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PubMed2001

Recombinant bovine/human parainfluenza virus type 3 (B/HPIV3) expressing the respiratory syncytial virus (RSV) G and F proteins can be used to achieve simultaneous mucosal immunization against RSV and HPIV3.

Recombinant bovine/human parainfluenza virus type 3 (rB/HPIV3), a recombinant bovine PIV3 (rBPIV3) in which the F and HN genes were replaced with their HPIV3 counterparts, was used to express the major protective antigens of respiratory syncytial virus (RSV) in order to create a bivalent mucosal vaccine against RSV and HPIV3. The attenuation of rB/HPIV3 is provided by the host range restriction of the BPIV3 backbone in primates. RSV G and F open reading frames (ORFs) were placed under the control of PIV3 transcription signals and inserted individually into the rB/HPIV3 genome in the promoter-proximal position preceding the nucleocapsid protein gene. The recombinant PIV3 expressing the RSV G ORF (rB/HPIV3-G1) was not restricted in its replication in vitro, whereas the virus expressing the RSV F ORF (rB/HPIV3-F1) was eightfold restricted compared to its rB/HPIV3 parent. Both viruses replicated efficiently in the respiratory tract of hamsters, and each induced RSV serum antibody titers similar to those induced by RSV infection and anti-HPIV3 titers similar to those induced by HPIV3 infection. Immunization of hamsters with rB/HPIV3-G1, rB/HPIV3-F1, or a combination of both viruses resulted in a high level of resistance to challenge with RSV or HPIV3 28 days later. These results describe a vaccine strategy that obviates the technical challenges associated with a live attenuated RSV vaccine, providing, against the two leading viral agents of pediatric respiratory tract disease, a bivalent vaccine whose attenuation phenotype is based on the extensive host range sequence differences of BPIV3.

Animals↗
PubMed2005

Development of a real-time RT-PCR assay for detection and quantitation of parainfluenza virus 3.

A TaqMan-based real-time RT-PCR assay was developed to detect and quantify human parainfluenza virus 3 (PIV3). Two sets of primer-probe pairs were designed based on the nucleotide (nt) sequence of the nucleocapsid (N) gene. The primer-probe pairs were derived from the 3' end of the N gene (set 1) and the 5' region of the gene (set 2), respectively. Using real-time RT-PCR, the sensitivity of set 1 was determined to be about 9 copies of PIV3 genome, while the sensitivity of set 2 was about 93 copies of PIV3 genome. Set 1 was chosen for subsequent experiments. This primer-probe pair detected PIV3, but not any of several other respiratory viruses, indicating that the assay is PIV3 specific. For clinical evaluation, the assay was employed to test 80 nasopharyngeal aspirates from children with respiratory symptoms. The results confirmed the presence of PIV3 in 12 specimens previously identified as positive by culture confirmation, and showed all of which contained more than 100 copies of PIV3 genome. In addition, the method also detected PIV3 genomes in specimens found negative by culture confirmation, indicating the value of this RT-PCR assay. These data thus demonstrate the application of the real-time RT-PCR assay for the detection and quantification of PIV3 in clinical specimens.

Child↗
PubMed2005

Inhibition of STAT 1 phosphorylation by human parainfluenza virus type 3 C protein.

The P mRNA of the viruses belonging to the subfamily Paramyxovirinae possesses a unique property of giving rise to several accessory proteins by a process that involves the utilization of overlapping open reading frames (the C proteins) and by an "RNA-editing" mechanism (the V proteins). Although these proteins are considered accessory, numerous studies have highlighted the importance of these proteins in virus transcription and interferon signaling, including our previous observation on the role of human parainfluenza virus type 3 (HPIV 3) C protein in the transcription of viral genome (Malur et al., Virus Res. 99:199-204, 2004). In this report, we have addressed its role in interferon signaling by generating a stable cell line, L-C6, by using the lentiviral expression system which expresses HPIV 3 C protein. The L-C6 cells were efficient in abrogating both alpha and gamma interferon-induced antiviral states and demonstrated a drastic reduction in the formation of gamma-activated factor complexes in the cell extracts. Western blot analysis subsequently revealed a defect in the phosphorylation of STAT 1 in these cells. Taken together, our results indicate that HPIV 3 C protein is capable of counteracting the interferon signaling pathway by specifically inhibiting the activation of STAT 1.

Cell Line↗
PubMed2004

Beta-catenin associates with human parainfluenza virus type 3 ribonucleoprotein complex and activates transcription of viral genome RNA in vitro.

Several studies have indicated that human parainfluenza virus type 3 (HPIV-3) requires polymeric actin for transcription of its genome RNA in vitro and in vivo. In the current study, we have identified beta-catenin, an actin-bound protein, as one of the transcriptional activators for HPIV-3 genome RNA. Beta-catenin was packaged within the purified HPIV-3 virions and was associated with the HPIV-3 ribonucleoproteins (RNP) from infected cells. Moreover, purified beta-catenin interacted with bacterially expressed HPIV-3 nucleocapsid protein (N) and phosphoprotein (P) fused to glutathione S-transferase (GST). Double-labeled immunofluorescent confocal microscopic analysis revealed colocalization of beta-catenin with HPIV-3 RNP at cell periphery in infected cells. The HPIV-3 RNP-associated beta-catenin functioned as a transactivator of HPIV-3 genome, because purified beta-catenin stimulated transcription of viral RNP in an in vitro transcription assay. These results demonstrate that beta-catenin, a multifunctional protein that is involved in cell-cell adhesion and embryogenesis, acts as one of the transcriptional activators of HPIV-3 genome RNA.

Cytoskeletal Proteins↗
PubMed1991

The nucleoproteins of human parainfluenza virus type 1 and Sendai virus share amino acid sequences and antigenic and structural determinants.

The complete nucleotide sequence of the nucleoprotein (NP) gene of human parainfluenza virus type 1 (hPIV-1) was determined from a cDNA clone of mRNA. The mRNA is 1683 nucleotides long (excluding polyadenylic acid) and encodes a protein of 524 amino acids with a predicted Mr of 57,548. An amino acid identity of 83% was predicted between the NPs of the human pathogen hPIV-1 and the murine paramyxovirus, Sendai virus, compared to 72% similarity at the level of the nucleotide sequence. In contrast, the amino acid sequence identity between the NPs of hPIV-1 and hPIV-3 was 59%, suggesting a more distant evolutionary relationship. The NP amino acid sequences of hPIV-1 and Sendai virus were highly conserved in the amino-terminal half of the molecule, in which 395 of the first 420 amino acids were identical. Of 11 monoclonal antibodies (MAbs) targeted against the Sendai virus NP, five cross-reacted with the hPIV-1 NP. The MAbs that cross-reacted recognize epitopes within regions of high amino acid similarity between the NPs of the two viruses. Also, five of the eight MAbs raised against hPIV-1 NP cross-reacted with Sendai virus NP. Taken together, our observations suggest that the essential amino acid sequence determinants of the NP structures of hPIV-1 and Sendai virus are conserved despite changes in their nucleotide sequences during evolution. This implies that there was a selective pressure to maintain the important functional domains of the protein.

Amino Acid Sequence↗
PubMed1992

Distinct hemagglutinin and neuraminidase epitopes involved in antigenic variation of recent human parainfluenza virus type 2 isolates.

A panel of fourteen neutralizing anti-HN monoclonal antibodies (mAbs) to the prototype Greer strain of human parainfluenza virus type 2 (PI2) was used to determine the extent of antigenic variation in recent virus isolates. Competitive binding analysis with the mAbs indicated the presence of at least five distinct antigenic sites (I to V) on the HN glycoprotein molecule. MAbs recognizing different antigenic sites were found to be associated with the hemagglutinin (sites I, IV and V), hemagglutinin and neuraminidase (site II), or neuraminidase (site III) activities. The location of two distinct epitopes identifying the neuraminidase sites (II and III) was further verified from the generation of escape mutants. Antibodies directed to sites I and III failed to show any detectable binding or neutralizing activity against a number of natural PI2 virus isolates collected in Texas between 1986 and 1987. Interestingly, these natural variants, unlike the prototype virus, did not show any detectable neuraminidase activity with fetuin as a substrate and the enzyme activity was only detected with N-acetylneuramin-lactose as an alternative substrate. Despite the observed variation in the antigenic sites, primary infection with the prototype virus or the natural variants generated a protective immune response against challenge infection with the other virus strains.

Animals↗
PubMed1993

Suppression of lymphocyte proliferation by parainfluenza virus type 3-infected bovine alveolar macrophages.

Lymphocytes stimulated with concanavalin A (Con A) or antigen in the presence of bovine parainfluenza virus type 3 (PIV-3) infected bovine alveolar macrophages (BAM) or monocytes, had depressed [3H]thymidine incorporation. This failure of lymphocytes to incorporate radiolabel required live virus, was time dependent and was most pronounced when BAM were infected for 48 hr prior to the addition of lymphocytes. The rate of infection of alveolar macrophages and the release of infectious virus into culture supernatants paralleled suppression of lymphocyte mitogenesis by PIV-3. However, the peak titre of exogenous, live or inactivated virus was not suppressive when added to lymphocyte macrophage cultures just prior to Con A stimulation. Neither the loss of viable alveolar macrophages nor a shift in antigen or mitogen dose response in virally infected cultures could account for the deficit in [3H]thymidine incorporation by lymphocytes. Despite the presence of lymphocyte-associated virus antigen detected by direct immunofluorescence, no increase in PIV-3 titre above baseline was seen from infected lymphocytes, irrespective of mitogen stimulation. Likewise, lymphocytes did not contribute to the extracellular virus pool in lymphocyte-macrophage cultures as the increases in viral titre above basal levels in supernatants were equal to levels released by macrophages alone. The expression of viral antigen on lymphocytes stimulated in the presence of PIV-3-infected BAM suggests a non-productive or abortive infection of lymphocytes mediated through contact with infected macrophages.

Animals↗
PubMed1984

Interaction of influenza and parainfluenza viruses with polycations, organic oligocations and chromosome preparations.

As evaluated by light scattering at 90 degrees, natural organic oligocations such as putrescine, spermidine and spermine interfered with myxovirus aggregates which were induced by the histone H2A and strongly amplified by shaking during incubation. In contrast, the synthetic oligocation 1.7-diamino heptane itself aggregated the virus particles, its action being unmodified by adding polycationic H2A in abundance. When human chromosome preparations treated with protamine solution and shaked during incubation were covered with a stable polycationic molecular layer, the chromosomes had become unstainable by the Giemsa method even if the dye was used in excess. Nevertheless, the affinity of influenza virus particles for protamine was so high that they were able to dissociate the protamine molecules from the preformed complexes reconstituting the affinity of chromosome preparations to Giemsa stain. The virus-caused shift in the staining ability of chromosomes did not occur when bacterial suspension was added instead of the viral one. The model of oligocationic relaxation and of polycation condensation accounting for the modulatory effects of polyamines is discussed.

Cations↗
PubMed1984

Parainfluenza virus type 3: seasonality and risk of infection and reinfection in young children.

In Houston the temporal occurrence of infections with parainfluenza virus type 3 has evolved from an endemic to an epidemic pattern. Continuous virological surveillance for six years demonstrated that most infections occurred the late winter or spring after influenza virus activity. At least two-thirds of children observed in the Houston Family Study were infected with this virus in each of the first two years of life, and the risk of illness was about 30/100 children per year. After two years of age, the infection and illness rates dropped to 32 and 8 per 100 child-years, respectively. Most lower-respiratory-tract disease was associated with primary infection, and the risk for infection was greater during the second year for the smaller proportion of children who escaped infection during the first year. The risk during the first year may have been modified by passively acquired maternal antibody.

Adolescent↗
PubMed1994

Human parainfluenza virus type 1 evolution combines cocirculation of strains and development of geographically restricted lineages.

The hemagglutinin neuraminidase (HN) glycoprotein of human parainfluenza virus type 1 (HPIV-1) mediates attachment to the host cell and is the target of protective antibody. Since the efficacy of a potential vaccine depends on antigenic constancy, the antigenic and genetic stability of the HPIV-1 HN glycoprotein was examined for 13 isolates obtained between 1981 and 1989. Antigenic analysis with a panel of 11 monoclonal antibodies demonstrated a single change among 3 isolates from 1989 that distinguished them from all other isolates. The HN genes from all 13 isolates and 13 previously published HN gene sequences shared > 95% homology. Evolutionary analysis demonstrated cocirculation of strains, without a dominant lineage. The 1989 isolates and the previously proposed subtype A isolates occupied distinct evolutionary branches, indicating geographically limited evolution. The slow rate of evolution and HN homogeneity may allow development of a single vaccine formulation for the prevention of disease.

Antigens, Viral↗
PubMed2001

Half-life of human parainfluenza virus type 3 (hPIV3) maternal antibody and cumulative proportion of hPIV3 infection in young infants.

During a phase 2 trial of parainfluenza virus type 3 (PIV3) vaccine, sequential serum samples were obtained from infants at 2, 6, 7, 12-15, and 13-16 months of age. Paired serum samples obtained at 2 and 6 months of age were used to estimate the biologic half-life of human PIV3 (hPIV3) maternal antibody in young infants. On the basis of the assumption that hPIV3 maternal antibody decays exponentially and constantly, the biologic half-life was estimated without adjusting for body weight increases. Cumulative proportions of hPIV3 infection in young infants were further estimated after adjusting for maternal antibody decline. A hemagglutination inhibition assay was used to quantify hPIV3 antibody. The mean (95% confidence interval) biologic half-life was estimated to be 51 (42-60) days, on the basis of which cumulative proportions of hPIV3 infection were estimated to be 11% at 6 months of age, 47% at 12-15 months of age, and 50% at 13-16 months of age.

Animals↗
PubMed1995

Identification of regions on the hemagglutinin-neuraminidase protein of human parainfluenza virus type 2 important for promoting cell fusion.

The hemagglutinin-neuraminidase (HN) and fusion (F) glycoproteins of two paramyxoviruses, human parainfluenza virus type 2 (PIV2) and simian virus 41 (SV41), were expressed in HeLa cells by transfecting with recombinant plasmid harboring each glycoprotein gene. Expressed F proteins could not induce cell fusion by themselves, but evoked prominent cell fusion when coexpressed with homologous HN proteins. It was also proved that PIV2 HN protein could weakly promote SV41 F-mediated cell fusion. By analyzing the fusion-promoting function of chimeric HN proteins of PIV2 and SV41, it was revealed that the N-terminal region (about 16% of total amino acids) of either PIV2 HN or SV41 HN protein could define the type-specific fusion-promoting function for homologous F protein. Analyses of additional chimeras indicated that the N-terminal region in PIV2 HN protein (designated region I, consisting of 94 amino acids) could be reduced to a 58-amino-acid region (region I') which was located at the membrane-proximal end of the ectodomain. Furthermore, PIV2 HN protein proved to promote cell fusion mediated by PIV4A F protein. Unexpectedly, analyses of another set of chimeras revealed that the promoting function of PIV2 HN protein for PIV4A F-mediated cell fusion was not merely carried by its region I but also by another region ranging from residue 148 to 209 (region II). Finally, it was indicated that regions I' (in the presumed stalk domain) and II (in the globular head) in PIV2 HN protein might play important roles in promoting cell fusion mediated by the F proteins.

Amino Acid Sequence↗
PubMed2001

Human parainfluenza virus type 3 inhibits gamma interferon-induced major histocompatibility complex class II expression directly and by inducing alpha/beta interferon.

Human parainfluenza virus type 3 (HPIV3) is one of the major causes of bronchiolitis, pneumonia, and croup in newborns and infants. Cellular immunity involving major histocompatibility complex (MHC) class I and class II molecules plays an important role in controlling virus infection. Several viruses have been shown to down-regulate gamma interferon (IFN-gamma)-mediated MHC class II expression. In this communication, we show that HPIV3 strongly inhibits the IFN-gamma-induced MHC class II expression in HT1080 human fibrosarcoma cells. The culture supernatant of HPIV3-infected cells also inhibited IFN-gamma-induced MHC class II expression, a phenomenon that was found to be due, in large part, to alpha/beta interferon (IFN-alpha/beta). Expression of MHC class I and intercellular adhesion molecule 1 occurred efficiently in cells simultaneously infected with HPIV3 and treated with IFN-gamma, indicating that the inhibitory effect of HPIV3 was specific to MHC class II. STAT1 activation was not affected by HPIV3 at early postinfection times but was partially inhibited at later times. These data suggested that the potent inhibition of MHC class II expression was, in major part, due to a defect downstream of STAT1 activation in the IFN-gamma-induced MHC class II expression pathway. Class II transactivator (CIITA) is the unique mediator of IFN-gamma-induced transcription from the MHC class II promoter. By RNase protection analysis, CIITA expression was found to be strongly inhibited in HPIV3-infected cells. The culture supernatant containing IFN-alpha/beta, on the other hand, inhibited MHC class II expression without affecting STAT1 and CIITA expression. These data indicate that HPIV3 inhibits IFN-gamma-induced MHC class II expression primarily by the viral gene products targeting CIITA and additionally by inducing IFN-alpha/beta to target one or more steps further downstream.

Animals↗
PubMed1991

Congenital hydrocephalus in suckling hamsters caused by transplacental infection with parainfluenza virus type 3.

The possible occurrence of congenital hydrocephalus by viral infection of the mother was examined by inoculating pregnant hamsters intravenously with parainfluenza virus type 3 (PIV-3). We could produce congenital hydrocephalus in littermates born to a mother which had been inoculated into the left cervical vein on the 14th day of pregnancy. This result may indicate that the virus could pass through the placenta to arrive at the fetus, and infect the central nervous system.

Animals↗
PubMed1987

Glycoproteins of human parainfluenza virus type 3: affinity purification, antigenic characterization and reconstitution into lipid vesicles.

Monoclonal antibodies to the envelope glycoproteins, HN and F, of human parainfluenza virus type 3 were coupled to a Sepharose 4B matrix and used for affinity purification of the viral glycoproteins. The purity of the glycoproteins was demonstrated by SDS-PAGE followed by fluorography or silver staining. The antigenicity of the glycoproteins was determined by immunization of rabbits; polyclonal rabbit antisera demonstrated inhibition of functional activities of the virus glycoproteins. The F glycoprotein, when reconstituted into lipid vesicles, showed distinct spike-like projections similar to those of intact virions.

Animals↗
PubMed1992

Genetic variation and evolution of human parainfluenza virus type 1 hemagglutinin neuraminidase: analysis of 12 clinical isolates.

The extent of genetic variation and evolution in a population of human parainfluenza virus type 1 was investigated. The hemagglutinin neuraminidase genes of 13 isolates collected over a 26-year period were sequenced and compared. All isolates except the 1957 type strain were from a single geographic location and demonstrated significant consistent genetic change from the type strain (47/7 [nucleotide/amino acid] substitutions). Antigenic subgroup A isolates demonstrated minor intragroup differences (9/1 substitutions). However, 18/7 unique substitutions separated subgroup A from B regardless of geographic location or year of isolation. Multiple strains of both subgroups appeared and reappeared over decades with only minor variation. There may be significant genetic differences between clinical isolates based on geographic location, and progressive mutational change may occur. Previously defined antigenic and now genetic subgroups were stable and at least regional in distribution over the period studied. The biologic implications and extent of this variation need further evaluation.

Animals↗
PubMed2005

Live-attenuated intranasal parainfluenza virus type 2 vaccine candidates developed by reverse genetics containing L polymerase protein mutations imported from heterologous paramyxoviruses.

Live-attenuated recombinant human parainfluenza virus type 2 (rHPIV2) vaccine candidates were created using reverse genetics by importing known attenuating mutations in the L polymerase protein from heterologous paramyxoviruses into the homologous sites of the HPIV2 L protein. Four recombinants (rF460L, rY948H, rL1566I, and rS1724I) were recovered and three were attenuated for replication in hamsters. The genetic stability of the imported mutations at three of the four sites was enhanced by use of alternative codons or by deletion of a pair of amino acids. rHPIV2s bearing these modified mutations exhibited enhanced attenuation. The genetically stabilized mutations conferring a high level of attenuation will be useful in generating a live-attenuated virus vaccine for HPIV2.

Administration, Intranasal↗