruses. Recent data have shown that the effector functions of NK cells can be specifically stimulated when NK cell activation receptors engage cellular major histocompatibility complex (MHC) class I-like ligands induced after infection or by specific viral gene products. However, to counter this NK cell response viruses have evolved an array of strategies to subvert efficient NK cell activation. These data indicate that the balance of host NK cell responses and viral NK cell escape mechanisms can be strategically poised as each strives for survival.     

Abduction of Chemokine Elements by Herpesviruses

Chemokines play a key role in orchestrating leukocytic recruitment during inflammatory responses, including those to viral infections. Chemokines are soluble cytokines which mediate their effects through specific G protein-coupled, seven-transmembrane receptors which are expressed on a wide range of cells, including monocytes, T-cells, dendritic cells, and NK cells. Analyses of herpesvirus genomes have revealed that these viral pathogens encode their own versions of both chemokines and chemokine receptors. Viral genes encoding chemokine elements were likely to have been acquired from the host genome and have been remodeled during virus evolution to presumably optimize function or acquire new properties not displayed by their cellular homologues. Virus-encoded chemokines and chemokine receptors are important players in the continuing confrontation between viruses and their mammalian hosts. Detailed characterization of these elements will provide a better understanding of how the immune system responds to viral infection and may suggest new antiviral drug targets and new avenues for the development of antiviral therapies. We will review here the chemokine elements encoded by herpesviruses and how they may aid viral infection and propagation.     

Comparative Analysis of the Mosaic Genomes of Tailed Archaeal Viruses and Proviruses Suggests Common Themes for Virion Architecture and Assembly with Tailed Viruses of Bacteria

Tailed double-stranded DNA viruses (order Caudovirales) represent the dominant morphotype among viruses infecting bacteria. Analysis and comparison of complete genome sequences of tailed bacterial viruses provided insights into their origin and evolution. Structural and genomic studies have unexpectedly revealed that tailed bacterial viruses are evolutionarily related to eukaryotic herpesviruses. Organisms from the third domain of life, Archaea, are also infected by viruses that, in their overall morphology, resemble tailed viruses of bacteria. However, high-resolution structural information is currently unavailable for any of these viruses, and only a few complete genomes have been sequenced so far. Here we identified nine proviruses that are clearly related to tailed bacterial viruses and integrated into chromosomes of species belonging to four different taxonomic orders of the Archaea. This more than doubled the number of genome sequences available for comparative studies. Our analyses indicate that highly mosaic tailed archaeal virus genomes evolve by homologous and illegitimate recombination with genomes of other viruses, by diversification, and by acquisition of cellular genes. Comparative genomics of these viruses and related proviruses revealed a set of conserved genes encoding putative proteins similar to virion assembly and maturation, as well as genome packaging proteins of tailed bacterial viruses and herpesviruses. Furthermore, fold prediction and structural modeling experiments suggest that the major capsid proteins of tailed archaeal viruses adopt the same topology as the corresponding proteins of tailed bacterial viruses and eukaryotic herpesviruses. Data presented in this study strongly support the hypothesis that tailed viruses infecting archaea share a common ancestry with tailed bacterial viruses and herpesviruses.     

Human natural killer cell deficiencies and susceptibility to infection

There are a surprisingly large number of human natural killer (NK) cell deficiency states that provide insight into the role of NK cells in defense against human infectious disease. Many disorders associated with NK cell defects are caused by single gene mutations and, thus, give additional understanding concerning the function of specific molecules in NK cell development and activities. A resounding theme of NK cell deficiencies is susceptibility to herpesviruses, suggesting that unexplained severe herpesviral infection should raise the possibility of an NK cell deficit.     

Virus-driven evolution of natural killer cell receptors

Natural killer (NK) cells can mount an immediate response against viral infection, secreting cytokines and killing virus-infected cells. However, viruses have devised strategies to avoid immune detection. Here, we discuss NK cell recognition of viruses and propose that viruses may provide the evolutionary pressure causing the diversification of the NK cell receptors.     

Natural killer cell activation receptors in innate immunity to infection

Natural killer (NK) cells are best known for their capacity to kill tumors but they are also critical in early innate responses to infection, especially herpesviruses. Recent studies indicate that NK cell receptors involved in tumor target specificity are also involved in responses to viral infections.     

Understanding human T-cell-mediated immunoregulation through herpesviruses

Human herpesviruses have coevolved with humans over millions of years, and adaptation of latent infection within the cells of the immune system is a unique characteristic of many of these viruses. Following primary infection, these herpesviruses establish an asymptomatic-persistent infection in healthy individuals that is strictly controlled by virus-specific CD8(+) and CD4(+) T cells. Here, we provide a brief overview of how the human immune system interacts with these latent viruses and regulates the lifelong host-virus relationship in healthy virus carriers. Extensive studies on T-cell-mediated immune regulation over the last decade has allowed researchers to successfully translate these findings into the clinical setting to treat various herpesvirus-associated diseases in transplant patients and individuals with virus-associated malignancies. It is highly likely that these newly emerging T-cell-based therapeutic and diagnostic technologies will revolutionize the clinical management of patients with herpesvirus-associated diseases.     

Virus Encoded MHC-Like Decoys Diversify the Inhibitory KIR Repertoire

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.     

Viral immune evasion: a masterpiece of evolution

Coexistence of viruses and their hosts imposes an evolutionary pressure on both the virus and the host immune system. On the one hand, the host has developed an immune system able to attack viruses and virally infected cells, whereas on the other hand, viruses have developed an array of immune evasion mechanisms to escape killing by the host's immune system. Generally, the larger the viral genome, the more diverse mechanisms are utilized to extend the time-window for viral replication and spreading of virus particles. In addition, herpesviruses have the capacity to hide from the immune system by their ability to establish latency. The strategies of immune evasion are directed towards three divisions of the immune system, i.e., the humoral immune response, the cellular immune response and immune effector functions. Members of the herpesvirus family are capable of interfering with the host's immune system at almost every level of immune clearance. Antibody recognition of viral epitopes, presentation of viral peptides by major histocompatibility complex (MHC) class I and class II molecules, the recruitment of immune effector cells, complement activation, and apoptosis can all be impaired by herpesviruses. This review aims at summarizing the current knowledge of viral evasion mechanisms.     

Fusing structure and function: a structural view of the herpesvirus entry machinery

Herpesviruses are double-stranded DNA, enveloped viruses that infect host cells through fusion with either the host cell plasma membrane or endocytic vesicle membranes. Efficient infection of host cells by herpesviruses is remarkably more complex than infection by other viruses, as it requires the concerted effort of multiple glycoproteins and involves multiple host receptors. The structures of the major viral glycoproteins and a number of host receptors involved in the entry of the prototypical herpesviruses, the herpes simplex viruses (HSVs) and Epstein-Barr virus (EBV), are now known. These structural studies have accelerated our understanding of HSV and EBV binding and fusion by revealing the conformational changes that occur on virus-receptor binding, depicting potential sites of functional protein and lipid interactions, and identifying the probable viral fusogen.     

The two-faces of NK cells in oncolytic virotherapy

Oncolytic viruses (OVs) are immunotherapeutics capable of directly killing cancer cells and with potent immunostimulatory properties. OVs exert their antitumor effect, at least partially, by activating the antitumor immune response, of which NK cells are an important component. However, if on the one hand increasing evidence revealed that NK cells are important mediators of oncolytic virotherapy, on the other hand, NK cells have evolved to fight viral infections, and therefore they can have a detrimental effect for the efficacy of OVs. In this review, we will discuss the dichotomy between the antitumor and antiviral functions of NK cells related to oncolytic virotherapy. We will also review NK cell-based and OV-based therapies, engineered OVs aimed at enhancing immune stimulation, and combination therapies involving OVs and NK cells currently used in cancer immunotherapy.     

嗜神经性疱疹病毒：神经科学研究的有力工具

病毒是研究现代神经科学的有力工具。对神经元的连接方式及功能研究大都是利用重组病毒完成的,嗜神经性疱疹病毒便是其中一种重要工具。随着基因工程学以及分子生物学技术的不断发展,多种嗜神经性疱疹病毒被改造为不同的重组病毒工具应用于神经科学研究。本文基于几种常见且应用较为广泛的嗜神经性疱疹病毒作为神经传导示踪工具、治疗神经性疾病的病毒载体和溶瘤病毒治疗神经肿瘤等应用进行阐述及讨论,为进一步开发嗜神经性疱疹病毒的功能提供参考。     

Regulation of Herpesvirus Reactivation by Host MicroRNAs

The interplay between latent and lytic modes of infection is central to successful infection of all herpesviruses, yet knowledge of the determinants that govern reactivation of these viruses from latent to lytic infection is limited. Recently, several studies have identified roles for specific cellular microRNAs in inhibiting reactivation of various herpesviruses, thereby promoting latent infections. These studies are discussed in the context of current knowledge on mechanisms of regulation of reactivation of specific herpesviruses.     

Alterations in receptor binding properties of recent human influenza H3N2 viruses are associated with reduced natural killer cell lysis of infected cells

Natural killer (NK) cell recognition of influenza virus-infected cells involves hemagglutinin (HA) binding to sialic acid (SA) on activating NK receptors. SA also acts as a receptor for the binding of influenza virus to its target host cells. The SA binding properties of H3N2 influenza viruses have been observed to change during circulation in humans: recent isolates are unable to agglutinate chicken red blood cells and show reduced affinity for synthetic glycopolymers representing SA-alpha-2,3-lactose (3'SL-PAA) and SA-alpha-2,6-N-acetyl lactosamine (6'SLN-PAA) carbohydrates. Here, NK lysis of cells infected with human H3N2 influenza viruses isolated between 1969 and 2003 was analyzed. Cells infected with recent isolates (1999 to 2003) were found to be lysed less effectively than cells infected with older isolates (1969 to 1996). This change occurred concurrently with the acquisition of two new potential glycosylation site motifs in HA. Deletion of the potential glycosylation site motif at 133 to 135 in HA1 from a recent isolate partially restored the agglutination phenotype to a recombinant virus, indicating that the HA-SA interaction is inhibited by the glycosylation modification. Deletion of either of the recently acquired potential glycosylation sites from HA led to increased NK lysis of cells infected with recombinant viruses carrying modified HA. These results indicate that alterations in HA glycosylation may affect NK cell recognition of influenza virus-infected cells in addition to virus binding to host cells.     

Evolutionary struggles between NK cells and viruses

Natural killer (NK) cells are well recognized for their ability to provide a first line of defence against viral pathogens and they are increasingly being implicated in immune responses against certain bacterial and parasitic infections. Reciprocally, viruses have devised numerous strategies to evade the activation of NK cells and have influenced the evolution of NK-cell receptors and their ligands. NK cells contribute to host defence by their ability to rapidly secrete cytokines and chemokines, as well as to directly kill infected host cells. In addition to their participation in the immediate innate immune response against infection, interactions between NK cells and dendritic cells shape the nature of the subsequent adaptive immune response to pathogens.     

The switch from latent to productive infection in epstein-barr virus-infected B cells is associated with sensitization to NK cell killing

Following activation of Epstein-Barr virus (EBV)-infected B cells from latent to productive (lytic) infection, there is a concomitant reduction in the level of cell surface major histocompatibility complex (MHC) class I molecules and an impaired antigen-presenting function that may facilitate evasion from EBV-specific CD8+ cytotoxic T cells. In some other herpesviruses studied, most notably human cytomegalovirus (HCMV), evasion of virus-specific CD8+ effector responses via downregulation of surface MHC class I molecules is supplemented with specific mechanisms for evading NK cells. We now report that EBV differs from HCMV in this respect. While latently infected EBV-positive B cells were resistant to lysis by two NK lines and by primary polyclonal NK cells from peripheral blood, these effectors efficiently killed cells activated into the lytic cycle. Susceptibility to NK lysis coincided not only with downregulation of HLA-A, -B, and -C molecules that bind to the KIR family of inhibitory receptors on NK cells but also with downregulation of HLA-E molecules binding the CD94/NKG2A inhibitory receptors. Conversely, ULBP-1 and CD112, ligands for the NK cell-activating receptors NKG2D and DNAM-1, respectively, were elevated. Susceptibility of the virus-producing target cells to NK cell lysis was partially reversed by blocking ULBP-1 or CD112 with specific antibodies. These results highlight a fundamental difference between EBV and HCMV with regards to evasion of innate immunity.     

NK cells and HIV infection: lessons from other viruses

Although the means by which NK cells may contribute to anti viral defense are still incompletely understood, various studies merge to a better comprehension of pathways that mediate NK cell activation (NK cell mediated cytotoxic activity and cytokine production) and their implications during the immune response towards a variety of viruses. Characterization of a specific expression pattern of ligands for NK receptors on virally infected cells and consequent modulation of NK cell activity have provided new insights in the field. A major break through to a direct evidence of a role for NK cells and NK cell receptors in immune protection against viral infection, was the recent implication of the murine activating Ly49H receptors in immune protection against MCMV infection. Although much remains to be learned concerning implication of NK cells in HIV infection, various reports have documented alteration in NK cell function and numbers during the course of HIV infection or treatment of AIDS. This review will focus on the current knowledge about the factors which might influence NK cell activation during various viral challenge and an emerging view of their alteration during HIV infection.