Modulation of CD112 by the alphaherpesvirus gD protein suppresses DNAM-1–dependent NK cell-mediated lysis of infected cells

Grauwet, Korneel; Cantoni, Claudia; Parodi, Monica; Maria, Andrea De; Devriendt, Bert; Pende, Daniela; Moretta, Alessandro; Vitale, Massimo; Favoreel, Herman

doi:10.1073/pnas.1409485111

Cited by 52 publications

(70 citation statements)

References 51 publications

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“…Second, gD might perform essential in vivo functions, such as suppression of NK cell-mediated lysis of infected cells (48) or modulation of innate antiviral responses (49). We propose that B virus evolutionarily selected for a unique gD-independent entry mechanism while still maintaining the ability to use gD-mediated pathways, in view of our data presented here.…”

Section: Discussionmentioning

confidence: 68%

“…After adsorption at 37°C for 1 h, the cell monolayers were rinsed with PBS, overlaid with 1 ml of medium (set as 0 h on the time scale), and returned to a 37°C humidified incubator (5% CO 2 ). At selected time points (0, 4,8,12,24,48, and 72 h postinfection [p.i. ]), infected cells were harvested by placing the plates on dry ice, followed by a short freeze-thaw procedure and scraping the cells into medium.…”

Section: Virusesmentioning

confidence: 99%

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B Virus (Macacine herpesvirus 1) Glycoprotein D Is Functional but Dispensable for Virus Entry into Macaque and Human Skin Cells

Perelygina

Patrusheva

Vasireddi

et al. 2015

J Virol

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Glycoprotein D (gD) plays an essential role in cell entry of many simplexviruses. B virus (Macacine herpesvirus 1) is closely related to herpes simplex virus 1 (HSV-1) and encodes gD, which shares more than 70% amino acid similarity with HSV-1 gD. Previously, we have demonstrated that B virus gD polyclonal antibodies were unable to neutralize B virus infectivity on epithelial cell lines, suggesting gD is not required for B virus entry into these cells. In the present study, we confirmed this finding by producing a B virus mutant, BV-⌬gDZ, in which the gD gene was replaced with a lacZ expression cassette. Recombinant plaques were selected on complementing VD60 cells expressing HSV-1 gD. Virions lacking gD were produced in Vero cells infected with BV⌬gDZ. In contrast to HSV-1, B virus lacking gD was able to infect and form plaques on noncomplementing cell lines, including Vero, HEp-2, LLC-MK2, primary human and macaque dermal fibroblasts, and U373 human glioblastoma cells. The gD-negative BV-⌬gDZ also failed to enter entry-resistant murine B78H1 cells bearing a single gD receptor, human nectin-1, but gained the ability to enter when phenotypically supplemented with HSV-1 gD. Cell attachment and penetration rates, as well as the replication characteristics of BV-⌬gDZ in Vero cells, were almost identical to those of wild-type (wt) B virus. These observations indicate that B virus can utilize gD-independent cell entry and transmission mechanisms, in addition to generally used gD-dependent mechanisms. A lphaherpesviruses share a strategy to enter host cells (1-3). Initial cell attachment of free virions is mediated by glycoprotein C (gC) and/or gB binding to cell surface heparan sulfate (4). This interaction facilitates specific binding of gD to one of several cellular receptors. To date, five gD receptors have been identified, including herpesvirus entry mediator (HVEM, or HveA), nectin-1 (HveC), nectin-2 (HveB), poliovirus receptor (PVR, or HveD), and 3-O-sulfated heparin sulfate (5-8). Receptor binding induces a conformational change in gD and subsequent transition into an active state. Activated gD then induces gB and gH-gL conformational changes, which trigger fusion between viral and cellular membranes (9). A key role of gD homologs in cell entry was established for all known alphaherpesviruses expressing the protein, including herpes simplex virus 1 (HSV-1), pseudorabies virus (PRV), bovine herpesvirus 1 (BHV-1), and equine herpesvirus 1 (EHV-1). Investigations of deletion mutants of these viruses showed that gD is essential for virus penetration into target cells (10)(11)(12)(13)(14). Numerous studies showing complete inhibition of virus cell entry by monoclonal gD antibodies, soluble recombinant gD protein, or soluble gD receptors further confirmed the crucial role of gD in in vitro infectivity of alphaherpesviruses (15)(16)(17)(18). Experiments demonstrating that vaginal infection of experimental animals with HSV-1 and HSV-2 could be prevented by pretreatment of a virus inoculum with gD-specific anti...

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Section: Discussionmentioning

confidence: 68%

Section: Virusesmentioning

confidence: 99%

B Virus (Macacine herpesvirus 1) Glycoprotein D Is Functional but Dispensable for Virus Entry into Macaque and Human Skin Cells

Perelygina

Patrusheva

Vasireddi

et al. 2015

J Virol

View full text Add to dashboard Cite

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“…Nectin-2 is also a ligand of the activating natural killer (NK) cell receptor DNAX accessory molecule 1 (DNAM-1) (43,(89)(90)(91)(92). Work in PRV and HSV-2 showed that following cellular transfection with gD or viral infection, DNAM-1 was downregulated to prevent NK cell-mediated cytolysis of infected cells (93). Because B virus can interact with nectin-2, B virus may have a similar mechanism to evade NK cell-mediated cytolysis.…”

Section: Discussionmentioning

confidence: 99%

B Virus (Macacine Herpesvirus 1) Divergence: Variations in Glycoprotein D from Clinical and Laboratory Isolates Diversify Virus Entry Strategies

Patrusheva

Perelygina

Torshin

et al. 2016

J Virol

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Bvirus (Macacine herpesvirus 1) is an enveloped, doublestranded DNA virus belonging to the genus Simplexvirus of the subfamily Alphaherpesvirinae. B virus generally produces either mild disease or asymptomatic infection in monkeys of the Macaca genus, which are natural reservoir hosts. Similar to human herpes simplex viruses (HSV), B virus in natural host animals initially infects mucosal or skin epidermal and dermal cells and then enters nerve terminals of the sensory neurons subserving these sites. Subsequently, B virus travels in a retrograde direction to the dorsal root ganglion, where it can establish a latent lifelong infection with periodic reactivation (1, 2). B virus infections of the central nervous system (CNS) are extremely rare in the natural host and are usually associated with immunosuppression or intercurrent diseases (3, 4). In most human cases, B virus spreads to the CNS, causing an acute ascending paralysis and encephalomyelitis with an ϳ80% mortality rate if not treated in a timely manner. Postmortem examinations reveal focal neuronal lesions occasionally seen in parietal neurons, but far more often in the brainstem and cervical spinal cord, which are primary sites of virus recovery (5-11). The molecular basis for the differences in neurovirulence between HSV and B virus in humans remains a mystery despite the fact that specific molecular differences between these two viruses have been identified (12)(13)(14)(15)(16)(17)(18)(19).B virus is genetically and immunologically closely related to HSV, and some aspects of cell entry and cell-to-cell transmission of B virus and HSV are conserved (14,(20)(21)(22)(23). The specific interactions of glycoprotein D (gD) with cognate cellular receptors, viz., herpesvirus entry mediator (HVEM), nectin-1, and nectin-2, as well as one of the several isoforms of 3-O-sulfated heparan

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“…Interestingly, the interaction of DNAM-1 with one of its ligands, CD112, is a pathogenic target of herpesvirus, in which a viral gene product (gD) stimulates degradation of CD112 to avoid NK-cell-mediated lysis of infected cells and subsequent viral clearance. 25 Similarly, HIV infection drives an exhausted T-cell phenotype, characterized by loss of DNAM-1 expression. 26 In line with a central role for DNAM-1 in cancer immunosurveilance, genetic evidence has emerged implicating DNAM-1 mutations as a significant cancer risk factor.…”

Section: Introductionmentioning

confidence: 99%

Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing

et al. 2016

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Acute myeloid leukemia (AML) is associated with poor natural killer (NK) cell function through aberrant expression of NK-cell-activating receptors and their ligands on tumor cells. These alterations are thought to promote formation of inhibitory NK-target cell synapses, in which killer cell degranulation is attenuated. Allogeneic stem cell transplantation can be effective in treating AML, through restoration of NK cell lytic activity. Similarly, agents that augment NK-cell-activating signals within the immunological synapse may provide some therapeutic benefit. However, the receptor-ligand interactions that critically dictate NK cell function in AML remain undefined. Here, we demonstrate that CD112/CD155 expression is required for DNAM-1-dependent killing of AML cells. Indeed, the low, or absent, expression of CD112/CD155 on multiple AML cell lines resulted in failure to stimulate optimal NK cell function. Importantly, isolated clones with low CD112/155 expression were resistant to NK cell killing while those expressing abundant levels of CD112/155 were highly susceptible. Attenuated NK cell killing in the absence of CD112/CD155 originated from decreased NK-target cell conjugation. Furthermore, we reveal by time-lapse microscopy, a significant increase in NK cell 'failed killing' in the absence of DNAM-1 ligands. Consequently, NK cells preferentially lysed ligandexpressing cells within heterogeneous populations, driving clonal selection of CD112/CD155-negative blasts upon NK cell attack. Taken together, we identify reduced CD155 expression as a major NK cell escape mechanism in AML and an opportunity for targeted immunotherapy.

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Modulation of CD112 by the alphaherpesvirus gD protein suppresses DNAM-1–dependent NK cell-mediated lysis of infected cells

Cited by 52 publications

References 51 publications

B Virus (Macacine herpesvirus 1) Glycoprotein D Is Functional but Dispensable for Virus Entry into Macaque and Human Skin Cells

B Virus (Macacine herpesvirus 1) Glycoprotein D Is Functional but Dispensable for Virus Entry into Macaque and Human Skin Cells

B Virus (Macacine Herpesvirus 1) Divergence: Variations in Glycoprotein D from Clinical and Laboratory Isolates Diversify Virus Entry Strategies

Loss of DNAM-1 ligand expression by acute myeloid leukemia cells renders them resistant to NK cell killing

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