encyclopedia of life sciences || parainfluenza viruses

Parainfluenza VirusesRaychel Chambers, University of Rochester Medical Center, Rochester, New York, USA

Toru Takimoto, University of Rochester Medical Center, Rochester, New York, USA

Based in part on the previous version of this Encyclopedia of Life Sciences(ELS) article, Parainfluenza Viruses by Toru Takimoto.

Parainfluenza viruses are enveloped viruses that contain

nonsegmented negative-strand genomic ribonucleic acid

(RNA). Replication of these viruses begins with entry by

attachment and fusion, followed by genomic transcrip-

tion and replication. Next, the de novo synthesised viral

components are trafficked to assembly sites at the plasma

membrane where newly formed virions bud out from the

cell. These viruses are respiratory pathogens which act as

the causative agents for croup, bronchiolitis and pneu-

monia. As a group, the parainfluenza viruses are second

only to human respiratory syncytial virus as the cause of

acute paediatric respiratory tract disease and are

responsible for hundreds of thousands of additional U.S.

hospitalisations per year. Despite their clinical import-

ance, licensed vaccines or antiviral compounds for pre-

vention or treatment of parainfluenza viruses are not

currently available, making understanding the patho-

genesis of these viruses critical for antiviral drug and

vaccine development.

Introduction

Parainfluenza viruses are enveloped ribonucleic acid(RNA) viruses, which cause serious respiratory infections,especially among children. These viruses mainly replicatein the respiratory tract and transmit through aerosolisa-tion. Many structural and virological analyses haverevealed the basic mechanism of virus replication in thecytoplasm. In addition, a reverse genetics system, which

allows recovery of infectious virus from complementarydeoxyribonucleic acid (cDNA) has significantly contrib-uted to the studies of virus replication and assembly, aswellas in the development of live vaccines.

Classification

The parainfluenza viruses, whose genomes consist ofnonsegmented negative-strand RNA, belong to the familyParamyxoviridae, order Mononegavirales. The subfamily,Paramyxovirinae, comprises five genera, Respirovirus,Rubulavirus, Avulavirus, Henipavirus and Morbillivirus.Humanparainfluenza virus (HPIV) serotypes1 and3belongto the genusRespirovirus, whereas serotypes 2 and 4 belongto the genus Rubulavirus. The HPIV-4 serotype hasbeen divided into two antigenic subgroups, 4a and 4b, onthe basis of their reactivity with monoclonal antibodies(Table 1). All of the nonsegmented negative-strand RNAviruses have these features in common: (1) the RNA gen-ome is tightly associated with nucleoprotein to form ahelical nucleocapsid; (2) the viral RNA polymerase isattached to the nucleocapsid; (3) replication takes placeentirely in the cytoplasm and (4) progeny virions areassembled at the plasma membrane of infected cells andreleased by the process of budding. See also: HumanPathogenic Viruses; Measles Virus; Mumps Virus; New-castle Disease Virus; Respiratory Syncytial Virus; ViralClassification and Nomenclature

Virion and Genome Structure

Virion

Parainfluenza viruses are pleomorphic enveloped virusesthat range in average diameter from 150 to 200 nm. Thelipid-bilayer envelope is derived from the plasma mem-brane of the infected cell. A schematic diagram and anelectron micrograph of a typical parainfluenza virion areshown in Figure 1. The outer layer of the lipid membranebears spike-like haemagglutinin-neuraminidase (HN) andfusion (F) glycoproteins, which extend approximately

Advanced article

Article Contents

. Introduction

. Classification

. Virion and Genome Structure

. Viral Replication

. Recovery of Parainfluenza Viruses from cDNAs

. Epidemiology

. Clinical Features

. Control

Online posting date: 15th March 2011

ELS subject area: Virology

How to cite:Chambers, Raychel; and Takimoto, Toru (March 2011) Parainfluenza

Viruses. In: Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd:Chichester.

DOI: 10.1002/9780470015902.a0001078.pub3

ENCYCLOPEDIA OF LIFE SCIENCES & 2011, John Wiley & Sons, Ltd. www.els.net 1

http://dx.doi.org/10.1038/npg.els.0000424









8–12 nm from the surface of the virus membrane orinfected cell. Underlying the viral lipid bilayer is the matrix(M) protein, which is the most abundant protein in thevirion. The viral membrane encompasses the viral RNAwhich is encapsidated with nucleoprotein (NP) to formnucleocapsids. The nucleocapsid is attached to the poly-merase complex composed of phospho (P) and large (L)proteins to form the biologically active ribonucleocapsid.See also: Virus Structure

Surface glycoproteins

The HN and F glycoproteins are anchored in the viralenvelope by a hydrophobic transmembrane domain. Mostof the protein lies external to the membrane, with a shorthydrophilic cytoplasmic domain lying internal to themembrane. HN is a type-II glycoprotein which has atransmembrane domain near the N-terminus of the pro-tein. The parainfluenza HN glycoproteins contain 4–10sites for the addition of N-linked carbohydrate chains.Most of the parainfluenza HNs form oligomers consistingof disulphide-linked homodimers. HN is a multifunctionalprotein and is the virion’s main type-specific antigenic

determinant. HN is responsible for binding the virus tosialic acid-containing receptors (glycolipid or glycoprotein)on cells. In addition, HN mediates enzymatic cleavage ofsialic acids from cell surface receptors; this cleavageenhances the release of progeny virions from infectedcells and aids their spread to uninfected target cells. Thethree-dimensional structure of HN revealed the protein tobe a six-sheeted b-propeller, similar to influenza virusand bacterial neuraminidases (Crennell et al., 2000). Thereceptor-binding activity resides in the same site as theneuraminidase activity. However, some paramyxovirusescontain a 2nd receptor-binding site on HN (Zaitsev et al.,2004).The other surface glycoprotein, F, is a type-I molecule

with a transmembrane domain near the C-terminus. Fmediates fusion of the virus with the host cell membraneand fusion of infected cells with adjacent cells. The F pro-tein is synthesised in infected cells as a biologically inactiveprecursor protein, F0. A host cell proteolytic enzymecleaves F0 to produce the biologically active disulphide-linked subunits F1 and F2, with F1 containing the C-terminal transmembrane domain. The sequence spanningapproximately the first 25 amino acids at theN-terminus ofF1 is hydrophobic and is the most highly conserved regionin the F protein. These N-terminal residues are called thefusion peptide, and direct insertion of the fusion peptideinto the target cell membrane is believed to play the largestrole in the fusion of the virus envelope with the cell mem-brane. Crystal structure of the paramyxovirus F protein intwo conformations, representing pre- and post-fusionstates, revealed a large scale, irreversible refolding duringmembrane fusion (Lamb and Jardetzky, 2007). See also:Glycoproteins

Matrix protein

The M protein is the smallest of the major structural pro-teins (Mr approximately 40 000) and is the most abundantprotein produced in the paramyxoviruses. The parain-fluenza virus M proteins contain 348–383 residues and arebasic proteins. Although the M proteins do not havehydrophobic sequences long enough to span a cell mem-brane, the general hydrophobic and basic nature of theprotein allows association with cell membranes. On thecytoplasmic side of the plasma membrane, M proteinsinteract with each other to form a sheet that excludes cel-lular membrane proteins. The M proteins are thought toassociate with specific HN and F glycoproteins throughtheir cytoplasmic domains. In addition to glycoproteins,the M proteins also recognise and associate with viralnucleocapsids. Freeze-fracture electron micrographs ofvirus particles show that the M protein forms a sheetbetween the lipid bilayer on the outside and the viralnucleocapsid on the inside. When treated with non-ionicdetergents, the M protein remains bound to the nucleo-capsid, although it is dissociated from the glycoproteins.The interaction between the M protein and the nucleo-capsid is highly specific, and dissociation requires

Table 1 Classification of parainfluenza viruses within

nonsegmented negative-strand RNA viruses

Order Mononegavirales

Family Paramyxoviridae

Subfamily Paramyxovirinae

Genus Respirovirus

Human parainfluenza virus 1 and 3

Sendai virus (also called murine parainfluenza virus 1)

Bovine parainfluenza virus 3

Genus Rubulavirus

Human parainfluenza virus 2, 4A and 4B

Parainfluenza virus 5 (previously known as Simian virus

5/Canine parainfluenza virus 2)

Simian virus 41

Mumps virus

Genus Avulavirus

Newcastle disease virus

Avian parainfluenza viruses 2-9

Genus Morbillivirus

Measles virus

Rinderpest virus

Genus Henipavirus

Hendra virus

Nipah virus

Subfamily Pneumovirinae

Genus Pneumovirus

Human respiratory syncytial virus

Bovine respiratory syncytial virus

Genus Metapneumovirus

Human metapneumovirus

Avian metapneumovirus

Note: Type species are shown in bold.

Parainfluenza Viruses

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treatment with highly ionic reagents. Furthermore, the Mprotein expressed singly can trigger the budding process(Coronel et al., 1999). The expression of M protein fromcDNA results in the formation of M-containing virus-likeparticles (VLPs), and these VLPs are released into themedium. Because of these functions, the M protein isconsidered to be the central organiser of viral assembly.

Nucleocapsid

The viral genome consists of a nonsegmented negative-strand RNAmolecule 15 000–16 000 nucleotides in length.The genomic RNA is tightly associated with NP to form ahelical nucleocapsid core that has a buoyant density of1.30–1.31 g cm23 in caesium chloride (Figure 1). A viralpolymerase complex that consists of P and L proteinsassociates with the nucleocapsid core, and together thesefour components compose the nucleocapsid. The Sendaivirus nucleocapsid is composed of approximately 2600NP,300 P and 50 L protein molecules. Sequence analysis of theNP gene has shown that theN-terminal 80%of the proteinis relatively well conserved among related viruses, whereastheC-terminal 20% is poorly conserved. ThehypervariableC-terminus appears to be the region exposed at the surfaceof the nucleocapsid, and it contains the domain that bindsto the M protein. The well-conserved N-terminal regioncontains the determinants for the NP–NP interaction thatforms the helical structure and RNA-binding domain. TheP protein, which was named for its highly phosphorylatednature, plays a central role in RNA synthesis, and formshomotetramers via predicted coiled-coils. Sendai virus Pprotein is composed of N- and C-terminal conserved do-mains separated by a hypervariable region. These domainsinteract with the NP and L proteins. The C-terminal halfis essential for transcription and contains the domainrequired for binding to the L protein and to the nucleo-capsid. The L protein has a molecular size greater than

200 kDa and is the least abundant of the structural pro-teins. Although the precise composition of the L–P poly-merase complex is unclear, it is known that the P-bindingsite on the L protein is located in theN-terminal half of theprotein. This P–L complex is responsible for the tran-scription that producesmessengerRNA (mRNA),which iscapped at its 5’ end and polyadenylated at its 3’ end, and forthe replication of the viral genome. The L proteins arethought to execute all of the catalytic steps of RNA syn-thesis, capping and methylation.

Accessory proteins

The accessory proteins C and V are expressed from the Pgene. The VmRNA is generated by RNA editing, in whichoneor twoGresidues are inserted into the transcripts of theP gene at the editing site, except in Rubulaviruses, whichproduce V from intact mRNA and P from edited mRNA.Respiroviruses express C proteins from the open readingframe (ORF) that overlaps theN-terminal portion of the Pgene, in the+1 frame. The accessory proteins can abrogatevarious facets of type I interferon (IFN) induction andsignalling, and are therefore, major factors of viruspathogenicity. In addition, the C protein regulates viralgenome transcription/replication through an interactionwith L protein.

Genomic RNA

The complete genome sequences of many parainfluenzaviruses are now known (e.g. Sendai virus, 15 384 nucleot-ides; HPIV-3, 15 462 nucleotides). The genome map ofSendai virus, one of the best-characterised parainfluenzaviruses, is shown in Figure 1. The genomic RNA of allparainfluenza viruses generates six separate nonoverlap-ping polyadenylatedmRNAs that encodeNP, P,M,F,HNand L proteins. The mRNA that encodes the P proteincontains several additional ORFs that encode C and V

Figure 1 Structure of parainfluenza virus. Diagram of parainfluenza virus (Sendai virus, top left) and its genomic RNA (bottom). Electron micrograph of

Sendai virus (top middle) and its helical nucleocapsid (top right).



proteins. The genome consists, in 3’–5’ order, of the leadersequence, the genes for NP, P, M, F, HN and L, and thetrailer sequence. The 3’ leader and 5’ trailer regions containthe viral promoters for synthesis of complementary RNAfrom the template RNAs. The viral polymerase complextranscribes the genome in a linear, sequential, stop–startmanner guided by transcriptional start and stop signals.The Sendai virus gene start sequence consists of 10 nucle-otides (3’-UCCCU/AG/C/AUUU/AC) that encode thefirst 10 nucleotides of the mRNA. Each gene ends withthe conserved sequence 3’-C/A/UAUUCUUUUU, whichencodes the 3’ end of each mRNA and encodes the poly(A)tail by reiterative copying of the U tract. The genes areseparated by the trinucleotides GAA or GGG, intergenicsequences that are highly conserved amongRespiroviruses.These trinucleotides, flanked on either side by the gene endand gene start sequences, are thought to participate in thesignalling of transcriptional termination and initiation bythe viral polymerase complex. In contrast, the intergenicsequences of Rubulaviruses are quite variable in com-position and length; this variation suggests that, withRubulaviruses, intergenic sequences do not provide cis-acting signals involved in viral transcription. See also:RNA Virus Genomes; Viruses: Genomes and Genomics

Viral Replication

Entry

Parainfluenza virus infection is initiated by viral attach-ment to cellular receptors. After viral HN glycoproteinbinds to sialic acid-containing glycolipids or glycoproteinson the cell surface, F protein induces fusion of the viral

envelope and the cellular plasma membrane. Membranefusion occurs at a neutral pH, suggesting that the event ismediated at the cell surface. The HN protein is alsoinvolved in the fusion process. Significant membranefusion (syncytium formation) is observed only when HNandFproteins of the same virus or of closely related virusesare expressed in the same cells (Figure 2). Thus, a virus type-specific interaction is necessary for membrane fusioninduced by the F protein. In fact, it has been suggested thatphysical interaction between HN and F proteins of hom-ologous viruses occurs. Experiments using chimeric andmutant HN proteins have shown that both the stalk region(close to the transmembrane domain) and the head regionare responsible for promoting fusion activity (Bousse et al.,1994). Solution of the atomic structure of HN and a sub-sequent mutagenesis study provided insight into the roleof HN in membrane fusion (Takimoto et al., 2002). Thefusion promotion domain is located at the hydrophobicsurface of the HN protein, which includes the area wherethe structure changes upon binding to the receptor. Acurrent model for the fusion process is that a structuralchange in HN induced by receptor-binding triggers aconformational change in F that exposes the fusion pep-tide. The fusion peptide is then inserted into the cellmembrane tomediate fusionwith the viral envelope. In thisway, F and HN operate together as a molecular scaffold toexpose and direct the fusion peptide to the target mem-brane (Baker et al., 1999; Takimoto et al., 2002). See also:Viral Replication; Virus Host Cell Receptors

Transcription and genome replication

After fusion of the virus and the cell membrane, viralnucleocapsid is dissociated fromMprotein by an unknown

Figure 2 Syncytium formation induced by haemagglutinin-neuraminidase (HN) and fusion (F) proteins. Membrane fusion occurs when HN and F proteins

of the homologous viruses (b) but not heterologous viruses (a) are expressed; this finding indicates that specific interaction between HN and F is required for

membrane fusion (Bousse et al., 1994).







mechanism and released into the cytoplasm of the cell.RNA synthesis is thought to begin as soon as the genomeencounters the cytoplasmic ribonucleoside triphosphates.The viral polymerase complex (P–L) transcribes each genein the viral RNA template. The frequency with which thepolymerase restarts mRNA synthesis at each junction ishigh, but themechanism is not perfect. Thus, less mRNA ismade from downstream genes than from their upstreamneighbours, and mRNA quantity varies with the positionof the gene relative to the 3’ end of the template. Aftertranslation of the primary transcripts and accumulation ofthe viral proteins, antigenome synthesis begins. The sameviral polymerase complex copies the same viral RNAtemplate and synthesises an exact, complementary copy(antigenome RNA). Newly synthesised NP associates withnascent antigenome RNA to form the helical nucleocapsidstructure. The antigenome RNA is found only in anassembled form with NP and considerable amounts ofantigenome nucleocapsid are present in parainfluenzavirus-infected cells (10–40% in Sendai virus-infected cells).The antigenome nucleocapsid is then utilised as a templateto generate viral nucleocapsid with negative-strand gen-ome RNA. The viral polymerase complex recognises theviral RNAonlywhen it is encapsidatedwithNP. TheRNAreplication of Respiroviruses is efficient only if the numberof nucleotides in the genome is a multiple of six (the rule ofsix; Calain andRoux, 1993). This observation is believed toreflect a requisite association in the nucleocapsid of eachNP monomer with exactly six nucleotides. See also: RNAPlant and Animal Virus Replication

Assembly

Paramyxoviruses replicate in the cytoplasmof infected cells,and the progeny virions are assembled at the plasma mem-brane of the cells. Two glycoproteins are synthesised in therough endoplasmic reticulumand transported to the plasmamembrane through the exocytic pathway from the trans-Golgi network. The HN protein contains a single hydro-phobic domain, located close to theN-terminus, that acts asa combined signal and anchorage domain, targeting thenascent chain as it moves from the ribosome towards themembrane of the endoplasmic reticulum and during trans-location of the polypeptide chain across the membrane. TheF gene sequences encode anN-terminal hydrophobic signalpeptide of approximately 18 amino acids that mediatesinsertion into the rough endoplasmic reticulum duringsynthesis and is cleaved by the cellular signal peptidase. Ahydrophobic transmembrane domain at the C-terminusanchors the protein in the membrane, leaving a short cyto-plasmic tail. Glycosylation and cleavage of the signal pep-tide may occur co-translationally, followed by folding,disulphide bond formation and rearrangement, and assem-bly into noncovalently associated F0 homotrimers. Theoligomer is then transported through the exocytic pathwayto the plasmamembrane.Mproteins are synthesised on freecytoplasmic polyribosomes and are likely to be transportedto the plasma membrane in part by an association with

envelope glycoproteins. The mechanism of how progenyviral nucleocapsids are translocated to the plasma mem-brane is not clear. However, a study using recombinantSendai virus containing L protein tagged with enhancedgreen fluorescent protein (eGFP) revealed nucleocapsidtrafficking through the cytoplasm along microtubule struc-tures in live cells (Figure3). Additional analysis suggests thatthe virus utilises the recycling endosomepathway regulatedby an Rab GTPase (guanosine triphosphatase), Rab11afor nucleocapsid trafficking (Chambers and Takimoto,2010). The mechanisms by which the virus particles areassembled at the plasma membrane and budding (the finalstage of virion formation) occurs are largely unknown,although, as discussed earlier, the M protein is believed tobe the central organiser of assembly. Many studies impli-cate lipid rafts as sites of enveloped virus assembly andbudding. In fact, caveolin 1, an integral membrane proteinthat forms the coat structure of plasmamembrane caveolaewas shown to affect assembly and production of infectiousparainfluenza virus 5 (Ravid et al., 2010). See also:Membrane Rafts and Caveolae

Anti-interferon activity

To establish infections in vivo, viruses must replicate in theface of powerful immune defence mechanisms includingthose induced by interferon (IFN). Like other viruses,parainfluenza viruses have evolved strategies to counteractthe antiviral effects of IFNs. Sendai virus, PIV5, HPIV-2and HPIV-3 block type-I IFN signalling by degrading orpreventing appropriate phosphorylation of STAT pro-teins, key components of IFN signalling (Goodbourn andRandall, 2009). The anti-IFN activity is provided by theaccessory proteins C and V, which are encoded in the viralP gene (Gotoh et al., 2001) and this IFN antagonism isspecies specific (Chambers andTakimoto, 2009). Althoughthese accessory proteins are nonessential for viral repli-cation in tissue culture cells, mutant viruses that do notexpress C or V proteins have attenuated in vivo replicationand pathogenicity. This indicates that anti-IFN activityplays a key role in viral pathogenicity. See also: Interferons

Recovery of Parainfluenza Virusesfrom cDNAs

An important breakthrough in paramyxovirus researchhas been the construction of cDNA clones of viral RNAgenomes fromwhich infectious virus canbe recovered.Thisadvance has made it possible to use ‘reverse genetics’studies to test several hypotheses about viral assembly andentry mechanisms and to investigate the production ofattenuated viruses that can be used as live vaccines. Thesystem requires transcription of full-length genomic cDNAinto positive-sense RNA that is complementary to thegenome. When co-expressed in cells with the NP andpolymerase proteins, the RNA transcripts are packaged





http://dx.doi.org/10.1002/9780470015902.a0021022


into ribonucleocapsids that can initiate an infectious cycle,resulting in the generation of recombinant virus. This sys-tem was first developed for rabies virus, a member of theRhabdoviridae family (Schnell et al., 1994). Now, similarrescue systems have been developed for several para-myxoviruses, including measles and rinderpest viruses(Morbillivirus genus; Table 1), Sendai virus, HPIV-1, 2, 3,PIV5 and Newcastle disease virus. See also: Rabies Virus

Epidemiology

The predominant disease caused by human parainfluenzaviruses is acute respiratory tract infection. More than 5million lower respiratory tract infections (LRTIs) aredocumented each year in theUnited States among childrenless than 6 years of age; HPIV serotypes 1, 2 and 3 areresponsible for approximately one-third of these LRTIs.Annual epidemics of HPIV-3 infection are the rule, butepidemics involving types 1 and 2 commonly occur inalternate years. The epidemics caused by HPIV-1 and -2build quickly to a peak in the autumn or early winter, butHPIV-3 may circulate through much of the year. ChildreninfectedwithHPIV-3 are often younger than those infectedwith the other viruses. Maternally derived antibodies givesubstantial protection for the first 4 months of life, afterwhich the infection rate rises rapidly and is at its peakduring the next 18 months. In a typical cosmopolitanpopulation, 50% of children have experienced type 3infection before they reach the age of 2, and types 1 and 2infection before they reach the age of 5. Both adults and

children can be re-infected with parainfluenza viruses.Most persons are probably infected repeatedly with HPIVserotypes 1, 2 and 3. Illness tends to be less frequent and lesssevere after re-infection than after primary infection.Parainfluenza virus is transmitted by direct person-to-

person contact or by large-droplet spread; the viruses donot remain infectious in the environment. Studies of adultvolunteers suggested that the infectious dose of HPIV-1 issmall. Two-thirds of adults who possessed a moderatelyhigh level of pre-existing neutralising antibodies in serumbecame infected after intranasal instillation of 80 infectiousHPIV-1 units. The HPIV-3 serotype appears to spreadmost efficiently fromperson to person. There is no evidencethat infection is transmitted from humans to animals orvice versa. See also: Immunity to Infection

Clinical Features

In children, the most common type of illness from para-influenza consists of rhinitis, pharyngitis and bronchitis,usually accompanied by fever. The usual initial symptomsare cough, hoarseness and fever. Approximately three-quarters of these children have a temperature above 37.78C(1008F) for 2–3 days. Infection in immuno-compromisedpatients is usually prolonged and may be severe. There isconsiderable diversity in the clinical manifestations ofinfections caused by parainfluenza viruses. The HPIV-1and -2 serotypes cause most cases of laryngotracheobron-chitis (croup) in children, averaging approximately 600 000cases per year in the United States. HPIV-3 is responsible

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Figure 3 Live cell tracking of viral nucleocapsid movement. Sendai virus nucleocapsid, which contains L protein tagged with eGFP can be visualised in live

cells using fluorescence microscopy. These nucleocapsids move along microtubule structures in infected cells. Trafficking of nucleocapsid is shown in the

time lapse series of images (b) taken from the boxed area of the infected cells shown in (a). Reproduced from Chambers and Takimoto (2010).





for 3–10% of hospitalisations and usually causes bronch-iolitis, pneumonia or croup.

Control

No vaccine is currently available to protect against infec-tion caused by any of the HPIVs. Currently, live-attenu-ated and subunit vaccine approaches are underinvestigation (Girard et al., 2005; Sato and Wright, 2008).

Live-attenuated, cold-adapted vaccines

Cold-passage (cp) HPIV-3 mutants were selected by serialpassage of HPIV-3 in cell culture at temperatures that wereprogressively reduced to 208C or 228C. The cp45 mutantpossessed the desired properties of cold adaptation, tem-perature sensitivity (ts) and attenuation (att) of virulence inrodents and nonhuman primates. The cp45 candidatevaccine virus was highly infectious, satisfactorily attenu-ated, immunogenic, poorly transmissible and geneticallystable during replication in seronegative infants and youngchildren (Durbin et al., 1999). Highly attenuated recom-binant HPIV-1 vaccine strains were created by introducingmutations in the C, HN and L proteins of HPIV-1. Theresultant vaccine strains were exceedingly ts, att andimmunogenic and efficacious against HPIV-1 wt challenge(Bartlett et al., 2007). See also: Vaccines: Whole Organism

Bovine parainfluenza virus 3 and Sendaivirus-based vaccines

Bovine parainfluenza virus 3 (BPIV-3) was chosen as acandidate live-virus vaccine for preventing HPIV-3 infec-tion because it is closely related to HPIV-3, inducesresistance to HPIV-3 challenge and is avirulent in nonhu-man primates. In humans, the BPIV-3 vaccine straininduced an immune response to HPIV-3 in most infants,and is safe for use in treating seronegative infants andchildren of 2–36 months of age. Later, a chimeric BPIV-3whoseHNandFgeneswere replacedwith those ofHPIV-3was produced from cDNA using the reverse genetics sys-tem (Haller et al., 2000). This chimeric virus induces ahigher level of serum antibody to HPIV-3 with the hostrange restriction and attenuation phenotype of BPIV-3. Astrategy similar to the BPIV-3 chimeric vaccinewas utilisedto create multiple recombinant Sendai virus vaccinestrains. Sendai virus is closely related to HPIV-1 insequence and structure. The human immune memoryresponse towards HPIV-1 is largely cross-reactive withSendai virus. Intranasal administration of Sendai virus toAfrican green monkeys fully protected them from HPIV-1challenge (Hurwitz et al., 1997). Recombinant Sendai vir-uses expressing the envelope glycoproteins of HPIV-2 andHPIV-3 induced long lasting protection in cotton ratsagainst challenge with HPIV-1, HPIV-2 and HPIV-3(Jones et al., 2009; Zhan et al., 2008). These results dem-onstrate that BPIV-3 and Sendai virus can be useful as

effective vaccine vectors against human parainfluenzaviruses.

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Further Reading

Chambers R and Takimoto T (2009) Antagonism of innate

immunity by paramyxovirus accessory proteins. Viruses 1:

574–593.

HarrisonMS,SakaguchiTandSchmittAP (2010)Paramyxovirus

assembly and budding: building particles that transmit infec-

tions. International Journal of Biochemistry and Cell Biology 42:

1416–1429.

Karron RA and Collins PL (2007) Parainfluenza viruses. In:

Fields BN, Knipe DM and Howley PM et al. (eds) Fields Vir-

ology, 5th ed, pp. 1497–1526. Philadelphia: Lippincott-Raven.

LambRAandParksGD (2007) Paramyxoviridae: the viruses and

their replication. In: Fields BN, Knipe DM and Howley PM

et al. (eds) Fields Virology, 5th ed, pp. 1449–1496. Philadelphia:

Lippincott-Raven.

Randall RE and Goodbourn S (2008) Interferons and viruses: an

interplay between induction, signalling, antiviral responses and

virus countermeasures. Journal of General Virology 89: 1–47.



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