Enhanced pulmonary histopathology is observed in cotton rats immunized with formalin-inactivated respiratory syncytial virus (RSV) or purified F glycoprotein and challenged with RSV 3–6 months after immunization

Murphy, Brian R.; Sotnikov, Alex V.; Lawrence, Lisa; Banks, Steven M.; Prince, Gregory A.

doi:10.1016/0264-410x(90)90253-i

Cited by 258 publications

(210 citation statements)

References 16 publications

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“…Although formalin-inactivated RSV vaccines and subunit vaccines based on the G and F viral glycoproteins were associated in several past trials with disease enhancement (43)(44)(45)(46), live attenuated vaccine candidates tested to date were-although safe in infants-poorly immunogenic, reflected by insufficient neutralizing antibody titers (47). Antiviral therapeutics may ameliorate disease in high-risk pediatric patients and possibly the elderly, especially because viral load in the early phase of clinical disease was found predictive for the severity of disease progression and the risk of life-threatening complications (16,17).…”

Section: Discussionmentioning

confidence: 99%

Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors

Yan

Lee

Thakkar

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

109

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Respiratory syncytial virus (RSV) is a leading pediatric pathogen that is responsible for a majority of infant hospitalizations due to viral disease. Despite its clinical importance, no vaccine prophylaxis against RSV disease or effective antiviral therapeutic is available. In this study, we established a robust high-throughput drug screening protocol by using a recombinant RSV reporter virus to expand the pool of RSV inhibitor candidates. Mechanistic characterization revealed that a potent newly identified inhibitor class blocks viral entry through specific targeting of the RSV fusion (F) protein. Resistance against this class was induced and revealed overlapping hotspots with diverse, previously identified RSV entry blockers at different stages of preclinical and clinical development. A structural and biochemical assessment of the mechanism of unique, broad RSV cross-resistance against structurally distinct entry inhibitors demonstrated that individual escape hotspots are located in immediate physical proximity in the metastable conformation of RSV F and that the resistance mutations lower the barrier for prefusion F triggering, resulting in an accelerated RSV entry kinetics. One resistant RSV recombinant remained fully pathogenic in a mouse model of RSV infection. By identifying molecular determinants governing the RSV entry machinery, this study spotlights a molecular mechanism of broad RSV resistance against entry inhibition that may affect the impact of diverse viral entry inhibitors presently considered for clinical use and outlines a proactive design for future RSV drug discovery campaigns.antiviral drugs | drug resistance

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Section: Discussionmentioning

confidence: 99%

Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors

Yan

Lee

Thakkar

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

109

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“…Virus was released from harvested cells by rapid freeze-thaw, which was repeated three times. Recovered RSV was quantified by plaque assay as described (25). Virus titers from vaccinia virus-infected cells were quantified by plaque assay on BSC-40 cell monolayers at 37°C as described; staining with crystal violet allowed for visualization of plaques (26).…”

Section: Methodsmentioning

confidence: 99%

Apical recycling systems regulate directional budding of respiratory syncytial virus from polarized epithelial cells

Brock

Goldenring

Crowe

2003

Proc. Natl. Acad. Sci. U.S.A.

107

114

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Respiratory syncytial virus (RSV) is the major viral cause of serious lower respiratory tract illness in infants and young children worldwide. RSV infection is limited to the superficial layers of the respiratory epithelium in immunocompetent individuals. Consistent with this in vivo observation, we and others have found that RSV buds preferentially from the apical surface of infected polarized epithelial cells. In contrast, directional budding is not observed in nonpolarized human epithelial cells. These findings suggest that RSV uses specific cellular trafficking pathways to accomplish viral replication. The host cell proteins that regulate directional budding of RSV are undefined. Apical sorting of cellular proteins in polarized epithelial cells involves the apical recycling endosome (ARE). To investigate whether ARE-mediated protein sorting plays a role during RSV replication, we expressed a fragment of the myosin Vb tail that functions as a dominant negative inhibitor of ARE-mediated protein sorting in polarized Madin-Darby canine kidney cells. When these cells were infected with RSV, a >9,000-fold reduction in viral yield was observed. A similar effect on virus replication was observed when a carboxyl-terminal fragment of another AREassociated protein, the Rab11 family interacting protein 1, was expressed in Madin-Darby canine kidney cells. These data suggest that RSV requires proper ARE-mediated protein sorting for efficient egress from the apical surface of polarized epithelial cells.

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“…Serum IgG Abs binding to RSV F surface glycoprotein were quantitated in an ELISA using F glycoprotein that had been immunoaffinity-purified from RSV subgroup A (Long strain)-infected cell lysates as described (19,27). The neutralizing Ab titer of serum samples was determined by a complement-enhanced 60% plaque reduction assay in HEp-2 cells (28); plaques were visualized using the RSV-specific immunohistological staining procedure (26). Neutralizing Ab titers were expressed as the reciprocal of the highest Ab (or serum) dilutions that yielded a 60% reduction in PFU as compared with the control wells.…”

Section: Immunological Studiesmentioning

confidence: 99%

Passively Acquired Antibodies Suppress Humoral But Not Cell-Mediated Immunity in Mice Immunized with Live Attenuated Respiratory Syncytial Virus Vaccines

Crowe

Firestone

Murphy

2001

The Journal of Immunology

Self Cite

101

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A respiratory syncytial virus (RSV) vaccine will need to be administered by 1 mo of age to protect young infants; therefore, it will need to be effective in the presence of maternally acquired RSV Abs. In the present study, the immunogenicity and efficacy of two live attenuated RSV vaccine candidates of different level of attenuation were evaluated in mice passively immunized with varying quantities of RSV Abs. The replication of the RSV vaccines was suppressed in the lower, but not the upper, respiratory tract of the passively immunized mice. Immunization with either vaccine candidate was highly efficacious against challenge with wild-type RSV in both passively immunized and control mice. Nonetheless, a high level of immunity was seen even in passively/actively immunized animals that failed to develop a humoral immune response, suggesting that T cells mediated the immunity. Depletion of CD4+ and CD8+ T cells in passively/actively immunized and control animals at the time of challenge with wild-type RSV demonstrated that CD4+ and CD8+ T cells made significant independent contributions to the restriction of replication of RSV challenge virus in both the upper and lower respiratory tracts. Although passively acquired serum RSV Abs suppressed the primary systemic and mucosal Ab responses of IgM, IgG, and IgA isotypes, B lymphocytes were nevertheless primed for robust secondary Ab responses. Thus, immunity mediated by CD4+ and CD8+ T cells and Abs can be readily induced in mice by live RSV vaccine candidates in the presence of physiologic levels of RSV neutralizing Abs.

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Enhanced pulmonary histopathology is observed in cotton rats immunized with formalin-inactivated respiratory syncytial virus (RSV) or purified F glycoprotein and challenged with RSV 3–6 months after immunization

Cited by 258 publications

References 16 publications

Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors

Cross-resistance mechanism of respiratory syncytial virus against structurally diverse entry inhibitors

Apical recycling systems regulate directional budding of respiratory syncytial virus from polarized epithelial cells

Passively Acquired Antibodies Suppress Humoral But Not Cell-Mediated Immunity in Mice Immunized with Live Attenuated Respiratory Syncytial Virus Vaccines

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