Field evaluation of a respiratory syncytial virus vaccine and a trivalent parainfluenza virus vaccine in a pediatric population.
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Hemadsorption focus assay for growth of influenza and parainfluenza viruses in human dermal fibroblasts.
An assay for virus-induced hemadsorption foci in cultures of human dermal fibroblasts is described. The assay allows determination of activity of species-specific as well as nonspecific antiviral agents or biological factors, such as interferons. The assay may be used for abortive (e.g., influenza virus) and productive (e.g., parainfluenza virus) infections of human fibroblasts.
Fibroblasts↗
[Proteins of the human parainfluenza virus].
Proteins of human parainfluenza type 3 virus propagated in green monkey kidney cultures are described. The presence of 4 major and 3 minor polypeptides is described along with their molecular weights. Protein F1 was found as a double band, its both components having a similar intensity. Only the upper band of F1 protein was found in the virus grown in Vero cell culture which has a low sensitivity for this virus. Fractionation of the virus and analysis of the proteins of subviral structures were carried out. Nucleocapsid had a buoyant density of 1.32 g/cm3 in cesium chloride and contained major NP protein and minor P and L proteins.
Animals↗
Acquisition of serum antibodies to specific viral glycoproteins of parainfluenza virus 3 in children.
A radioimmunoprecipitation assay was used to study antibody responses to parainfluenza virus 3 glycoproteins in human sera. The method was not only more sensitive than the neutralization test for the detection of antibody but also provided semiquantitative assessments of the antibody response to both glycoproteins in a single assay system. Anti-hemagglutinin-neuraminidase titers were consistently higher than anti-fusion levels in the same serum specimen. Thirteen children were monitored serologically and virologically from birth until 12 months or more after their primary infection with parainfluenza virus 3. At 1 to 3 months after infection, a significant increase in the level of antibody to the hemagglutinin-neuraminidase protein developed in 12 children; of these, 9 showed rises in the level of fusion protein. In 11 of the children, antibody titers continued to rise and the geometric mean titers to the hemagglutinin-neuraminidase protein was highest in sera collected 8 to 10 months after primary infection. Reinfection as the reason for these progressive increases in antibody levels could only be confirmed for four of the children. Three other children had reinfections after the 10-month sera were obtained; in each instance the only antibody responses were to the fusion protein.
Age Factors↗
Antiviral effect of 6-diazo-5-oxo-L-norleucine, antagonist of gamma-glutamyl transpeptidase, on replication of human parainfluenza virus type 2.
The antiviral effects of 6-diazo-5-oxo-L-norleucine (L-DON) on the replication of human parainfluenza virus type 2 (HPIV-2), mumps and vesicular stomatitis viruses were studied. L-DON suppressed growth of these viruses and, in particular, HPIV-2 in four cell types. L-DON was not toxic to the cells at the active dose and did not significantly inhibit cellular macromolecular synthesis. The L-DON-sensitive step of HPIV-2 replication was considered to be relatively early. The NP, P and M proteins were, although at a low level, clearly detectable in HPIV-2-infected Vero cells treated with L-DON, whereas the HN and F proteins were scarcely detected by either immunostaining or immunoprecipitation, indicating that L-DON mainly decreased the amounts of viral glycoproteins. Furthermore, Northern blot hybridization showed that secondary transcription of virus RNA was also inhibited.
Animals↗
Human parainfluenza virus 4 outbreak and the role of diagnostic tests.
Owing to the difficulties in isolating the virus and the lack of routine surveillance, the clinical significance of human parainfluenza virus 4 (HPIV-4) is less well defined than that of the other human parainfluenza viruses. We describe the first outbreak of HPIV-4 infection in a developmental disabilities unit, involving 38 institutionalized children and three staff members, during a 3-week period in autumn 2004. Most subjects had upper respiratory tract infections (URTI), while lower respiratory tract infections (LRTI) occurred in three children (7%), one complicated by respiratory failure requiring ventilation support. All patients recovered. Nasopharyngeal aspirates tested for HPIV-4 were positive by reverse transcriptase PCR (RT-PCR) in all 41 cases (100%), by direct immunofluorescence in 29 of 39 tested cases (74%), and by cell cultures in 6 of 37 cases (16%), and serum was positive for antibodies against HPIV-4 in all 35 cases (100%) with serum samples available. In addition, RT-PCR detected HPIV-4 in four children (three LRTI and one URTI) out of 115 patients with community-acquired respiratory tract infection. Molecular analysis of the 1,198-bp phosphoprotein sequences showed that HPIV-4 isolates among the cases were genetically similar, whereas the community controls were more genetically distant, supporting nosocomial transmission of a single HPIV-4 genotype during the outbreak. Moreover, the HPIV-4 causing the outbreak is more closely related to HPIV-4A than HPIV-4B. HPIV-4 may be an important cause of more severe respiratory illness in children. The present RT-PCR assay is a sensitive, specific, and rapid method for the diagnosing HPIV-4 infection. To better define the epidemiology and clinical spectrum of disease of HPIV-4 infections, HPIV-4 should be included in the routine panels of respiratory virus detection on respiratory specimens.
Adolescent↗
Parainfluenza virus type 1 infects olfactory neurons and establishes long-term persistence in the nerve tissue.
A mouse model of Sendai virus infection was adopted to examine the in vivo neurovirulence of parainfluenza viruses. A nested polymerase chain reaction detected the Sendai virus nucleoprotein gene in the olfactory bulbs of intranasally infected mice for at least 168 days post-infection (p.i.) and virus-specific messenger RNAs for 28 days p.i. Viral proteins were histochemically detected in some olfactory neurons for 7 days p.i. They were also found in glomeruli of the olfactory bulbs but not in the mitral cells and the tufted cells. No virus was detected in the whole brain not including the olfactory bulbs. When mice were inoculated with UV-inactivated virus, the viral RNA was present in the olfactory bulbs for a short period of 14 days, with no demonstrable viraemia. These results demonstrate that the parainfluenza virus directly accesses the central nervous system via olfactory neurons and establishes long-term persistence in the nerve tissue.
Animals↗
Sequencing analyses and comparison of parainfluenza virus type 4A and 4B NP protein genes.
The nucleotide sequences of the cDNA copies of the mRNA coding for the nucleocapsid proteins (NPs) of human parainfluenza viruses type 4A (PIV-4A) and type 4B (PIV-4B) were determined. The copy of PIV-4A NP mRNA contained 1885 nucleotides encoding a protein with a calculated molecular weight of 62,561. The same number of amino acids with a similar molecular weight (62,425) were predicted for the PIV-4B NP protein. Comparisons on the nucleotide sequence and the amino acid sequence of NP protein between these two subtypes revealed extensive homologies in the nucleotide sequence (87%) and in the amino acid sequence (93%). Furthermore, a conserved region with about 100 amino acids was observed between PIV-4s and other paramyxoviruses, Newcastle disease virus (NDV), Sendai virus, mumps virus (MuV), PIV-3, BPIV-3, measles virus (MV), and canine distemper virus (CDV), indicating a common ancestor for these nine viruses. Our data also indicated that the PIV-4 NP proteins were more closely related to MuV and NDV than to other parainfluenza viruses, PIV-3, BPIV-3, and Sendai virus. Interestingly, the NP protein homology between PIV-4s and the morbillivirus group, MV and CDV, was slightly higher than that between PIV-4s and the parainfluenza viruses, PIV-3, BPIV-3, and Sendai virus.
Amino Acid Sequence↗
Proteins associated with human parainfluenza virus type 3.
The polypeptides associated with human parainfluenza virus type 3 were identified. Five proteins were present in detergent- and salt-resistant viral cores. Of these, three proteins designated NP0, NP1, and NP2 of 68,000, 58,000, and 52,000 daltons, respectively, were stably associated with 50S RNA in CsCl gradient-purified nucleocapsids. The amounts of NP1 and NP2 were variable, and these proteins were shown to be structurally related to the major nucleocapsid protein (NP0) by partial Staphylococcus aureus V8 protease mapping. The other core proteins included a 240K protein designated L (candidate for the viral polymerase) and an 84K protein designated as the phosphoprotein (P) on the basis of a predominant incorporation of Pi. The viral envelope had four prominent proteins (72, 53, 40, and 12K) under reducing conditions of electrophoresis. The 72 and 53K proteins were specifically labeled with [3H]glucosamine and [3H]mannose. When sulfhydryl reagents were removed, a new 62K protein was visualized in place of the 72, 53, and 12K proteins. The 53 and 12K proteins were interpreted to be the two subunits (F1 and F2) of the fusion protein, and the 72K protein was designated as the HN (hemagglutinin-neuraminidase) glycoprotein. The unglycosylated 40K protein represented the viral matrix protein (M). Immunoprecipitation of infected cell lysates with rabbit hyperimmune antiserum against purified virus confirmed the viral origin of these polypeptides.
Capsid↗
Characterization of human parainfluenza virus type 3 persistent infection in cell culture.
Three cell lines persistently infected with human parainfluenza virus type 3 were characterized on a molecular level in this study. All six structural protein genes were transcribed into monocistronic RNAs in the persistently infected cells. In both acutely and persistently infected cells, polycistronic transcripts were abundant, although the ratio of polycistronic to monocistronic transcripts was reduced in the persistently infected cells. Each of the persistently infected cell lines contained a distinct subgenomic RNA species. The subgenomic RNAs were present in purified nucleocapsid cores, indicating that they represent viral genome RNA, were far more abundant than full-length RNA, and were stably maintained through at least 36 cell passages. Nucleotide sequence analysis of the subgenomic RNAs from two of the persistently infected cell lines revealed that the 5' ends are identical to that of the standard genome. Hybridization experiments with oligonucleotide probes showed that both fragments retain sequences from the 5' end of the standard genome and contain approximately 1,200 nucleotides (cell line 1) and 1,500 nucleotides (cell line 2) of the polymerase gene sequence. The demonstration of several alterations in viral gene expression in persistently infected cells offers insight into the factors associated with persistence of parainfluenza virus 3.
Animals↗
Incomplete replication of human parainfluenza virus type 2 in mouse L929 cells.
Human parainfluenza virus type 2 (HPIV-2) was tested for its ability to replicate in murine L929 cells. L929 cells were non-permissive for replication of HPIV-2. Interferon produced endogenously played no role in its incomplete replication. The mechanism by which growth of HPIV-2 was suppressed in L929 cells was studied. Synthesis of virus-specific polypeptides, particularly glycoprotein(s), was suppressed in HPIV-2-infected L929 cells. The HN mRNA could scarcely be detected in virus-infected L929 cells.
Animals↗
Fusion glycoprotein of human parainfluenza virus type 3: nucleotide sequence of the gene, direct identification of the cleavage-activation site, and comparison with other paramyxoviruses.
The complete sequences of the fusion (F) mRNA and protein of human parainfluenza virus type 3 (PF3) were determined from overlapping cDNA clones. To confirm the cDNA sequence, the complete sequence of the F gene was determined independently by dideoxynucleotide sequencing of genomic RNA using synthetic oligonucleotide primers. The mRNA contains 1845 nucleotides, exclusive of poly (A), has an unusually long (193-nucleotide) 5' nontranslated region, and encodes an F0 protein of 539 amino acids. The site within F0 of the proteolytic cleavage that activates fusion activity was established by direct amino acid sequencing of the NH2 terminus of the F1 subunit. The PF3 F0 protein shares major structural features with the previously sequenced F0 proteins of Sendai virus (murine parainfluenza type 1) and simian virus 5 (SV5, canine parainfluenza type 2), including: similarity in overall length; similarity in location of the site of the activating proteolytic cleavage; the presence of an NH2-terminal signal peptide and COOH-proximal membrane anchor; strong conservation of the sequence at the NH2 terminus of the F1 subunit; and nearly exact conservation in the number and positions of cysteine residues. Alignment of the F0 protein sequences of PF3 with those of Sendai, SV5, and respiratory syncytial virus (RSV) using a matrix that scores both amino acid matches and mismatches provided highly significant statistical evidence that all four proteins are related. The order of decreasing relatedness to PF3 was found to be: Sendai virus, SV5, and RSV.
Amino Acid Sequence↗
Biological properties and carbohydrate composition of human parainfluenza virus type 1 in two host systems.
Human parainfluenza virus type 1 (HA2 virus) grown either in embryonated hens' eggs or in M. rhesus monkey kidney cells showed differences in size, biological properties and carbohydrate composition. Egg-grown virus showed a larger size (233 nm versus 167 nm), a higher neuraminidase activity (specific activity and initial and maximum velocity) and a higher haemolytic activity than monkey kidney cell-grown virus. The haemagglutinin titre was identical for the HA2 strain grown in both host systems when tested with human O Rh+, guinea-pig and hen red blood cells, but reduced by more than 100-fold when tested with grivet monkey red blood cells. In addition, the carbohydrate content (mainly neutral sugars) was higher in egg-grown virus (9.2%) than in virus grown in MK cells (5.7%), and the amino to neutral sugar ratio was lower (1.2 versus 2.1). The sugars were identified as fucose, mannose, galactose, glucose, glucosamine and galactosamine. The prominent neutral monosaccharide was glucose in egg-grown virus and fucose in MK cell-grown virus. HA2 virus infection of MK cells increased fucose and glucose, and decreased mannose and galactose levels.
Animals↗
Ultrastructural evaluation of the acute encephalitis and hydrocephalus in dogs caused by canine parainfluenza virus.
Intracranial infection of neonatal dogs with canine parainfluenza virus (strain 78-238) progressed from an acute phase of encephalitis to a chronic phase of internal hydrocephalus. Acute encephalitis was characterized ultrastructurally by laminar cortical necrosis, neuronal degeneration, neocapillary formation, reactive gliosis, and ependymitis. Viral nucleocapsids were seen in the cytoplasm of neurons. Ultrastructural lesions in hydrocephalic dogs were restricted to ventricular surfaces. The earliest light microscopic change in ependymal cells occurred four weeks post-infection and consisted of segmental loss of ependymal cells. Dogs killed at three and six months post-infection had quantitatively similar ultrastructural alterations in ependymal cells regardless of the extent and severity of hydrocephalus. The shape of these cells changed from cuboidal to squamous. There was progressive loss of cilia and cell organelles along with a concomitant increase of cytoplasmic filaments. Viral nucleocapsids and inflammatory cells were not present in convalescent hydrocephalic dogs. These results suggested that virus-associated hydrocephalus can occur in the absence of obvious viral persistence in ependymal cells and in the absence of inflammation in the ventricular system.
Acute Disease↗
Development and evaluation of NucliSens basic kit NASBA for diagnosis of parainfluenza virus infection with 'end-point' and 'real-time' detection.
New methods for the detection of human parainfluenza viruses (HPIVs) were developed. These were based on nucleic acid sequence-based amplification (NASBA) and utilised the NucliSens Basic Kit. Primers and probes were selected from the haemagglutinin neuraminidase (HN) gene of HPIV1, HPIV2 and HPIV3, and from the phosphoprotein (P) of HPIV4a and -4b. Synthetic RNA, titrated control virus stocks and respiratory specimens (n=44) were utilised to evaluate performance of the assays. Detection of NASBA products was by probe hybridisation and electrochemiluminescence (ECL) ('end-point' detection) or using molecular beacons ('real-time' detection). The assays using ECL detection proved to be both sensitive and specific. Typically, less than or equal to 100 RNA copies or one TCID(50) input was detectable with no cross-reaction between the specific HPIV assays and other respiratory viruses. Results for clinical samples were concordant with those obtained by 'conventional' procedures by classical viral diagnostic methods. 'Real-time' detection utilised probes specific for either HPIV1 or HPIV3 with similar performance characteristics to the assays with 'end-point' detection. The feasibility of multiplexing targets together was confirmed using a combined HPIV1 and HPIV3 assay with good results for ECL and molecular beacon detection on control material and clinical samples.
Base Sequence↗
Selection of temperature-sensitive mutants in persistent infection by parainfluenza virus type 3.
Vero cells persistently infected with parainfluenza virus type 3 (para 3) were examined for the production of temperature-sensitive (ts) mutants. After 6 months and 33 passages, ts mutants formed the great majority of the virus being shed into the supernatant fluid. Complementation studies gave evidence that the mutants shared a common lesion. Although ts mutants may play a role in the maintenance of persistent infection in this system, the mutants proved to be unstable when removed from the milieu of persistent infection. It is thus possible that their selection may be secondary to (an) unidentified factor(s) which play(s) a more primary role in the maintenance process.
Animals↗
Cloning and gene assignment of mRNAs of human parainfluenza virus 3.
Cytoplasmic poly(A)-containing RNA from parainfluenza virus 3-infected cells was used as template to construct a cDNA library that was cloned into the EcoRV site of the plasmid pMG5. The resulting clones were screened with [32P]-labeled cDNA probes made from infected and mock-infected cell mRNAs. The virus specificity of the clones was confirmed by Northern blot hybridization. The viral clones were grouped into five different families by hybridization with individual size-selected reverse transcripts representing the major classes of poly(A)+-RNA from virus-infected cells. The five groups were shown to be unrelated on the basis of cross-colony hybridization and corresponded to five unique classes of intracellular viral poly(A)+-RNAs. Clones representing the NP and P genes of PIV-3 were identified by both hybrid-selected and hybrid-arrested translation. Clones specific for the P gene selected mRNA that directed the synthesis of P protein and another polypeptide of 21 kDa. This additional polypeptide comigrated with protein VP8 previously identified in virions and in infected cell lysates.
Animals↗
Respiratory disease due to parainfluenza virus in adult leukemia patients.
Reports of human parainfluenza viruses (HPIV) in patients with leukemia have been limited to a few cases or as a portion of general surveys. In order to expand the knowledge of these infections in this patient group, the frequency and clinical course of HPIV infections was determined among 1,787 patients with leukemia treated at The University of Texas M.D. Anderson Cancer Center between July 1994 and December 1997. HPIV was isolated from 47 (6.2%) of the 770 patients who were cultured for respiratory viruses. HPIV type 3 accounted for 39 of the 47 HPIV infections. Twenty-six patients developed pneumonia, and the associated mortality was 27%. Multivariate analysis revealed that a low absolute lymphocyte count and pneumonia were associated with increased mortality. Concurrent respiratory and other infections were associated with an increased frequency of pneumonia. Only five patients with pneumonia received antiviral therapy and four of them survived the infection. HPIV infection in leukemic patients is frequently associated with pneumonia and the mortality rate from pneumonia is substantial among lymphopenic patients.
Adolescent↗