Establishment of Respiratory Syncytial Virus Persistence in Cell Lines: Association with Defective Interfering Particles

Romero‐Valdovinos, Mirza; Gómez, Beatrı́z

doi:10.1159/000071461

Cited by 33 publications

(22 citation statements)

References 17 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Similar to other RNA viruses such as measles virus (14), Sendai virus (SeV) (15), mumps virus (16), vesicular stomatitis virus (17,18), parainfluenza virus type 3 (PIV3) (19), and respiratory syncytial virus (RSV) (20), NDV can establish persistent infection under some circumstances, as reported previously (15,21,22). For establishment of persistent infection in vitro, there is normally a fine dynamic equilibrium between virus infection and viral clearance by host innate immune responses.…”

supporting

confidence: 63%

Newcastle Disease Virus Establishes Persistent Infection in Tumor Cells In Vitro : Contribution of the Cleavage Site of Fusion Protein and Second Sialic Acid Binding Site of Hemagglutinin-Neuraminidase

Rangaswamy

Wang

Cheng

et al. 2017

J Virol

View full text Add to dashboard Cite

Newcastle disease virus (NDV) is an oncolytic virus being developed for the treatment of cancer. Following infection of a human ovarian cancer cell line (OVCAR3) with a recombinant low-pathogenic NDV, persistent infection was established in a subset of tumor cells. Persistently infected (PI) cells exhibited resistance to superinfection with NDV and established an antiviral state, as demonstrated by upregulation of interferon and interferon-induced genes such as myxoma resistance gene 1 (Mx1) and retinoic acid-inducing gene-I (RIG-I). Viruses released from PI cells induced higher cell-to-cell fusion than the parental virus following infection in two tumor cell lines tested, HT1080 and HeLa, and remained attenuated in chickens. Two mutations, one in the fusion (F) protein cleavage site, F117S (F 117S ), and another in hemagglutinin-neuraminidase (HN), G169R (HN 169R ), located in the second sialic acid binding region, were responsible for the hyperfusogenic phenotype. F 117S improves F protein cleavage efficiency, facilitating cell-to-cell fusion, while HN 169R possesses a multifaceted role in contributing to higher fusion, reduced receptor binding, and lower neuraminidase activity, which together result in increased fusion and reduced viral replication. Thus, establishment of persistent infection in vitro involves viral genetic changes that facilitate efficient viral spread from cell to cell as a potential mechanism to escape host antiviral responses. The results of our study also demonstrate a critical role in the viral life cycle for the second receptor binding region of the HN protein, which is conserved in several paramyxoviruses.IMPORTANCE Oncolytic Newcastle disease virus (NDV) could establish persistent infection in a tumor cell line, resulting in a steady antiviral state reflected by constitutively expressed interferon. Viruses isolated from persistently infected cells are highly fusogenic, and this phenotype has been mapped to two mutations, one each in the fusion (F) and hemagglutinin-neuraminidase (HN) proteins. The F 117S mutation in the F protein cleavage site improved F protein cleavage efficiency while the HN 169R mutation located at the second receptor binding site of the HN protein contributed to a complex phenotype consisting of a modest increase in fusion and cell killing, lower neuraminidase activity, and reduced viral growth. This study highlights the intricate nature of these two mutations in the glycoproteins of NDV in the establishment of persistent infection. The data also shed light on the critical balance between the F and HN proteins required for efficient NDV infection and their role in avian pathogenicity.KEYWORDS NDV, Newcastle disease virus, fusion, paramyxovirus, persistent infection

show abstract

supporting

confidence: 63%

Newcastle Disease Virus Establishes Persistent Infection in Tumor Cells In Vitro : Contribution of the Cleavage Site of Fusion Protein and Second Sialic Acid Binding Site of Hemagglutinin-Neuraminidase

Rangaswamy

Wang

Cheng

et al. 2017

J Virol

View full text Add to dashboard Cite

show abstract

“…Vesicular stomatitis virus has also been shown to gain type I IFN induction ability specifically with the presence of copy-back DI particles, suggesting that this mechanism is applicable to other pathogenic viruses (43). Similar effects remain to be studied in other paramyxoviruses of medical concern such as measles and respiratory syncytial virus, which also naturally produce DI particles (49,50). Thus, knowledge of DI particle enhancement of virus-induced DC maturation should be considered in the rational design of viral vaccines.…”

Section: Discussionmentioning

confidence: 99%

“…SeV-52 and SeV-C stocks were analyzed for their total particle titers using a HA assay based on the binding of chicken RBC to the external HN protein of SeV particles. Infectious particle quantifications (tissue culture infectious dose (TCID) 50 ) were obtained by titration in LLCMK2 cells. As shown in Table I, SeV-52 and SeV-C stocks have equivalent TCID 50 values.…”

Section: Sev-c Stocks Have a Higher Proportion Of DI Particles Than Smentioning

confidence: 99%

See 1 more Smart Citation

A Novel Role for Viral-Defective Interfering Particles in Enhancing Dendritic Cell Maturation

Yount

Kraus

Horvath

et al. 2006

The Journal of Immunology

109

152

View full text Add to dashboard Cite

Dendritic cell (DC) maturation is a crucial event in the development of adaptive immune responses that confer long-lasting protection against reinfection with the same virus. Sendai virus strain Cantell has a particularly strong ability to mature DCs independently of type I IFNs and TLR signaling, currently the best-described pathways for the induction of DC maturation. In this study, we demonstrate that defective-interfering (DI) particles present in Sendai virus-Cantell stocks are required for its robust DC maturation ability. DI particles contain incomplete genomes that are unable to replicate unless the viral polymerase is supplied by coinfection with complete virus. Accordingly, the improvement in the virus-induced maturation of DCs provided by DI particles requires standard virus coinfection and likely results from increased production of dsRNA replication intermediaries. This unique ability of DI particles to stimulate DC maturation cannot be mimicked by simply increasing the dose of standard virus. Furthermore, viruses with weak DC maturation abilities can be converted into potent DC stimulators with the addition of DI particles, supporting a potential application for DI particles as a novel natural adjuvant for viral immunizations.

show abstract

“…HMPV shares epidemiological and clinical traits with RSV causing clinical symptoms ranging from upper respiratory tract disease to severe bronchiolitis and pneumonia and may exacerbate chronic obstructive pulmonary disease (6,12,48,51,57,61,73). RSV has been shown to persist in a variety of cells and animal models (10,17,37,60,61,66,72), and infection with RSV has been shown to induce acute and chronic airway disease correlated with pulmonary function abnormalities (23,52). Since HMPV can cause persistent infection (1, 2, 32), this suggests that persistence may be a potential mechanism that could contribute to post-bronchiolitis disease.…”

Section: Discussionmentioning

confidence: 99%

Human Metapneumovirus Establishes Persistent Infection in the Lungs of Mice and Is Reactivated by Glucocorticoid Treatment

Liu

Haas

Poore

et al. 2009

J Virol

View full text Add to dashboard Cite

Human metapneumovirus (HMPV) has been identified as a worldwide agent of serious upper and lower respiratory tract infections in infants and young children. HMPV is second only to respiratory syncytial virus (RSV) as a leading cause of bronchiolitis, and, like RSV, consists of two major genotypes that cocirculate and vary among communities year to year. Children who have experienced acute HMPV infection may develop sequelae of wheezing and asthma; however, the features contributing to this pathology remain unknown. A possible mechanism for postbronchiolitis disease is that HMPV might persist in the lung providing a stimulus that could contribute to wheezing and asthma. Using immunohistochemistry to identify HMPV-infected cells in the lungs of mice, we show that HMPV mediates biphasic replication in respiratory epithelial cells then infection migrates to neuronal processes that innervate the lungs where the virus persists with no detectable infection in epithelial cells. After glucocorticoid treatment, the virus is reactivated from neural fibers and reinfects epithelial cells. The findings show that HMPV persists in neural fibers and suggest a mechanism for disease chronicity that has important implications for HMPV disease intervention strategies.Human metapneumovirus (HMPV), a recently recognized paramyxovirus in the Pneumovirus genus, was first isolated in 2001 from nasopharyngeal aspirates of young children with respiratory disease (73). HMPV is a ubiquitous and important respiratory pathogen causing upper and lower respiratory tract disease in infants and young children, but infection may also cause disease in the elderly and immunocompromised (15, 26, 38, 45,73,75). It is recognized that severe respiratory viral infections in childhood are associated with the development of asthma later in life (47), and HMPV disease has been implicated as a trigger for bronchiolitis and asthma in infants and young children (38, 45). These features related to HMPV infection can be severe with prolonged recovery times, a feature that is not well understood.HMPV replication initiates in the upper respiratory tract; however, it can spread to the lower airways involving the bronchi, bronchioles, and alveoli. Evidence from experimental infection in cynomolgus macaques indicates that HMPV replication is short-lived and limited to the apical surface of ciliated respiratory epithelial cells (42). However, the various cell types that may be susceptible to HMPV infection are not completely understood. The HMPV G protein is considered to be the principal means for virus attachment to host cells, and F protein is required for penetration mediated by fusion with the plasma membrane (11, 59). Penetration requires proteolytic cleavage of the F protein, incorporation of the viral envelope into the cell membrane, nucleocapsid release into the cytoplasm, and L protein initiation of viral transcription where replication proceeds in the cytoplasm without nuclear involvement (11,59). Virions assemble at the plasma membrane, where inclusion bod...

show abstract

Establishment of Respiratory Syncytial Virus Persistence in Cell Lines: Association with Defective Interfering Particles

Cited by 33 publications

References 17 publications

Newcastle Disease Virus Establishes Persistent Infection in Tumor Cells In Vitro : Contribution of the Cleavage Site of Fusion Protein and Second Sialic Acid Binding Site of Hemagglutinin-Neuraminidase

Newcastle Disease Virus Establishes Persistent Infection in Tumor Cells In Vitro : Contribution of the Cleavage Site of Fusion Protein and Second Sialic Acid Binding Site of Hemagglutinin-Neuraminidase

A Novel Role for Viral-Defective Interfering Particles in Enhancing Dendritic Cell Maturation

Human Metapneumovirus Establishes Persistent Infection in the Lungs of Mice and Is Reactivated by Glucocorticoid Treatment

Contact Info

Product

Resources

About