Human parainfluenza viruses (HPIVs) are the viruses that cause human parainfluenza. HPIVs are a paraphyletic group of four distinct single-stranded RNA viruses belonging to the Paramyxoviridae family. These viruses are closely associated with both human and veterinary disease. Virions are approximately 150–250 nm in size and contain negative sense RNA with a genome encompassing about 15,000 nucleotides.
The viruses can be detected via cell culture, immunofluorescent microscopy, and PCR. HPIVs lack antiviral drug options and vaccine, remain a major contributor toward the annual burden of hospitalisations among children younger than age 5—being second only to respiratory syncytial virus (RSV) in this regard—and are the predominant cause of laryngotracheobronchitis (also known as croup).
Classification The first HPIV was discovered in the late 1950s. The taxonomic division is broadly based on antigenic and genetic characteristics, forming four major serotypes or clades, which today are considered distinct viruses. These include:
HPIVs belong to two genera: Respirovirus (HPIV-1 & HPIV-3) and Rubulavirus (HPIV-2 & HPIV-4).
Viral structure and organisation HPIVs are characterised by producing enveloped virions and containing single stranded negative sense RNA. Non-infectious virions have also been reported to contain RNA with positive polarity. HPIV genomes are about 15,000 nucleotides in length and encode six key structural proteins. The structural gene sequence of HPIVs is as follows: 3′-NP-P-M-F-HN-L-5′ (the protein prefixes and further details are outlined in the table below).
With the advent of reverse genetics, it has been found that the most efficient human parainfluenza viruses (in terms of replication and transcription) have a genome nucleotide total that is divisible by the number 6. This has led to the "rule of six" being coined. Exceptions to the rule have been found, and its exact advantages are not fully understood. Electrophoresis has shown that the molecular weight of the proteins for the four HPIVs are similar (with the exception of the phosphoprotein, which shows significant variation).
Viral entry and replication Viral replication is initiated only after successful entry into a cell by attachment and fusion between the virus and the host cell lipid membrane. Viral RNA (vRNA) is initially associated with nucleoprotein (NP), phosphoprotein (P) and the large protein (L). The hemagglutinin–neuraminidase (HN) is involved with viral attachment and thus hemadsorption and hemagglutination. Furthermore, the fusion (F) protein is important in aiding the fusion of the host and viral cellular membranes, eventually forming syncytia. Initially the F protein is in an inactive form (F0) but can be cleaved by proteolysis to form its active form, F1 and F2, linked by di-sulphide bonds. Once complete, this is followed by the HPIV nucleocapsid entering the cytoplasm of the cell. Subsequently, genomic transcription occurs using the viruses own 'viral RNA-dependent RNA polymerase' (L protein). The cell's own ribosomes are then tasked with translation, forming the viral proteins from the viral mRNA. Towards the end of the process, (after the formation of the viral proteins) the replication of the viral genome occurs. Initially, this occurs with the formation of a positive-sense RNA (intermediate step, necessary for producing progeny), and finally, negative-sense RNA is formed which is then associated with the nucleoprotein. This may then be either packaged and released from the cell by budding or used for subsequent rounds of transcription and replication. The observable and morphological changes that can be seen in infected cells include the enlargement of the cytoplasm, decreased mitotic activity and 'focal rounding', with the potential formation of multi-nucleate cells (syncytia). The pathogenicity of HPIVs is mutually dependent on the viruses having the correct accessory proteins that are able to elicit anti-interferon properties. This is a major factor in the clinical significance of disease.
Host range The main host remains the human. However, infections have been induced in other animals (both under natural and experimental situations), although these were always asymptomatic.
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