Human Parainfluenza Virus
Human Parainfluenza viruses (HPIVs) include four differentiated RNA viruses of the Paramyxoviridae genus. Many viruses in this family cause significant human and veterinary diseases. The viruses were first isolated in the 1950s from children with lower respiratory disease. While they are distinct from the influenza virus, the different viruses share some antigenic sites1. Parainfluenza viruses are believed to cause 23,000 hospitalizations in children under the age of five every year in the United States2. Additionally, the viruses cause lower respiratory infections in the immunocompromised, chronically ill, and elderly. Taken together, infections from HPV result in 30-80 times more outpatient visits than inpatient visits. Vaccines are currently in development, with one in phase I and II trials, and others in phase II and III clinical trials3,4. The negative sense RNA viral genome and viral proteins are well characterized; however, the ecology of the virus is still poorly defined5.
Viruses; ssRNA viruses; ssRNA negative-strand viruses; Mononegavirales; Paramyxoviridae; Respirovirus; Human respirovirus6
Genome and Proteome of HPIV
The genome of HPIV is 15 kilobases in length, encoding for six proteins7. The proteins are coded in the following order: nucleocapsid associated protein (N), phosphoprotein (P), internal matrix protein (M), fusion protein (F), hemagglutinin-neuraminidase glycoprotein (HN), and the large polymerase (L). Unlike the other proteins, which have a single coding sequence, or open reading frame (ORF), the phosphoprotein has several reading frames8. These variable reading frames provide a range of functions for the phosphoprotein, from serving as a cofactor for the large polymerase involved in viral replication9, to increasing virion production10. The nucleocapsid associated protein is involved in viral capsid production. The matrix protein surrounds and connects the capsid to the envelope, resulting in a virus with an average size of 150-250 nm in diameter11. The hemagglutinin-neuraminidase glycoprotein, binds to the sialic acid on the surface membrane of target cells in the respiratory tract12, similar to the influenza glycoproteins. The hemagglutinin is responsible for cell entry while the neuraminidase is important for cell exit. The fusion protein is critical for passage across the cell membrane and release of the viral genome into the host cell. Like its analog in influenza, the fusion protein is activated by proteolysis13.
HPIV infects the human body at any age and normally inhabits the upper respiratory tract, causing inflammation and croup, especially in children. Four variants of HPIV exist, but not all infect the same regions of the respiratory tract. Each variant has a unique clinical pattern, ranging from the upper to the lower airways. Epithelial cells in the small upper airways are infected first. As the infection progresses, the virus travels to the lower respiratory tract. Eventually it spreads to the rest of the body if it is not removed by the immune system14.
The extracellular environment of the small airways is important to the life cycle of HPIV. HPIVs fuse to host epithelial cells optimally at neutral pH2. Additionally, the immune system has a mixed effect on viral survival; humoral and cell mediated components around infected epithelium contribute to positive and negative changes to the viral life cycle15.
Viral Metabolism and Mechanism
HPIV life cycle begins when the host cell membrane fuses with the viral membrane. The process is mediated by the viral fusion protein via a hemagglutinin-neuraminidase receptor-binding molecule16. The process is mediated by the F protein, or viral fusion protein. The virus then introduces its genetic material into the cytoplasm of the host cell, followed by subsequent transcription through viral RNA large polymerase or L protein. The virus overrides cellular ribosomal machinery to produce an initial wave of viral proteins which assist production of the rest of the viral genome17.
HPIV life cycle ends by integrating the previously translated viral proteins with the cell membrane to form newly packaged virions4. The virus attaches itself to the cellular membrane of its host using sialic acid-containing receptor moieties. These moieties are ultimately cleaved by neuraminidase in the HN molecule to release new particles, permitting subsequent cycles of infection18.
The Parainfluenza Virus (PIV) targets young children and leads to many respiratory illnesses. For children younger than five years old, it is estimated that PIV-1 infected 3,888 children yearly, PIV-2 infected 8,481 children yearly, and PIV-3 infected 10,186 children yearly19. PIV-1 and PIV-2 are associated with croup syndrome in children. The most common form, PIV-3, can produce croup syndrome but is also associated with many different respiratory issues. Two different strains of rats were infected with PIV-3, exhibiting different responses. Sigmodon hispidus rats developed bronchiolitis but Sigmodon fulviventer developed pneumonia20, suggesting that the exact effects of PIV-3 on a given patient is based on the genotype of the patient. A similar study also looked at S. hispidus rats infected with PIV-3, and these rats developed laryngotracheitis. Studies on the effectiveness of anti-inflammatory glucocorticoids as a treatment method revealed a linear relationship between topical steroid dose and reduction of overall pathology of PIV-321. Overall, PIV induces respiratory infections in young children, with varying symptoms depending on the PIV strain and the individual.
Most of the current research for PIV is focused on treatment and prevention methods, or using PIV to cure or prevent other diseases. Since PIV-3 is the most common strain, many studies have revolved around finding treatments for this strain. Using an enzyme to inhibit a key amino acid, Tyr530 in the hemagglutinin-neuraminidase protein, investigators inhibited the catalytic mechanism of PIV. Furthermore, this opens possible therapeutic strategies using other potential inhibitors22. Using this workflow, two vaccines were tested that targeted hemagglutinin, resulting in production of inhibiting antibodies23. Another treatment developed uses seven PIV-3 antigens, inducing CD4+ and CD8+ T cells to produce cytokines that kill PIV-3 expressing cells. These findings could guide clinical studies to test the viability of this treatment option24. One possibility is to use PIV for vaccine delivery. Using PIV-5 as a vector, investigators could deliver a vaccine against tuberculosis25. Overall, current research is directed to learning about how PIV behaves and the various ways to prevent and treat it.
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