The Interferon Antagonist NS2 Protein of Respiratory Syncytial Virus Is an Important Virulence Determinant for Humans

Johns Hopkins University, Baltimore, Maryland, United States
The Journal of Infectious Diseases (Impact Factor: 6). 03/2006; 193(4):573-81. DOI: 10.1086/499600
Source: PubMed


Respiratory syncytial virus (RSV) is targeted for vaccine development, because it causes severe respiratory tract illness in the elderly, young children, and infants. A primary strategy has been to derive live attenuated viruses for use in intranasally administered vaccines that will induce a protective immune response. In the present study, the NS2 gene, whose encoded protein antagonizes the host's interferon- alpha / beta response, was deleted from RSV vaccine candidates by use of reverse genetics.
Three NS2 gene-deleted RSV vaccine candidates were studied: rA2cp Delta NS2, rA2cp248/404 Delta NS2, and rA2cp530/1009 Delta NS2. rA2cp Delta NS2, which had the fewest attenuating mutations, was evaluated in adults and RSV-seropositive children. rA2cp248/404 Delta NS2 and rA2cp530/1009 Delta NS2 were evaluated in adults and RSV-seropositive and RSV-seronegative children.
At a high dose (10(7.0) pfu), rA2cp Delta NS2 was not shed by adults, and only 13% of them had an immune response. The other vaccine candidates, rA2cp248/404 Delta NS2 and rA2cp530/1009 Delta NS2, had greatly decreased infectivity in RSV-seronegative children, compared with that of their immediate parent strains, which possess an intact NS2 gene.
Deletion of the NS2 gene attenuates RSV in subjects of all ages studied. This validates the strategy of developing live respiratory tract virus vaccines in which the virus's ability to inhibit the human innate immune system is blocked. rA2cp248/404 Delta NS2 should be studied in children at a higher input titer, because it was more infectious and immunogenic than was rA2cp530/1009 Delta NS2.

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    • "It also promoted SOCS1 expression, which could result in a bias in the Th1/Th2 ratio indirectly correlated with pathogenesis. Deletion of the gene encoding NS2 attenuates its activity, and our results support the strategy of developing live respiratory tract virus vaccines in which the ability to inhibit the human innate immune system is blocked (Wright et al., 2006). Overexpression of RSV NS1, but not NS2, impairs glucocorticoid-induced transactivation . "
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    ABSTRACT: Respiratory syncytial virus (RSV) nonstructural (NS) proteins 1 and 2 have multiple functions in suppressing the innate immune response and modulating T helper cell subset differentiation. However, little is known about the roles of NS proteins as independent virulence factors. We investigated the effects of recombinant NS1- and NS2-expressing plasmids on the pathogenesis of murine respiratory tissues and splenetic Foxp3+ regulatory T (Treg) cell distribution. Both NS proteins caused weight loss in mice, and NS2 transfection resulted in a persistent weight loss. NS1 dramatically suppressed the induction of interferon beta and interferon-induced GTP-binding protein Mx1. NS1 and NS2 demonstrated different effects in regulating Treg cell differentiation; NS2 increased the proportion of Tregs, whereas NS1 suppressed it. Inhibiting either NS1 or NS2 alleviated the pathology of lung tissues. Thus, NS1 and NS2 are independent pathogenic factors and could be targets for therapeutic strategies in treating RSV infection. Copyright © 2015 Elsevier Inc. All rights reserved.
    Virology 08/2015; 485:223-232. DOI:10.1016/j.virol.2015.07.016 · 3.32 Impact Factor
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    • ", temperature - sensitive RSV vaccine candidates that were primarily targeted for use in young infants were shown to induce inadequate protection , being under - or over - attenuated in a variety of animal models ( Crowe et al . , 1994 ; Crowe et al . , 1993 ; Piedra et al . , 1996 ) or infants or sero - negative children ( Karron et al . , 2005 ; Wright et al . , 2006 ) . Other RSV vaccine approaches include recombinant viral vectors , including vaccinia virus ( Olmsted et al . , 1986 ; Wyatt et al . , 1999 ) , bovine / human parainfluenza virus type 3 ( Haller et al . , 2003 ; Liang et al . , 2014 ) , and adenovirus ( Hsu et al . , 1992 ) . Although some of these vaccines showed promising preclinica"
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    ABSTRACT: Respiratory syncytial virus (RSV) is the leading cause of viral bronchiolitis in both children and the elderly. There is no vaccine available for the prevention of RSV infection. Here, we generated recombinant influenza virus (PR8/RSV.HA-F) expressing an RSV F243-294 neutralizing epitope in the hemagglutinin (HA) as a chimeric protein. Neutralizing antibodies specific for both RSV and influenza virus were induced by a single intranasal immunization of mice with PR8/RSV.HA-F. Mice that were immunized with PR8/RSV.HA-F were protected against RSV infection comparable with live RSV as evidenced by significant reduction of RSV lung viral loads, as well as the absence of lung eosinophilia and RSV-specific cellular immune responses. In contrast, formalin-inactivated RSV-immunized mice showed severe disease and high cellular immune responses in lungs after RSV infection. These findings support a concept that recombinant influenza virus carrying the RSV F243-294 neutralizing epitope can be developed as a promising RSV vaccine candidate which induces protective neutralizing antibodies but avoids lung immunopathology. Copyright © 2014 Elsevier B.V. All rights reserved.
    Antiviral Research 12/2014; 115. DOI:10.1016/j.antiviral.2014.12.009 · 3.94 Impact Factor
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    • "To date there is no vaccine for RSV and early attempts with a formalin-inactivated vaccine proved fatal. Interestingly, viruses deleted in NS1 and/or NS2 are novel candidates for vaccine development (Wright et al., 2006). Although this is primarily due to their limited virulence it is possible that the loss of the glucocorticoid suppressive action may also help in the production of a useful vaccine. "
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    ABSTRACT: Respiratory syncytial virus (RSV)-induced bronchiolitis in infants is not responsive to glucocorticoids. We have shown that RSV infection impairs glucocorticoid receptor (GR) function. In this study, we have investigated the mechanism by which RSV impairs GR function. We have shown that RSV repression of GR-induced transactivation is not mediated through a soluble autocrine factor. Knock-down of mitochondrial antiviral signaling protein (MAVS), but not retinoic acid-inducible gene 1 (RIG-I) or myeloid differentiation primary response gene 88 (MyD88), impairs GR-mediated gene activation even in mock-infected cells. Over-expression of the RSV nonstructural protein NS1, but not NS2, impairs glucocorticoid-induced transactivation and viruses deleted in NS1 and/or NS2 are unable to repress glucocorticoid-induction of the known GR regulated gene glucocorticoid-inducible leucine zipper (GILZ). These data suggest that the RSV nonstructural proteins mediate RSV repression of GR-induced transactivation and that inhibition of the nonstructural proteins may be a viable target for therapy against RSV-related disease.
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