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PubMed1996

Strain-specific reverse transcriptase PCR assay: means to distinguish candidate vaccine from wild-type strains of respiratory syncytial virus.

Candidate live-virus vaccines for respiratory syncytial virus are being developed and are beginning to be evaluated in clinical trials. To distinguish candidate vaccine strains from wild-type strains isolated during these trials, we developed PCR assays specific to two sets of candidate vaccine strains. The two sets were a group A strain (3A), its three attenuated, temperature-sensitive variant strains, a group B strain (2B), and its four attenuated, temperature-sensitive variant strains. The PCR assays were evaluated by testing 18 group A wild-type strains, the 3A strains, 9 group B wild-type strains, and the 2B strains. PCR specific to group A wild-type strains amplified only group A wild-type strains, and 3A-specific PCR amplified only 3A strains. PCR specific to group B wild-type strains amplified all group A and group B strains but gave a 688-bp product for group B wild-type strains, a 279-bp product for 2B strains, a 547-bp product for all group A strains, and an additional 688-bp product for some group A strains, including 3A strains. These types of PCR assays can, in conjunction with other methods, be used to efficiently distinguish candidate vaccine strains from other respiratory syncytial virus strains.

Base Sequence↗
PubMed1996

Differential diagnoses of influenza A virus, influenza B virus, and respiratory syncytial virus infections by direct immunofluorescence using mixtures of monoclonal antibodies of different isotypes.

Differences between isotypes of monoclonal antibodies were employed to detect influenza A and B viruses and respiratory syncytial virus by direct immunofluorescence using fluorescein isothiocyanate or Texas Red conjugates. Examination of 56 specimens for influenza A and B viruses and 112 specimens for influenza A virus and respiratory syncytial virus showed the mixed-isotype test to be comparable to the conventional procedure.

Antibodies, Monoclonal↗
PubMed1998

Baculovirus expression of the fusion protein gene of bovine respiratory syncytial virus and utility of the recombinant protein in a diagnostic enzyme immunoassay.

The fusion (F) protein of bovine respiratory syncytial virus (BRSV) was expressed by using a baculovirus vector. Antigenicity was tested by immunofluorescence analysis with F-specific monoclonal and polyclonal antibodies. Antibodies to recombinant F protein raised in a rabbit neutralized BRSV and human respiratory syncytial virus infectivity when tested in a plaque reduction assay. The recombinant F protein was evaluated as a source of antigen in an enzyme-linked immunosorbent assay (ELISA), and this ELISA was compared with the virus neutralization (VN) test for detecting BRSV antibodies in 10 consecutive serum samples from four calves vaccinated with a live modified BRSV vaccine and from two nonvaccinated control calves. The ELISA with the baculovirus-expressed F protein as an antigen compared favorably with the VN test and is a rapid, sensitive, and specific method for detecting serum antibodies to BRSV.

Animals↗
PubMed2000

Extensive sequence divergence among bovine respiratory syncytial viruses isolated during recurrent outbreaks in closed herds.

The nucleotides coding for the extracellular part of the G glycoprotein and the full SH protein of bovine respiratory syncytial virus (BRSV) were sequenced from viruses isolated from numerous outbreaks of BRSV infection. The isolates included viruses isolated from the same herd (closed dairy farms and veal calf production units) in different years and from all confirmed outbreaks in Denmark within a short period. The results showed that identical viruses were isolated within a herd during outbreaks and that viruses from recurrent infections varied by up to 11% in sequence even in closed herds. It is possible that a quasispecies variant swarm of BRSV persisted in some of the calves in each herd and that a new and different highly fit virus type (master and consensus sequence) became dominant and spread from a single animal in connection with each new outbreak. Based on the high level of diversity, however, the most likely explanation was that BRSV was (re)introduced into the herd prior to each new outbreak. These findings are highly relevant for the understanding of the transmission patterns of BRSV among calves and human respiratory syncytial virus among humans.

Animals↗
PubMed2006

C5 modulates airway hyperreactivity and pulmonary eosinophilia during enhanced respiratory syncytial virus disease by decreasing C3a receptor expression.

Enhanced respiratory syncytial virus disease, a serious pulmonary disorder that affected recipients of an inactivated vaccine against respiratory syncytial virus in the 1960s, has delayed the development of vaccines against the virus. The enhanced disease was characterized by immune complex-mediated airway hyperreactivity and a severe pneumonia associated with pulmonary eosinophilia. In this paper, we show that complement factors contribute to enhanced-disease phenotypes. Mice with a targeted disruption of complement component C5 affected by the enhanced disease displayed enhanced airway reactivity, lung eosinophilia, and mucus production compared to wild-type mice and C5-deficient mice reconstituted with C5. C3aR expression in bronchial epithelial and smooth muscle cells in the lungs of C5-deficient mice was enhanced compared to that in wild-type and reconstituted rodents. Treatment of C5-deficient mice with a C3aR antagonist significantly attenuated airway reactivity, eosinophilia, and mucus production. These results indicate that C5 plays a crucial role in modulating the enhanced-disease phenotype, by affecting expression of C3aR in the lungs. These findings reveal a novel autoregulatory mechanism for the complement cascade that affects the innate and adaptive immune responses.

Animals↗
PubMed1994

Oligo(A) sequences of human respiratory syncytial virus G protein gene: assessment of their genetic stability in frameshift mutants.

We have described previously antibody-resistant mutants of the human respiratory syncytial virus Long strain that contained frameshift changes generated by deletions or insertions of a single adenosine in oligo(A) tracts (mRNA sense) of the G protein gene. Since these mutations introduced drastic structural and antigenic changes in the G protein C-terminal third, we decided to test the mutant stability by passaging the viruses in either the presence or the absence of selective antibody. Two such mutants (R63/1/2/3 and R63/2/4/8), with a single reading frame shift, reverted after a few passages in the absence of antibody to the wild-type genotype, by insertion of an A at the same homopolymeric tract as in the original deletion. In contrast, a double frameshift mutant (R63/2/4/1), generated by deletion of an A after nucleotide 623 and insertion of another A seven triplets later, was stably maintained after passage in either the absence or the presence of antibody. The stability of this mutant was manifested in its capacity to gradually displace the Long strain from mixed infections and by the fact that mutant R63/2/4/8 acquired the genotype of R63/2/4/1 after several passages in the presence of antibody. These results were indicative of genetic instability in the oligo(A) tract length of certain G protein mutants, which resulted in frameshift changes. The frequency of such errors among the viral RNA population obtained from a single infectious cycle was estimated to be lower than 1%. The relevance of these results for respiratory syncytial virus evolution is discussed.

Antibodies, Monoclonal↗
PubMed1999

Generation of bovine respiratory syncytial virus (BRSV) from cDNA: BRSV NS2 is not essential for virus replication in tissue culture, and the human RSV leader region acts as a functional BRSV genome promoter.

In order to generate recombinant bovine respiratory syncytial virus (BRSV), the genome of BRSV strain A51908, variant ATue51908, was cloned as cDNA. We provide here the sequence of the BRSV genome ends and of the entire L gene. This completes the sequence of the BRSV genome, which comprises a total of 15,140 nucleotides. To establish a vaccinia virus-free recovery system, a BHK-derived cell line stably expressing T7 RNA polymerase was generated (BSR T7/5). Recombinant BRSV was reproducibly recovered from cDNA constructs after T7 RNA polymerase-driven expression of antigenome sense RNA and of BRSV N, P, M2, and L proteins from transfected plasmids. Chimeric viruses in which the BRSV leader region was replaced by the human respiratory syncytial virus (HRSV) leader region replicated in cell culture as efficiently as their nonchimeric counterparts, demonstrating that all cis-acting sequences of the HRSV promoter are faithfully recognized by the BRSV polymerase complex. In addition, we report the successful recovery of a BRSV mutant lacking the complete NS2 gene, which encodes a nonstructural protein of unknown function. The NS2-deficient BRSV replicated autonomously and could be passaged, demonstrating that NS2 is not essential for virus replication in cell culture. However, growth of the mutant was considerably slower than and final infectious titers were reduced by a factor of at least 10 compared to wild-type BRSV, indicating that NS2 provides a supporting factor required for full replication capacity.

5' Untranslated Regions↗
PubMed2002

Respiratory syncytial virus fusion protein mediates inhibition of mitogen-induced T-cell proliferation by contact.

Human respiratory syncytial virus (HRSV) and bovine respiratory syncytial virus (BRSV) are major pathogens in infants and calves, respectively. Experimental BRSV infection of calves and lambs is associated with lymphopenia and a reduction in responsiveness of peripheral blood lymphocytes (PBLs) to mitogens ex vivo. In this report, we show that in vitro mitogen-induced proliferation of PBLs is inhibited after contact with RSV-infected and UV-inactivated cells or with cells expressing RSV envelope proteins on the cell surface. The protein responsible was identified as the RSV fusion protein (F), as cells infected with a recombinant RSV expressing F as the single envelope protein or cells transfected with a plasmid encoding F were able to induce this effect. Thus, direct contact with RSV F is necessary and sufficient to inhibit proliferation of PBLs. Interestingly, F derived from HRSV was more efficient in inhibiting human PBL proliferation, while F from BRSV was more efficient in inhibiting bovine PBLs. Since various T-cell activation markers were upregulated after presenter cell contact, T lymphocytes are viable and may still be activated by mitogen. However, a significant fraction of PBLs were delayed or defective in G0/G1 to S-phase transit.

Animals↗
PubMed2000

Interstitial pneumonia in feedlot cattle: concurrent lesions and lack of immunohistochemical evidence for bovine respiratory syncytial virus infection.

The objectives of this study were to describe the nature and distribution of microscopic lung lesions in feedlot cattle with interstitial pneumonia and to determine whether bovine respiratory syncytial virus (BRSV) antigen was present in affected lungs. Lungs with macroscopic lesions compatible with interstitial pneumonia were collected from cattle from 5 west-central Saskatchewan feedlots that had been on feed for greater than 60 days at the time of death. Interstitial pneumonia was most consistently present in dorsal portions of caudal lung lobes and in 21/28 cases (75%) had a multifocal to coalescing distribution. All 28 lungs exhibited hyaline membrane formation and some degree of type II alveolar epithelial cell hyperplasia, consistent with an acute to subacute duration. Twenty-one of 28 cases (75%) had concurrent bronchopneumonia in at least 1 lung lobe; bronchopneumonia was grossly evident in 9/28 cases (32%). Chronic bronchitis or bronchiolitis was present in at least 1 section in 12/28 (43%) of the lungs, and 25/28 (89%) had at least 1 focus of bronchiolitis fibrosa obliterans. Bronchopneumonia and bronchiolitis fibrosa obliterans were markedly less common in 10 sets of bovine lungs obtained from an abattoir. Bovine respiratory syncytial virus antigen was demonstrated using immunohistochemistry in 2/28 cases and was associated with bronchiolar epithelial necrosis that was more severe than the bronchiolar lesions in the BRSV antigen-negative cases. Interstitial pneumonia in feedlot cattle in this study was more frequently associated with suppurative bronchopneumonia and bronchiolitis fibrosa obliterans than with BRSV infection.

Animal Feed↗
PubMed2001

The ovine respiratory syncytial virus F gene sequence and its diagnostic application.

Ruminant respiratory syncytial viruses (RSVs) are classified into 2 subgroups, ovine RSV and bovine RSV. Although ovine RSV infects cattle, its contribution to bovine respiratory tract disease has not been established, which is an important issue for vaccine development in cattle. Diagnosis by virus isolation or serology has low or variable sensitivity and/or specificity and polymerase chain reaction (PCR) has been recommended as a rapid and sensitive technique for RSV detection. A simple procedure has been developed to detect and identify bovine and ovine RSVs. First, the nucleotide sequence of the ovine RSV fusion (F) gene was determined and compared with representative strains of bovine RSV and human RSV subgroups A and B. The ovine RSV F gene has 85 and 72-73% nucleotide identity with those of bovine RSV and human RSV, respectively. The predicted amino acid sequence of the ovine RSV F gene has 94 and 83-84% amino acid identity with those of bovine RSV and human RSV, respectively. Then PCR primers targeting a specific F gene fragment of bovine and ovine RSV were designed. The primers represented bases 85-103 and the complementary sequence to bases 510-493 of the ovine RSV F gene. A similar PCR product (426 bp) was obtained on agarose gel electrophoresis from bovine RSV and from ovine RSV. The products, however, were unique to the parent virus and could be distinguished by EcoRI or MspI restriction endonuclease cleavage. EcoRI cleaved the ovine product into 2 bands (285 and 141 bp) but failed to affect the bovine RSV PCR product. However, MspI cleaved the bovine product into 2 bands (229 and 197 bp) but had no effect on the ovine product. Also, this assay did not amplify any PCR product with human RSV. The reverse transcription-polymerase chain reaction (RT-PCR) followed by restriction enzyme digestion is a useful and practical approach for detection and differentiation of ruminant respiratory syncytial viruses.

Animals↗
PubMed1999

Cost-effectiveness of respiratory syncytial virus prophylaxis among preterm infants.

OBJECTIVES: To evaluate the costs and benefits of two new agents, respiratory syncytial virus immune globulin (RSVIG) and palivizumab, to prevent respiratory syncytial virus (RSV) infection among premature infants discharged from the neonatal intensive care unit (NICU) before the start of the RSV season. Method. Decision analysis was used to compare the projected societal cost-effectiveness of three strategies-RSVIG, palivizumab, and no prophylaxis-among a hypothetical cohort of premature infants. Probabilities and costs of hospitalization were derived from a cohort of 1721 premature infants discharged from six Kaiser Permanente-Northern California NICUs. Efficacies of prophylaxis were based on published trials. Costs of prophylaxis were derived from published sources. Mortality among infants hospitalized for RSV was assumed to be 1.2%. Future benefits were discounted at 3%. RESULTS: Palivizumab was both more effective and less costly than RSVIG. Cost-effectiveness varied widely by subgroup. Palivizumab appeared most cost-effective for infants whose gestational age was </=32 weeks, who required >/=28 days of oxygen in the NICU, and who were discharged from the NICU from September through November. In this subgroup, palivizumab was predicted to cost $12,000 per hospitalization averted (after taking into account savings from prevention of RSV admissions) or $33,000 per life-year saved, and the number needed to treat to avoid one hospitalization was estimated at 7.4. However, for all other subgroups, ratios ranged from $39,000 to $420,000 per hospitalization averted or $110,000 to $1,200,000 per life-year saved, and the number needed to treat extended from 15 to 152. The results were sensitive to varying assumptions about the cost and efficacy of prophylaxis, as well as the probability of hospitalization, but were less sensitive to the cost of hospitalization. CONCLUSION: In our model, the cost of prophylaxis against RSV for most subgroups of preterm infants was high relative to the benefits realized. Lower costs might permit the benefits of prophylaxis to be extended to additional groups of preterm infants.

Antibodies, Monoclonal↗
PubMed2000

Respiratory syncytial virus infection in patients with phagocyte defects.

Patients with phagocyte defects frequently develop bacterial or fungal pneumonias, but they are not considered to be at increased risk for viral infections. We describe 3 patients with known phagocyte immunodeficiencies who developed lower respiratory tract infections (LRTI) caused by respiratory syncytial virus (RSV). All 3 patients had dense pneumonias as indicated by computed tomography scan of the lungs and RSV was recovered. We conclude that RSV can present as a dense pneumonia in patients with phagocyte defects. Along with common pathogens causing LRTI, RSV should be considered in the differential diagnosis. Viral cultures as well as rapid antigen detection assays for respiratory viruses should be included in the evaluation of LRTI in patients with phagocyte defects. respiratory syncytial virus, phagocyte, immunodeficiency, pneumonia.

Child↗
PubMed2004

In search of a small-molecule inhibitor for respiratory syncytial virus.

Respiratory syncytial virus has been an ongoing health problem for 50 years. Hospitalization rates due to virus-induced respiratory illness continue to be substantial for infants, small children, the elderly and the immunocompromised. The only currently available treatments are a broad-spectrum antiviral and two immunoprophylactic antibodies, all of which are reserved for high-risk patients. The combination of this limited therapeutic repertoire and the lack of a vaccine clearly demonstrates the need to continue the search for more efficacious and safe agents against respiratory syncytial virus. The following is a review on the current progress of that search.

Animals↗
PubMed2005

Clinical-epidemiological evaluation of respiratory syncytial virus infection in children attended in a public hospital in midwestern Brazil.

UNLABELLED: Respiratory syncytial virus (RSV) is responsible for annual respiratory infection outbreaks in infants and young children worldwide, frequently causing bronchiolitis and pneumonia. We evaluated clinical and epidemiological features of acute respiratory infections (ARIs) caused by respiratory syncytial virus (RSV) in children less than five years old. Nasopharyngeal aspirate samples from children with ARI symptoms, attended at the 'Hospital das Clínicas'--Federal University of Uberlândia, MG, Brazil, were collected and tested for RSV by the immunofluorescence assay (IFA). Patients' clinical and epidemiological data were also obtained. From April 2000 to June 2003, 317 nasopharyngeal samples were collected from children less than 54 months old. Seventy-six samples (24.0%) were positive for RSV, with 53% (40/76) obtained from male patients. Hospitalization occurred in 50% (38/76) of the cases, with an average period of 10.6 days, in most cases (87%, 33/38) occurring in children less than 12 months of age. Although an association between this age group and the presentation of more severe clinical symptoms was observed, such as bronchiolitis in 51% (27/53) of the patients and pneumonia in 19% (10/53), no patients died. RSV was found from February to August, with the highest incidence in May. CONCLUSIONS: RSV is an important agent that causes ARIs; the clinical manifestations varied from mild to severe and patients frequently required hospitalization; RSV mostly affected children less than one year old.

Brazil↗
PubMed2004

Treatment of respiratory syncytial virus pneumonia in a lung transplant recipient: case report and review of the literature.

A 61-year-old woman who underwent lung transplantation developed severe respiratory syncytial virus (RSV) pneumonia and experienced respiratory failure requiring mechanical ventilation. She was treated initially with aerosolized ribavirin monotherapy; RSV hyperimmune globulin was later added to her regimen. Lung transplant recipients are acutely susceptible to respiratory infections, including community-acquired respiratory viruses. Respiratory syncytial virus is particularly difficult to treat in immunocompromised patients because of the lack of proved pharmaceutical agents and solid scientific evidence by which to guide therapy. The most important factor appears to be the early start of therapy; immunocompromised patients who develop RSV pneumonia and subsequent respiratory failure requiring mechanical ventilation have a mortality rate approaching 100%. This case report demonstrates the successful treatment of RSV pneumonia with the combination of aerosolized ribavirin and RSV hyperimmune globulin in a severely ill lung transplant recipient who required mechanical ventilation.

Antiviral Agents↗
PubMed2000

Bovine respiratory syncytial virus-specific IgE is associated with interleukin-2 and -4, and interferon-gamma expression in pulmonary lymph of experimentally infected calves.

OBJECTIVE: To study the local immune response of calves to bovine respiratory syncytial virus (BRSV) infection with emphasis on IgE production and cytokine gene expression in pulmonary lymph. ANIMALS: Twelve 6- to 8-week-old Holstein bull calves. Six similar control calves were mock infected to obtain control data. PROCEDURE: Lymphatic cannulation surgery was performed on 12 calves to create a long-term thoracic lymph fistula draining to the exterior. Cannulated calves were exposed to virulent BRSV by aerosol. Lymph fluid collected daily was assayed for BRSV and isotype-specific IgE antibody, total IgG, IgA, IgM, and protein concentrations. Interleukin-4 (IL-4), interleukin-2 (IL-2), and interferon-gamma were semi-quantitated by reverse transcription-polymerase chain reaction (RT-PCR). Cell counts and fluorescence-activated cell scanner (FACSCAN) analysis of T-cell subsets were performed on lymph cells. RESULTS: Calves had clinical signs of respiratory tract disease during days 5 to 10 after infection and shed virus. Bovine respiratory syncytial virus-specific IgE in infected calves was significantly increased over baseline on day 9 after infection. Mean virus-specific IgE concentrations strongly correlated with increases in severity of clinical disease (r = 0.903). Expression of IL-2, IL-4, and interferon-gamma was variably present in infected and control calves, with IL-4 expression most consistent during early infection. CONCLUSIONS AND CLINICAL RELEVANCE: Infection with BRSV was associated with production of BRSV-specific IgE, and IL-4 message was commonly found in lymph cells of infected calves. This finding supports the concept that BRSV-induced pathophysiology involves a T helper cell type-2 response. Effective therapeutic and prophylactic strategies could, therefore, be developed using immunomodulation to shift the immune response more toward a T helper cell type-1 response.

Animals↗
PubMed1999

Evaluation of severe disease induced by aerosol inoculation of calves with bovine respiratory syncytial virus.

OBJECTIVE: To develop a model of bovine respiratory syncytial virus (BRSV) infection that induces severe disease similar to that seen in some cattle with naturally acquired BRSV infection. ANIMALS: 25 male Holstein calves, 8 to 16 weeks old. PROCEDURE: 17 calves were given a low-passage field isolate of BRSV by aerosolization; 8 control calves were given supernatant from noninfected cell culture. Disease was characterized by evaluating clinical signs, virus isolation and pulmonary function tests, and results of blood gas analysis, gross and histologic postmortem examination, and microbiologic testing. RESULTS: Cumulative incidence of cough, harsh lung sounds, adventitious sounds, and dyspnea and increases in rectal temperature and respiratory rate were significantly greater in infected calves. Three infected calves developed extreme respiratory distress and were euthanatized 7 days after inoculation. Virus was isolated from nasal swab specimens from all infected calves but not from mock infected calves. On day 7 after inoculation, mean PaO2 and PaCO2 were significantly lower, and pulmonary resistance was significantly higher, in infected calves. During necropsy, infected calves had varying degrees of necrotizing and proliferative bronchiolitis and alveolitis with syncytial formation. The 3 calves euthanatized on day 7 had emphysematous bullae in the caudal lung lobes; 1 had unilateral pneumothorax. CONCLUSION AND CLINICAL RELEVANCE: Severe disease similar to that seen in some cattle with naturally acquired BRSV infection can be induced in calves with a single aerosol exposure of a low-passage clinical isolate of BRSV. Our model will be useful for studying the pathogenesis of BRSV infection and for evaluating vaccines and therapeutics.

Aerosols↗
PubMed1999

The epidemiology of respiratory syncytial virus (RSV) infections in South African children.

OBJECTIVES: To review the incidence, outcomes and risk factors associated with respiratory syncytial virus (RSV) infection in South African children. DESIGN: Review of published literature and laboratory records. METHODS: Review of the published literature. Articles listed on MEDLINE with 'South African' or 'children' and 'respiratory syncytial virus' or 'acute respiratory tract infections' as text words were retrieved. We analysed the data on respiratory virus activity from January 1990 to June 1996. Data were obtained from the National Institute for Virology database, which includes information on viral respiratory infections from the seven academic virology departments in South Africa. RESULTS: Acute respiratory tract infections cause approximately 8% of all deaths in the under-5 age group in South Africa. The published hospital-based incidence of RSV infection varies from 3% to 18%. Mortality rates in these studies were between 12% and 43%. Risk factors identified for severe RSV infection requiring hospitalisation were malnutrition, prematurity, age < 6 months, vitamin A deficiency, environmental pollution and congenital heart disease. There is a seasonal peak in RSV cases, with the majority occurring in winter. CONCLUSIONS: Acute respiratory tract infections and RSV infections are an important cause of mortality and morbidity in young children in South Africa. However, currently available information from laboratory records and published South African literature is not sufficient to assess the impact of this infection. Age-specific incidence data in the 0-5-year age group are essential for the rational planning and implementation of future vaccine strategies, public health interventions and treatment of RSV infections.

Age Distribution↗