Human Herpesviridae Methods of Natural Killer Cell Evasion

Odom, Carl I.; Gaston, David C; Markert, James M.; Cassady, Kevin A.

doi:10.1155/2012/359869

Cited by 16 publications

(12 citation statements)

References 131 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In the case of KSHV, K5 selectively removes HLA-A and HLA-B allotypes, while K3 targets HLA-A, HLA-B, HLA-C, and HLA-E (22). In addition, the removal of ligands for activating receptors on NK cells is a common way for viruses to prevent NK cell activation (65), and KSHV encodes several factors, including K5, that reduce the surface expression of such receptors (9,10,33). The distinct timing and substrate specificities of K3 and K5 suggest that allotype-specific downregulation of MHC class I molecules occurs during the immediate early stage of lytic replication, while indiscriminant and extensive reduction of surface MHC class I molecules is confined to later stages.…”

Section: Discussionmentioning

confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus K3 and K5 Ubiquitin E3 Ligases Have Stage-Specific Immune Evasion Roles during Lytic Replication

Brulois

Tóth

Wong

et al. 2014

J Virol

View full text Add to dashboard Cite

The downregulation of immune synapse components such as major histocompatibility complex class I (MHC-I) and ICAM-1 is a common viral immune evasion strategy that protects infected cells from targeted elimination by cytolytic effector functions of the immune system. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes two membrane-bound ubiquitin E3 ligases, called K3 and K5, which share the ability to induce internalization and degradation of MHC-I molecules. Although individual functions of K3 and K5 outside the viral genome are well characterized, their roles during the KSHV life cycle are still unclear. In this study, we individually introduced the amino acid-coding sequences of K3 or K5 into a ⌬K3 ⌬K5 recombinant virus, at either original or interchanged genomic positions. Recombinants harboring coding sequences within the K5 locus showed higher K3 and K5 protein expression levels and more rapid surface receptor downregulation than cognate recombinants in which coding sequences were introduced into the K3 locus. To identify infected cells undergoing K3-mediated downregulation of MHC-I, we employed a novel reporter virus, called red-green-blue-BAC16 (RGB-BAC16), which was engineered to harbor three fluorescent protein expression cassettes: EF1␣-monomeric red fluorescent protein 1 (mRFP1), polyadenylated nuclear RNA promoter (pPAN)-enhanced green fluorescent protein (EGFP), and pK8.1-monomeric blue fluorescent protein (tagBFP), marking latent, immediate early, and late viral gene expression, respectively. Analysis of RGB-derived K3 and K5 deletion mutants showed that while the K5-mediated downregulation of MHC-I was concomitant with pPAN induction, the reduction of MHC-I surface expression by K3 was evident in cells that were enriched for pPAN-driven EGFP high and pK8.1-driven blue fluorescent proteinpositive (BFP ؉ ) populations. These data support the notion that immunoreceptor downregulation occurs by a sequential process wherein K5 is critical during the immediately early phase and K3 plays a significant role during later stages. IMPORTANCEAlthough the roles of K3 and K5 outside the viral genome are well characterized, the function of these proteins in the context of the KSHV life cycle has remained unclear, particularly in the case of K3. This study examined the relative contributions of K3 and K5 to the downregulation of MHC-I during the lytic replication of KSHV. We show that while K5 acts immediately upon entry into the lytic phase, K3-mediated downregulation of MHC-I was evident during later stages of lytic replication. The identification of distinctly timed K3 and K5 activities significantly advances our understanding of KSHV-mediated immune evasion. Crucial to this study was the development of a novel recombinant KSHV, called RGB-BAC16, which facilitated the delineation of stage-specific phenotypes.

show abstract

Section: Discussionmentioning

confidence: 99%

Kaposi's Sarcoma-Associated Herpesvirus K3 and K5 Ubiquitin E3 Ligases Have Stage-Specific Immune Evasion Roles during Lytic Replication

Brulois

Tóth

Wong

et al. 2014

J Virol

View full text Add to dashboard Cite

show abstract

“…This co-existence led to the development of opposite mechanisms in which the NK cells try to kill the infected cells and the viruses on the other hand try to escape such killing [32]. Famous among these viruses are viruses of the Herpesviride that had developed numerous immune evasion mechanisms such as the use of viral miRNAs in order to escape NK cell attack [23], [24], [33]. Hence, we were quite surprised to observe that no changes were detected in the expression of the NK ligands tested, after transduction with 21 miRNAs of HSV-2 and that increased NK cell killing was observed following HSV-2 infection.…”

Section: Discussionmentioning

confidence: 99%

HSV-2 Specifically Down Regulates HLA-C Expression to Render HSV-2-Infected DCs Susceptible to NK Cell Killing

et al. 2013

View full text Add to dashboard Cite

Both NK cells and CTLs kill virus-infected and tumor cells. However, the ways by which these killer cells recognize the infected or the tumorigenic cells are different, in fact almost opposite. CTLs are activated through the interaction of the TCR with MHC class I proteins. In contrast, NK cells are inhibited by MHC class I molecules. The inhibitory NK receptors recognize mainly MHC class I proteins and in this regard practically all of the HLA-C proteins are recognized by inhibitory NK cell receptors, while only certain HLA-A and HLA-B proteins interact with these receptors. Sophisticated viruses developed mechanisms to avoid the attack of both NK cells and CTLs through, for example, down regulation of HLA-A and HLA-B molecules to avoid CTL recognition, leaving HLA-C proteins on the cell surface to inhibit NK cell response. Here we provide the first example of a virus that through specific down regulation of HLA-C, harness the NK cells for its own benefit. We initially demonstrated that none of the tested HSV-2 derived microRNAs affect NK cell activity. Then we show that surprisingly upon HSV-2 infection, HLA-C proteins are specifically down regulated, rendering the infected cells susceptible to NK cell attack. We identified a motif in the tail of HLA-C that is responsible for the HSV-2-meduiated HLA-C down regulation and we show that the HLA-C down regulation is mediated by the viral protein ICP47. Finally we show that HLA-C proteins are down regulated from the surface of HSV-2 infected dendritic cells (DCs) and that this leads to the killing of DC by NK cells. Thus, we propose that HSV-2 had developed this unique and surprising NK cell-mediated killing strategy of infected DC to prevent the activation of the adaptive immunity.

show abstract

“…Differences from healthy controls (HC) have, however, been suggested by some studies of the immune system. Several groups have described a decrease in cytotoxic activity of natural killer (NK) and T cells, predominantly by the reduction of granzyme or perforin levels , similar to which is also associated commonly with herpes virus infections . In contrast, Curriu et al .…”

Section: Introductionmentioning

confidence: 99%

“…Differences from healthy controls (HC) have, however, been suggested by some studies of the immune system. Several groups have described a decrease in cytotoxic activity V C 2016 British Society for Immunology, Clinical and Experimental Immunology, 184: 237-247 of natural killer (NK) and T cells, predominantly by the reduction of granzyme or perforin levels [10][11][12][13], similar to which is also associated commonly with herpes virus infections [14]. In contrast, Curriu et al found an increase of NKp46 (natural cytotoxicity on NK cells) and CD69 (activation marker) expression on NK cells [15].…”

Section: Introductionmentioning

confidence: 99%

Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome: a cross-sectional study

Mensah¹,

Bansal

Berkovitz

et al. 2016

Clinical and Experimental Immunology

View full text Add to dashboard Cite

SummaryMyalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a heterogeneous condition of unknown aetiology characterized by multiple symptoms including fatigue, post-exertional malaise and cognitive impairment, lasting for at least 6 months. Recently, two clinical trials of B cell depletion therapy with rituximab (anti-CD20) reported convincing improvement in symptoms. A possible but undefined role for B cells has therefore been proposed. Studies of the relative percentages of B cell subsets in patients with ME/CFS have not revealed any reproducible differences from healthy controls (HC). In order to explore whether more subtle alterations in B cell subsets related to B cell differentiation exist in ME/CFS patients we used flow cytometry to immunophenotype CD19 1 B cells. The panel utilized immunoglobulin (Ig)D, CD27 and CD38 (classical B cell subsets) together with additional markers. A total of 38 patients fulfilling Canadian, Centre for Disease Control and Fukuda ME/CFS criteria and 32 age-and sex-matched HC were included. We found no difference in percentages of classical subsets between ME/CFS patients and HC. However, we observed an increase in frequency (P < 0Á01) and expression (MFI; P 5 0Á03) of CD24 on total B cells, confined to IgD 1 subsets. Within memory subsets, a higher frequency of CD21 1 CD38 -B cells (>20%) was associated with the presence of ME/CFS [odds ratio: 3Á47 (1Á15-10Á46); P 5 0Á03] compared with HC, and there was a negative correlation with disease duration. In conclusion, we identified possible changes in B cell phenotype in patients with ME/CFS. These may reflect altered B cell function and, if confirmed in other patient cohorts, could provide a platform for studies based on clinical course or responsiveness to rituximab therapy.

show abstract

Human Herpesviridae Methods of Natural Killer Cell Evasion

Cited by 16 publications

References 131 publications

Kaposi's Sarcoma-Associated Herpesvirus K3 and K5 Ubiquitin E3 Ligases Have Stage-Specific Immune Evasion Roles during Lytic Replication

Kaposi's Sarcoma-Associated Herpesvirus K3 and K5 Ubiquitin E3 Ligases Have Stage-Specific Immune Evasion Roles during Lytic Replication

HSV-2 Specifically Down Regulates HLA-C Expression to Render HSV-2-Infected DCs Susceptible to NK Cell Killing

Extended B cell phenotype in patients with myalgic encephalomyelitis/chronic fatigue syndrome: a cross-sectional study

Contact Info

Product

Resources

About