Suppression of Herpes Simplex Virus 1 in MDBK Cells via the Interferon Pathway

Barreca, Cristina; O’Hare, Peter

doi:10.1128/jvi.78.16.8641-8653.2004

Cited by 26 publications

(26 citation statements)

References 46 publications

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“…Various systems have been pursued to recapitulate aspects of the cyclical pathway of productive infection, repression, and reactivation, usually involving the use of virus mutants and/or the use of inhibitors, e.g., acycloguanosine and cycloheximide (10,30,31,36,38,41,43). Here we expand on the characterization of an unusual pattern of infection with wild-type HSV-1 in MDBK cells, which results in the progressive suppression of replication, cell recovery and regrowth of infected monolayers, and maintenance of virus in a cyclical manner by virtue of a paracrine signaling involving the IFN pathway (4). In these cells, HSV-1 triggers and is unable to counteract the IFN pathway.…”

Section: Discussionmentioning

confidence: 99%

“…We have previously shown that pretreatment of fresh naïve MDBK cells with cMed causes a pronounced inhibition of plaque formation (4). Repressively infected MDBK cells are in the presence of IFN initially produced upon infection (4), and the delayed reactivation of infection observed after medium reversal is presumably due to delay in reversible events maintained by IFN signaling. We next wished to examine aspects of the kinetics of the establishment of repression and its longevity decided during pretreatment regimens and to compare the effects of cMed with IFN alone.…”

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confidence: 99%

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Characterization of a Potent Refractory State and Persistence of Herpes Simplex Virus 1 in Cell Culture

Barreca

O’Hare

2006

J Virol

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Herpes simplex virus (HSV) normally undergoes productive cytocidal infection in culture and is thought of as relatively resistant to innate immune responses such as interferon. We previously described an unusual pattern of infection in culture in MDBK cells, which after initial productive infection, surprisingly resulted in progressive suppression of replication and cell recovery. The dominance of the refractory state was due to the inability to suppress interferon production and subsequent paracrine signaling. Here, using a wild-type HSV-1 strain expressing green fluorescent protein (GFP)-VP16, we analyze aspects of long-term HSV persistence resulting from this oscillating refractory state. We show that the gradual suppression of GFP-VP16 expression correlated with a biphasic pattern of accumulation of viral DNA and extracellular virus titers. We quantify virus maintenance in a minor subpopulation of cells during subculture, show the reemergence of virus by infectious center assay, and demonstrate that this required intracellular events over a 24-to 48-h time course. We also demonstrate that conditioned medium (cMed) from infected cells induced a profound shutoff of HSV gene expression at the transcriptional level. Finally, we demonstrate that this suppression was extremely rapid, requiring only 1 h of treatment to essentially abolish HSV immediate-early expression, and surprisingly persisted for almost 2 days after removal of the cMed. These combined effects underpin the oscillating effect both in plaque progression, where infection spreads but is overwhelmed by the accumulation of inhibitory components, enabling cell recovery, and virus maintenance in a subpopulation of cells. These results may be relevant to consider in studies of HSV latency in different animal models.In cell culture, herpes simplex virus (HSV) normally undergoes productive cycles of replication resulting in cell destruction and virus production (7). Replication is studied not only in human cells but in a wide range of cells, including those of primate, murine, canine, or bovine origin. In vivo, in its natural host, after an acute stage of productive infection in epithelial cells at the site of primary infection, the virus is transported to neuronal cells innervating the primary sites, where it undergoes a nonproductive infection resulting in latency. Periodic reactivation occurs whereby, after undergoing productive rounds of infection within reactivating cells, HSV is transported back to surface sites where it may undergo further rounds of replication (12, 42). Various systems have been established in culture to recapitulate this cyclical pathway of productive infection, repression, and reactivation. These systems usually involve the use of virus mutants defective in several functions and/or the use of inhibitors to suppress virus replication (10,30,31,33,36,38,41,43).Cells have evolved mechanisms of innate and acquired antiviral responses (7). One of the most important innate response mechanisms is the production and secretion of interfer...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Characterization of a Potent Refractory State and Persistence of Herpes Simplex Virus 1 in Cell Culture

Barreca

O’Hare

2006

J Virol

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“…DCs were incubated with a recombinant HSV-1 virus (strain v44) expressing VP16 linked to GFP (HSV-1-GFP), which results in GFP expression following infection (Barreca & O'Hare, 2004). Cells were washed extensively and added to permissive target cells (GMK or Jurkat cells).…”

Section: Dc-sign Enhances Infection Of Dcs In Cismentioning

confidence: 99%

Dendritic cells mediate herpes simplex virus infection and transmission through the C-type lectin DC-SIGN

Jong

Witte

Bolmstedt

et al. 2008

Journal of General Virology

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Dendritic cells (DCs) are essential for the induction of specific immune responses against invading pathogens. Herpes simplex virus (HSV) is a common human pathogen that causes painful but mild infections of the skin and mucosa, and which results in latency and recurrent infections. Of the two HSV subtypes described, HSV-1 causes mainly oral-facial lesions, whilst HSV-2 is associated with genital herpes. DCs are involved in HSV-induced immune suppression, but little is known about the molecular interactions between DCs and HSV. This study demonstrated that HSV-1 and -2 both interact with the DC-specific C-type lectin DC-SIGN. Further analyses demonstrated that DC-SIGN interacts with the HSV glycoproteins gB and gC. Binding of HSV-1 to immature DCs depended on both DC-SIGN and heparan sulfate proteoglycans. Strikingly, HSV-1 infection of DCs was almost completely inhibited by blocking antibodies against DC-SIGN. Thus, DC-SIGN is an important attachment receptor for HSV-1 on immature DCs and enhances infection of DCs in cis. In addition, DC-SIGN captures HSV-1 for transmission to permissive target cells. These data strongly suggest that DC-SIGN is a potential target to prevent HSV infection and virus dissemination. Further studies will show whether these interactions are involved in HSV-induced immune suppression.

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“…It has been shown that herpes simplex virus 1 (HSV-1) expresses several proteins that interfere with the innate immune response in vitro (summarized in Barreca & O'Hare, 2004;Chee & Roizman, 2004;Melroe et al, 2004) and in vivo in a mouse model system (Leib et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

High-level expression of biologically active bovine alpha interferon by Bovine herpesvirus 1 interferes only marginally with recombinant virus replication in vitro

Höhle

Karger

König

et al. 2005

Journal of General Virology

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An artificial open reading frame (ORF) for bovine alpha interferon (boIFN-a) with the codon preference of Bovine herpesvirus 1 (BHV-1) glycoprotein B was constructed to assess the effect of expression of boIFN-a by BHV-1 from an expression cassette. Transient expression of the ORF revealed that transfected cells secreted substantial amounts of biologically active boIFN-a, which moderately inhibited replication of BHV-1 after stimulation of bovine cells with 10 4 U ml "1 .The boIFN-a-encoding expression cassette was recombined into the glycoprotein E locus of the glycoprotein E-negative BHV-1 vaccine strain GKD. Cells infected with the resulting recombinant BHV-1/boIFN-a secreted up to 10 7 U boIFN-a per ml cell culture supernatant, which is about 40-to more than 100-fold the activity reached with other virus expression systems. Bioassays demonstrated that the BHV-1-expressed interferon induced a rapid and sustained antiviral state in stimulated bovine cells. Analysis of the in vitro growth properties of the recombinant revealed, depending on the cell line used, no or only slight inhibition in direct spreading from cell to cell and a modest delay in virus egress from infected cells. Final titres, however, were comparable to those reached by the parent strain. Penetration into cells was not affected. The results from this study demonstrate that BHV-1/boIFN-a expresses high levels of boIFN-a, grows to high titres in cell culture and thus represents a potential alternative means to deliver endogenously produced boIFN-a in situ for a period of time. INTRODUCTIONThe first host cell responses to virus infections include expression and secretion of interferons (IFNs), which lead to an antiviral state in cells and contribute to induction and regulation of the subsequent antiviral immune response. Based on the cellular receptors used for signal transduction and on sequence homology, IFNs are assigned to type I IFN or type II IFN; gamma IFN (IFN-c) is the sole member of the latter type. Type I IFNs bind to a common receptor and include beta IFN (IFN-b), omega IFN, kappa IFN, tau IFN and, depending on the animal species, up to 24 isotypes of alpha IFN (IFN-a). Binding of type I IFNs to their receptor results in activation of the JAK/STAT pathway, which finally ends in the activation of IFN-a/b-responsive genes (for reviews see Caraglia et al., 2005;Malmgaard, 2004; Stark et al., 1998). Since IFN-a/b rapidly induces an antiviral state within cells, sensitive viruses must have developed mechanisms to prevent the innate antiviral response mediated by IFN-a/b (for reviews see Biron & Sen, 2001;Goodbourn et al., 2000). Different strategies have evolved to achieve this goal. For example, Vaccinia virus, the prototypic member of the poxvirus family, expresses an IFN-a/b receptor, the B18R gene-encoded protein, that neutralizes the antiviral effects of extracellular IFN (Alcami et al., 2000;Colamonici et al., 1995;Symons et al., 1995), whereas paramyxoviruses like Human and Bovine respiratory syncytial virus, Simian virus 5 or New...

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Suppression of Herpes Simplex Virus 1 in MDBK Cells via the Interferon Pathway

Cited by 26 publications

References 46 publications

Characterization of a Potent Refractory State and Persistence of Herpes Simplex Virus 1 in Cell Culture

Characterization of a Potent Refractory State and Persistence of Herpes Simplex Virus 1 in Cell Culture

Dendritic cells mediate herpes simplex virus infection and transmission through the C-type lectin DC-SIGN

High-level expression of biologically active bovine alpha interferon by Bovine herpesvirus 1 interferes only marginally with recombinant virus replication in vitro

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