Virology Ch.18 Influenza Virus

Virion Characteristics

• Enveloped particles, quasi-spherical or filamentous
• Diameter: 80-120 nm
• Envelope derived from host plasma membrane via budding
• Contains compact helical nucleocapsids

Genome Structure of Influenza Viruses

• Linear single-stranded RNA, negative sense
• Contains six to eight different segments
  • Key proteins:
  • PB1, PB2, PA (RNA polymerase)
  • HA (hemagglutinin)
  • NA (neuraminidase)
  • M2 (ion channel)
  • NP (nucleocapsid protein)
  • M1 (matrix protein)

Family Classification

• Orthomyxoviridae includes:
  • Influenza A: 8 segments, infects birds, mammals, humans
  • Influenza B: similar to A but limited to humans and seals
  • Influenza C: causes mild upper respiratory illness with 7 segments

Disease Symptoms

• Common symptoms:
  • High fever, sore throat, cough, headache, muscular pain
  • Can be fatal in the elderly, infants, and chronically ill due to secondary bacterial infections
• Notable pandemics:
  • Spanish flu (1918-1920): Over 20 million deaths
  • H1N1 pandemic (2009): Approximately 675,000 deaths in the U.S.

Pathogenesis of Influenza Infections

• Infections can lead to secondary bacterial infections
• Initial infection disrupts ciliated epithelium and mucociliary flow
• Induces production of interferons and cytokines

Genes and Proteins of Orthomyxoviruses

• Negative-strand RNA viruses with segmented genomes
• 8 segments encode 11 different viral proteins
  • Key proteins include:
  • HA and NA (envelope glycoproteins)
  • M2 (integral membrane protein)
  • NP (nucleocapsid protein)
  • PA, PB1, PB2 (RNA polymerase proteins)
  • NS1, NS2, PB1-F2 (nonstructural proteins)

Influenza A Virus Genome Structure

RNA segment details:

• Segment 1: Length 2341 nucleotides, encodes PB2 (759 aa)
• Segment 2: Length 2341, encodes PB1 (757 aa), PB1-F2 (87-90 aa)
• Segment 3: Length 2233, encodes PA (716 aa)
• Segment 4: Length 1778, encodes HA (566 aa)
• Segment 5: Length 1565, encodes NP (498 aa)
• Segment 6: Length 1413, encodes NA (454 aa)
• Segment 7: Length 1027, encodes M1 (252 aa), M2 (97 aa)
• Segment 8: Length 890, encodes NS1 (230 aa), NS2 (121 aa)

Hemagglutinin Protein (HA)

• Binds to cell receptors and mediates fusion of the viral envelope with the endosomal membrane
• Cleavage by cellular proteases exposes a fusion peptide essential for infecting cells
• Types of sialic acid binding:
  • Avian influenza: binds to alpha(2,3) linked sialic acid
  • Human influenza: binds to alpha(2,6) linked sialic acid

M2 Protein Function

• Ion channel facilitating nucleocapsid release
• Allows protons to weaken interactions with M1, enabling release during low pH conditions
• Amantadine is known to block the M2 channel

Viral RNA Synthesis Mechanism

• Utilizes cap-snatching mechanism to produce primers from host mRNAs
• Viral RNA polymerase cleaves cellular mRNAs near their 5' ends

Replication and Assembly

• Nucleocapsids enter nucleus; viral mRNA synthesis occurs here
• Exported with matrix protein and NS2
• Neuraminidase cleaves sialic acid, allowing viral release

Genetic Variability in Influenza

• Genetic shifts and drifts lead to new strains:
  • Antigenic Drift: gradual accumulation of mutations
  • Antigenic Shift: reassortment during mixed infections, leading to new strains

Influenza Pandemic Examples

• The 1918 pandemic was primarily a result of antigenic drift, confirmed by genome sequences of earlier strains
• Certain highly pathogenic strains (e.g., H5N1) pose a potential threat but have low transmission rates among humans.

Key Antiviral Drugs

• Zanamivir and Oseltamivir (Tamiflu) stockpiled in preparation for pandemics

Fundamental Concepts

• Cause serious diseases and pandemics
• Segmented genomes code for 11 proteins
• HA protein's role in cell receptor fusion
• NS1 and PB1-F2 proteins suppress host antiviral responses
• M2 ion channel facilitates nucleocapsid release
• Genetic variability enables adaptation and potential pandemics