Swine Flu
Swine flu is a variant of Influenza A virus (IAV) of the family Alphainfluenzavirus. This virus is a negative-sense, single-stranded, segmented RNA virus. While swine flu is endemic in pigs, variants may able to infect humans, resulting in symptomology similar to that of the seasonal flu such as fever, chills, muscle aches, sore throat, coughing, and headaches. Swine flus are classified by their antigenic proteins, hemagglutinin and neuraminidase, which can vary in identity from 1-18 and 1-11, respectively. Zoonosis of the disease is relatively uncommon, but those with frequent exposure to pigs are at greater risk. Human to human transmission is also unlikely, but notable breakouts have been recorded, including the 1918 flu pandemic, the 2009 swine flu pandemic, and several smaller, lesser-known outbreaks in India and the Middle East. During the 2009 H1N1 outbreak, vaccinations were available in the United States for those at greatest risk of complications, but vaccination against IAVs is largely nonexistent.
IAV RNA-Dependent RNA Polymerase
The RNA-dependent RNA polymerase (RdRp) is a critical protein complex for the replication and transcription of viral genes. This enzyme is of clinical significance in IAV because it is critical in the zoonosis of Influenza A viruses like swine flu. Because of its critical roles in viral replication and zoonosis, RdRp is the focus of much antiviral research. However, due to limited structural elucidation of the Influenza A RdRP, structural-based drug design to inhibit RdRp activity is also limited. Influenza A RdRp is also an especially difficult site for drug development because it is unique relative to other viral RdRps. Unlike many other viral RdRps, IAV RdRp must first enter the nucleus to transcribe and replicate viral genetic information as opposed to first initiating translation in the cytoplasm. To initiate transcription, primers must be taken from host RNAs through cap-snatching, wherein 5' caps are cleaved from host RNAs and transferred to viral RNA.
RdRp Structure
IAV RdRp consists of three unique polypeptide subunits called polymerase basic 1 (PB1), polymerase basic 2 (PB2) and polymerase acidic (PA).
The PB1 subunit constitutes the stereotypical right-handed model of RdRp, including the fingers, palm, and thumb of the hand. Motifs A-E are contained within the PB1 domain: motifs A, C, D, and E are all in the palm, and motifs B and F are in the fingers. The PB2 domain interacts with the PB1 thumb and C-terminus extension, conferring flexibility and stability to the overall complex. The PA domain spans the backside of PB1 and is responsible for the endonuclease activity of the RdRp.
The PB2 also contains the cap-binding domain necessary for cap-snatching. PB2 recognizes host primers and captures host RNA, allowing PA's endonuclease domain to cleave primers away.
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References
Swine influenza. The Merck Veterinary Manual. 2008. ISBN 978-1-4421-6742-1. Archived from the original on March 4, 2016. Retrieved April 30, 2009.
“Vaccine against 2009 H1N1 Influenza Virus.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 2010, https://www.cdc.gov/h1n1flu/vaccination/public/vaccination_qa_pub.htm.
“Variant Influenza Viruses: Background and CDC Risk Assessment and Reporting.” Centers for Disease Control and Prevention, Centers for Disease Control and Prevention, 12 Sept. 2016, https://www.cdc.gov/flu/swineflu/variant.htm.
Stubbs, Thomas M, and Aartjan Jw Te Velthuis. “The RNA-dependent RNA polymerase of the influenza A virus.” Future virology vol. 9,9 (2014): 863-876. doi:10.2217/fvl.14.66
Te Velthuis, Aartjan J W, and Ervin Fodor. “Influenza virus RNA polymerase: insights into the mechanisms of viral RNA synthesis.” Nature reviews. Microbiology vol. 14,8 (2016): 479-93. doi:10.1038/nrmicro.2016.87
