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PubMed1986

Characterization of four parainfluenza virus type 3 proteins by use of monoclonal antibodies.

Monoclonal antibodies directed against four structural components of the ATCC strain C243 of parainfluenza virus type 3 were produced. The specific reaction of the antibodies with individual structural components was determined by radioimmune precipitation assay. In the collection of monoclonal antibodies, 21 reacted with the haemagglutinin-neuraminidase (HN) glycoprotein (mol. wt. 72,000), eight with the fusion (F) glycoprotein (mol. wt. 64,000), 27 with the nucleocapsid (NP) protein (mol. wt. 69,000) and 24 with the matrix (M) protein (mol. wt. 40,000). The F-specific monoclonal antibodies precipitated two proteins which were interpreted to represent intact F protein and the large cleavage product F1 (mol. wt. 52,000). The numbers of epitopes were determined in a competition ELISA with the monoclonal antibodies. The epitopes found were six for the HN, two for the F, six for the NP and six for the M protein. The six groups of antibodies reacting with different epitopes on the HN molecule showed varying capacities to inhibit biological activities. Two exhibited high neutralization (NT), haemagglutination inhibition (HI) and haemolysis inhibition (HLI) activity. Three groups had somewhat lower NT, lower HI and no detectable HLI activity. One group showed no activity in these tests. Of the eight monoclonal antibodies directed to the F protein two had demonstrable HLI activity.

Antibodies, Monoclonal↗
PubMed1988

Role of individual glycoproteins of human parainfluenza virus type 3 in the induction of a protective immune response.

Affinity-purified hemagglutinin-neuraminidase (HN) and fusion (F) glycoproteins of human parainfluenza virus type 3 (P13 virus) were used to investigate their role in the induction of a protective immune response following immunization of hamsters. The efficacy of immunization with the glycoprotein antigens was tested by challenge infection. Results of virus recovery from lungs and trachea demonstrated that although immunization with HN or F alone induced an antibody response to the respective glycoproteins, it did not provide a significant level of protection. However, immunization with a mixture of both purified glycoproteins induced higher virus-neutralizing activity in bronchial lavages and afforded complete protection from challenge infection. Similarly, incomplete protection was observed after passive transfer of monospecific rabbit antibody to the purified HN or F in baby hamsters. On the other hand, passive transfer of a mixture of antibodies to HN and F conferred a higher level of protection. Thus, the presence of antibody to both glycoproteins of P13 virus may be essential for protective immunity.

Animals↗
PubMed1991

The fusion and hemagglutinin-neuraminidase glycoproteins of human parainfluenza virus 3 are both required for fusion.

Recombinant vaccinia viruses, VF and VHN, expressing the fusion (F) and hemagglutinin-neuraminidase (HN) glycoproteins of human parainfluenza virus 3 (HPIV3) were constructed. Infection of HeLa T4 cells with VF and VHN led to the synthesis of glycoproteins, with the correct apparent molecular weights, that were recognized by monoclonal antibodies specific for HPIV3F and HN. The HN glycoprotein was present on the surface of cells infected with VHN and these cells demonstrated both hemadsorbing and neuraminidase activities. The F glycoprotein was present in cleaved and uncleaved forms and was also expressed on the surface of VF-infected cells. Fusion activity, however, as evidenced by syncytium formation and lysis of human erythrocytes, could only be demonstrated when HeLa T4 cells were coinfected with VF and VHN. Fusion events that are mediated by HPIV3, therefore, require both the F and HN glycoproteins.

Antibodies, Monoclonal↗
PubMed1993

Crystals of hemagglutinin-neuraminidase of parainfluenza virus contain triple-stranded helices.

When purified dimers of hemagglutinin-neuraminidase molecules released by protease digestion from three strains of human parainfluenza virus 1 were used in crystallization trials, long thin needle crystals formed. Electron microscopic analysis of these needle crystals revealed that they are composed of stacks of triple-stranded helices with each strand of the helix made up of subunits of hemagglutinin-neuraminidase. To our knowledge, this is the first direct demonstration of the assembly of protein subunits into large triple-stranded helices. An understanding of the organization of these triple helices may shed light on the structural properties of the hemagglutinin-neuraminidase molecules that cause them to form these helices.

Crystallization↗
PubMed1992

Clinical characteristics of parainfluenza virus infection in hospitalized children.

Severity of illness and clinical characteristics of parainfluenza virus (PIV) infection were evaluated in 81 hospitalized children over a 4 year period. Fifty three patients were previously healthy and 28 had preexisting pulmonary abnormalities associated with bronchopulmonary dysplasia (BPD), congenital heart disease (CHD), asthma, or prematurity. When compared with formerly healthy children, the patients with preexisting pulmonary abnormalities were more likely to develop lower than upper respiratory tract illness (P less than 0.0001). In the lower respiratory tract infection group, patients with preexisting pulmonary abnormalities were sicker (P = 0.047), were hospitalized longer (P = 0.016), required more supplemental oxygen (P = 0.004), and were older (8.8 vs. 5.1 months) than previously healthy patients. Nosocomial infection occurred only in BPD patients. All these patients developed pneumonia. They were sicker (P = 0.0018), requiring more therapy (P = 0.0038) than other patients with preexisting pulmonary abnormalities and lower respiratory tract disease. Patients with BPD should be placed in protective isolation during PIV epidemics.

Age Factors↗
PubMed1991

Intranasal infection of ferrets (Mustela putorius furo) with canine parainfluenza virus.

Immunocompetent and cyclophosphamide-immunosuppressed ferrets were intranasally infected with canine parainfluenza virus (CPIV) and observed for clinical signs, histopathologic lesions, the immunocytochemical demonstration of CPIV antigen in the respiratory tract and scanning electron microscopic alterations of the tracheal epithelium until 36 days post infection (p.i.). In both groups, clinical signs were minimal, restricted to the upper respiratory tract and consisted of cough elicited by tracheal compression between 3 and 7 days p.i. Microscopically, inflammatory and degenerative lesions were observed in the trachea and less frequently in the nasal cavity; bronchiolitis or interstitial pneumonia was not demonstrated. By immunocytochemistry, CPIV antigen was demonstrated in tracheal epithelial cells, whereas nasal cavity, bronchi, bronchioles and lung were devoid of viral antigen. Ferrets given CPIV alone developed a minimal lymphocytic tracheitis with minimal loss of cilia and CPIV antigen was observed only 4 days p.i. 17 days p.i., normal epithelial organization and ciliary reappearance was reestablished. Ferrets treated with cyclophosphamide and infected with CPIV exhibited mild to moderate histological lesions as above with similar scanning electron microscopic changes until 36 p.i. Tracheal lesions consisted of intraepithelial and submucosal infiltration of lymphocytes and macrophages, focal epithelial hyperplasia and multifocal loss of cilia. In addition, mild and transient neutrophilic infiltration was observed. In immunosuppressed ferrets, viral antigen expression was prominent and demonstrated 4 and 8 days p.i. These data suggest that ferrets are susceptible to aerosol CPIV infection.

Animals↗
PubMed1967

Morphogenesis of type 2 parainfluenza virus examined by light and electron microscopy.

The development of type 2 parainfluenza virus in HeLa and stable human amnion cells was examined by use of antisera labeled with fluorescein and ferritin. Serum containing antibody predominantly to soluble viral antigen gave specific fluorescence which was first detectable in small cytoplasmic foci 8 to 10 hr after initiation of infection. By 20 to 24 hr, when the production of infective virus and hemagglutinin was maximal, large perinuclear aggregates of fluorescence were observed which corresponded in distribution and time of appearance to the eosinophilic inclusions seen in similar preparations stained with azure eosin. The inclusions, examined by electron microscopy, were composed of fibrils, presumably viral ribonucleoprotein, which specifically bound the antibody labeled with ferritin. With antiserum to concentrated virus, on the other hand, specific fluorescence was most marked at the surface of infected cells. Foci of fluorescence at the surface represented segments of membrane which had become differentiated morphologically and antigenically to resemble the viral envelope. These were the sites where mature virions appeared. The latter exhibited marked pleomorphism; in some instances, particles were formed which lacked recognizable internal fibrils but which possessed an enclosing membrane bearing viral antigen. Filamentous forms showing an organized internal structure were also observed at the cell surface, but were never encountered in negatively stained preparations. No clear relationship between these filaments and the spherical or oval forms could be established. In negatively stained preparations, nucleocapsid released by rupture of viral particles was similar in appearance to that reported for other paramyxoviruses. It seems probable that this component has a helical configuration.

Amnion↗
PubMed1991

In vitro cytopathogenicity and in vivo virulence of two strains of canine parainfluenza virus.

In vivo and in vitro properties of two strains of canine parainfluenza virus (CPIV) were investigated. One strain, designated CPIV(+), induced syncytial giant cell formation and cytolysis in vitro, whereas the second strain, CPIV(-), caused only a mild strand-forming cytopathic effect with few, small syncytial giant cells. Vero cells infected with CPIV(+) or CPIV(-) were 100% positive for CPIV antigen as determined by immunofluorescent staining; however, 100% of CPIV(+) and less than 10% of CPIV(-) infected cells were hemadsorption positive. Sodium dodecyl sulphate-polyacrylamide gel electrophoresis analysis revealed no differences in electrophoretic mobility of viral polypeptides between both strains; however, in CPIV(-), reduced or absent synthesis of the putative HN and F1 proteins was observed. Isopycnic separation of CPIV(+) progeny virions showed a high proportion of viral particles with a buoyant density of 1.18 g/cm3. In contrast, CPIV(-) progeny virions had a heterogeneous density profile ranging from 1.08 to 1.18 g/cm3. Intracerebral infection of six ferrets with CPIV(+) resulted in moderate lymphocytic and histiocytic choroiditis, meningitis, and ependymitis, whereas CPIV(-) infection caused only mild to moderate inflammation. Immunohistologically, CPIV antigen was prominent in ependymal lining cells of the ventricles in CPIV(+)-infected ferrets and was reduced or lacking in CPIV(-)-infected ferrets (n = 6). Sham-injected ferrets (n = 6) did not have histologic lesions and no viral antigen was identified. The present findings suggest that certain changes in the activities of CPIV glycoproteins may lead to alterations of CPIV virulence in vivo.

Animals↗
PubMed1998

Genetic characterization of parainfluenza virus 3 derived from guinea pigs.

To understand the relationship between novel parainfluenza virus 3 (PIV-3), which has recently been isolated from the lungs of guinea pigs, and other PIV-3 strains, we determined the complete nucleotide sequence of the novel PIV-3 (GPv) genome. A comparison of the nucleotide sequence among PIV-3s, including bovine PIV-3, revealed that GPv is closely related to human PIV-3. The results of the phylogenetic analysis clearly showed that GPv is a lineage of human PIV-3, suggesting that GPv has probably been introduced into guinea pig colonies via infected humans.

Animals↗
PubMed1996

Two distinct human parainfluenza virus type 1 genotypes detected during the 1991 Milwaukee epidemic.

The extent of genetic and antigenic variation found in a population of human parainfluenza virus type 1 (HPIV-1) during a single local epidemic was investigated. Fifteen HPIV-1 strains isolated from children in 1991 were analyzed. Nucleotide sequence variation in the hemagglutinin-neuraminidase protein (HN) gene demonstrated two distinct genotypes (genotypes C and D). Unique patterns were identified involving 62 nucleotide and 10 amino acid positions. These patterns represented 40% of all mutations within the HN gene. The remaining mutations were randomly distributed, and 74% involved only one (55%) or two isolates. Genotypes were statistically different from each other at both the nucleotide (P = 0.001) and amino acid (P = 0.001) levels and demonstrated unique potential N-linked glycosylation patterns. Thirty-eight monoclonal antibodies (MAbs) made to four different viral proteins (22 HN, 2 fusion [F], 1 phosphoprotein, and 13 nucleoprotein) (originating from two different genotypes [genotypes A and D]) were compared for their ability to bind to the clinical isolates in enzyme-linked immunosorbent assays (ELISAs) and hemagglutinin-inhibition (HI) assays. Twenty-one MAbs bound well to all clinical isolates in ELISAs and HI assays. The remaining 17 MAbs showed variation in all four structural proteins. Three HN MAbs demonstrated genotype C- and D-specific antigenic and neutralization differences. Evolutionary analysis using parsimony methods confirmed the differences between the two genotypes. No differences in either clinical presentation or disease severity between the two genotypes were found. Geographically localized HPIV-1 epidemics can be caused by at least two distinct genotypes with minor but specific antigenic changes. The clinical and immunologic roles of HPIV-1 genotypes have not been determined.

Amino Acid Sequence↗
PubMed2001

Human parainfluenza virus type 3 HN-receptor interaction: effect of 4-guanidino-Neu5Ac2en on a neuraminidase-deficient variant.

The envelope of human parainfluenza virus type 3 (HPF3) contains two viral glycoproteins, the hemagglutinin-neuraminidase (HN) and the fusion protein (F). HN, which is responsible for receptor attachment and for promoting F-mediated fusion, also possesses neuraminidase (receptor-destroying) activity. We reported previously that 4-guanidino-neu5Ac2en (4-GU-DANA) and related sialic acid-based inhibitors of HPF3 neuraminidase activity also inhibit HN-mediated receptor binding and fusion processes not involving neuraminidase activity. We have now examined this mechanism, as well as neuraminidase's role in the viral life cycle, using a neuraminidase-deficient HPF3 variant (C28a) and stable cell lines expressing C28a or wild-type (wt) HN. C28a, which has a wt F sequence and two point mutations in the HN gene corresponding to two amino acid changes in the HN protein, is the first HPF3 variant with insignificant neuraminidase activity. Cells expressing C28a HN did not bind erythrocytes at 4 degrees C unless pretreated with neuraminidase, but no such pretreatment was required for hemadsorption activity (HAD) at 22 or 37 degrees C. HAD was blocked by 4-GU-DANA, attesting to the ability of this compound to inhibit HN's receptor-binding activity. C28a or wt plaque enlargement, a process that involves cell-cell fusion and does not depend on virion release, is diminished by the presence of 4-GU-DANA, confirming the inhibitory effect of 4-GU-DANA on the fusogenic function of C28a HN. In C28a-infected cell monolayers, virion release and thus multicycle replication are severely restricted. This defect was corrected by supplementation of exogenous neuraminidase and also by the addition of 4-GU-DANA; neuraminidase destroys the receptors whereby newly formed C28a virions would remain attached to the cell surface, whereas 4-GU-DANA prevents the attachment itself, obviating the need for receptor cleavage. In accord with the ability of 4-GU-DANA to prevent attachment, the neuraminidase inhibitory effect of 4-GU-DANA on wt HPF3 did not diminish virion release into the medium. Thus, it is by inhibition of viral entry and syncytium formation that sialic acid analogs like 4-GU-DANA may counteract wt HPF3 infection.

Antiviral Agents↗
PubMed1988

Protective effects of monoclonal antibodies against parainfluenza virus type 3-induced brain infection in hamsters.

A collection of monoclonal antibodies (MAbs) against the haemagglutinin-neuraminidase (HN) and fusion (F) glycoproteins of parainfluenza virus type 3 (PIV3) was used for passive immunization of intracerebrally infected newborn hamsters. A significant degree of protection was obtained with MAbs against both the HN and F viral proteins, but no individual antibody conferred complete protection against disease. MAbs against different epitopes provided different degrees of protection. A MAb to the Sendai virus HN protein was found to confer protection against PIV3 brain infection.

Animals↗
PubMed2002

The recombinant chimeric human parainfluenza virus type 1 vaccine candidate, rHPIV3-1cp45, is attenuated, immunogenic, and protective in African green monkeys.

A recombinant live-attenuated chimeric human parainfluenza virus type 1 (HPIV1) candidate vaccine was previously generated by replacing the fusion (F) and hemagglutinin-neuraminidase (HN) glycoprotein open reading frames (ORFs) of the HPIV3 candidate vaccine, rHPIV3cp45, with those of wild-type HPIV1. Previously, this recombinant chimeric virus, designated rHPIV3-1cp45, exhibited a greater level of the temperature sensitivity of replication in vitro and a greater level of attenuation of replication in the respiratory tract of immunized hamsters when compared to its HPIV3cp45 parent virus. In the present study, rHPIV3-1cp45 was evaluated for its level of attenuation and efficacy in African green monkeys (Cercopithecus aethiops), a primate in which both HPIV1 and HPIV3 wild-type viruses replicate efficiently. The rHPIV3-1cp45 candidate vaccine was as restricted in replication in the upper and lower respiratory tract as its thoroughly characterized rHPIV3cp45 parent indicating that the attenuating mutations present in the rHPIV3cp45 backbone specified an appropriate level of attenuation of rHPIV3-1cp45 for primates. The level to which rHPIV3-1cp45 replicated in the respiratory tract of African green monkeys was also sufficient to induce a strong immune response to HPIV1 and provided protection against challenge with wild-type HPIV1. These results provide a basis for further evaluation of this HPIV1 candidate vaccine in humans.

Animals↗
PubMed1996

Temperature-sensitive phenotype of the human parainfluenza virus type 3 candidate vaccine strain (cp45) correlates with a defect in the L gene.

We have previously demonstrated that the temperature sensitivity of a human parainfluenza virus type 3 (HPIV-3) candidate vaccine strain (cp45), which is currently under evaluation in humans, is associated with poor transcriptional activity of the virus at the nonpermissive temperature (R. Ray, K. Meyer, F. Newman, and R. B. Belshe, J. Virol. 69:1959-1963, 1995). In this study, the temperature sensitivity of cp45 virus was further investigated by the complementation of a specific gene function. CV-1 cells were transfected with cloned genes from wild-type HPIV-3 encoding the large protein (L), phosphoprotein (P), and nucleocapsid protein (NP), alone or together, for the expression of biologically active proteins. Only cells expressing the L gene were able to rescue cp45 replication when incubated at the nonpermissive temperature (39.5 degrees C), whereas cells transiently expressing NP or P were incapable of rescuing the virus. The virus titers obtained following complementation of the L protein were 190 to 2,300 PFU/ml of culture medium, compared with the undetectable growth of the cp45 temperature-sensitive mutant at the nonpermissive temperature. Rescued progeny virus still maintained the temperature-sensitive phenotype. Results from this study suggest that the temperature sensitivity of the cp45 candidate vaccine strain is associated primarily with L-protein function and that the defect can be complemented by transient expression of the wild-type protein. This study underscores the importance of the L protein in RNA polymerase activity and its critical role in virus replication.

Animals↗
PubMed2001

Outbreak of human parainfluenza virus 3 infections in a hematopoietic stem cell transplant population.

Clinical manifestations and epidemiological features are described for a cluster of 12 cases of human parainfluenza virus 3 (HPIV3) infection that occurred among 64 allogeneic hematopoietic stem cell transplant (SCT) recipients in an 11-week period during spring 2000. Upper respiratory symptoms predominated. Pneumonia occurred in 3 patients and was a contributing factor in the death of 1 patient. Exposure histories and molecular analysis of HPIV3 isolates suggested that both community acquired and nosocomially transmitted infections occurred during this outbreak. A chain of transmission within the outpatient clinic appeared to have occurred in 4 outpatients and to have extended to 2 hospitalized patients. Molecular epidemiology was useful in discerning routes of transmission in this outbreak.

Disease Outbreaks↗
PubMed2005

Human parainfluenza virus type I (HPIV1) vaccine candidates designed by reverse genetics are attenuated and efficacious in African green monkeys.

A set of recombinant, live attenuated human parainfluenza virus type 1 (rHPIV1) vaccine candidates was evaluated for attenuation, immunogenicity, and protective efficacy in African green monkeys (AGMs). Temperature sensitive (ts) and non-ts attenuating (att) mutations in the P/C and L genes were introduced individually or in various combinations into rHPIV1, including the C(R84G) and HN(T553A) mutations identified in the present work and the C(F170S), L(Y942A), and L(L992C) mutations identified previously. The rHPIV1 vaccine candidates exhibited a spectrum of attenuation in AGMs. One genetically and phenotypically stable vaccine candidate, rC(R84G/F170S)L(Y942A/L992C), was attenuated and efficacious in AGMs and is a promising live attenuated intranasal HPIV1 vaccine candidate suitable for clinical evaluation.

Animals↗
PubMed1996

Analysis of human parainfluenza virus 3 receptor binding variants: evidence for the use of a specific sialic acid-containing receptor.

In order for the fusion protein (F) of the human parainfluenza virus type 3 (HPF3) to promote membrane fusion and viral entry, the haemagglutinin-neuraminidase (HN) glycoprotein must interact with its receptor. Sialoglycoconjugates are known to be the receptors for the HPF3 HN, however specific attachment factors or receptors for HPF3 have not been identified. In this report we describe the analysis of variants of HPF3 with increased fusion-promoting phenotypes that were selected by treatment with viral neuraminidase. The results suggest that for HPF3, the virus is specific in its use of sialic acid receptors; the majority of sialic-acid containing molecules are not targets for HPF3.

Genetic Variation↗
PubMed1991

The P gene of human parainfluenza virus type 1 encodes P and C proteins but not a cysteine-rich V protein.

The nucleotide sequence of the P gene of human parainfluenza virus type 1 (PIV1) was determined from cloned cDNA copies of the mRNA. By analogy with the gene organization of Sendai virus, two open reading frames in the mRNA sense of the gene were identified as coding sequences for the P protein (568 amino acids with an estimated molecular weight of 64,655) and the C protein (204 amino acids with an estimated molecular weight of 24,108). Comparison of the deduced amino acid sequences of the P and C proteins of PIV1 with those of Sendai virus showed a high degree of homology. However, a sequence for the cysteine-rich V protein, which was considered a common feature of other paramyxoviruses, was interrupted by the presence of multiple stop codons. The sequence analysis of three P-gene-specific cDNA clones generated from genomic RNA by polymerase chain reaction and one additional clone generated from mRNA confirmed that the coding sequence for the cysteine-rich region is silent in the PIV1 gene and thus is not translated into protein. Two potential editing sites with the consensus sequence 3'UUYUCCC were found in the PIV1 P gene at positions 564 to 570 and 1430 to 1436. However, examination of the PIV1 mRNA population by a primer extension method indicated that neither of these sites is utilized. These results indicate that the PIV1 P gene has a coding strategy different from those of other paramyxovirus P genes.

Amino Acid Sequence↗