What are the basic virological features of influenza viruses?

Basic Virological Features of Influenza Viruses

Viral Classification and Types

Influenza A and B are the two types of influenza viruses that cause epidemic human disease, with influenza A viruses further categorized into subtypes based on two critical surface antigens: hemagglutinin (H) and neuraminidase (N). 1

• Influenza B viruses are not categorized into subtypes and undergo antigenic drift less rapidly than influenza A viruses 1
• Since 1977, influenza A (H1N1), influenza A (H3N2), and influenza B viruses have been in global circulation 1
• Influenza A (H1N2) viruses emerged after genetic reassortment between human A (H3N2) and A (H1N1) viruses and have been detected in many countries 1

Viral Structure and Genome Organization

The influenza virus has a segmented, negative-strand RNA genome consisting of eight single-stranded RNA molecules that require a viral RNA-dependent RNA polymerase for replication. 2, 3

• Spherical virions are 80-120 nm (approximately 1000 Å) in diameter with a two-layer lipid envelope 4, 5
• The viral envelope is decorated with three transmembrane proteins: hemagglutinin (HA), neuraminidase (NA), and M2 6, 5
• An intermediate layer of matrix protein (M1) lies beneath the envelope 6
• The innermost core consists of helical viral ribonucleocapsid (vRNP) formed by nucleoprotein (NP) and negative-strand viral RNA (vRNA) 6

Key Viral Proteins and Their Functions

The eight RNA segments encode critical proteins including nucleoprotein (NP), polymerases (PB2, PB1, PA), matrix proteins (M1 and M2), and surface glycoproteins (hemagglutinin and neuraminidase). 4

• Hemagglutinin (HA) mediates viral attachment to host cells and is the primary target of neutralizing antibodies 1, 4
• Neuraminidase (NA) facilitates viral release from infected cells by cleaving sialic acid residues 4, 6
• M2 protein functions as a proton channel essential for viral uncoating 5
• HA and NA form spikes on the virion surface that are critical for viral entry and egress 4, 6

Antigenic Variation Mechanisms

Influenza viruses undergo two distinct mechanisms of antigenic change: antigenic drift through point mutations during viral replication, and antigenic shift involving major changes through genetic reassortment between different strains. 1, 7

Antigenic Drift

• Results from frequent point mutations and recombination events during viral replication 1
• Creates new influenza virus variants continuously 1
• Influenza A viruses undergo antigenic drift more rapidly than influenza B viruses 1
• This is the virologic basis for seasonal epidemics and necessitates annual vaccine strain updates 1

Antigenic Shift

• Occurs less frequently but results in more dramatic changes 1
• Can lead to emergence of novel influenza A virus subtypes with pandemic potential 1
• Happens when a new subtype appears that can cause human illness with efficient human-to-human transmission and little pre-existing immunity 1

Viral Replication Cycle

Influenza virus replication occurs in epithelial cells of the upper respiratory tract, producing approximately 1000 progeny virions during a single 6-12 hour cycle in one infected cell. 4

• The viral RNA-dependent RNA polymerase directs both transcription and replication of the viral RNA genome 2
• Promoter binding by the viral polymerase and formation of an active open complex are prerequisites for viral replication 2
• Necrosis of ciliary cells of the mucosa facilitates invasion of bacterial pathogens 4

Viral Assembly and Budding

Morphogenesis and budding occur at the apical plasma membrane of infected cells, where all viral components must be transported to produce infectious virions. 6

• HA and NA possess apical sorting signals and use exocytic pathways and lipid rafts for cell surface transport 6
• M1 binds to NP, exposed RNAs of vRNPs, and cytoplasmic tails of HA, NA, and M2 6
• Budding involves three processes: bud initiation, bud growth, and bud release 6
• The presence of lipid rafts and viral component assembly causes membrane bending leading to bud formation 6
• Bud release requires fusion of viral and cellular membranes and scission of virus buds from the infected cell membrane 6

Immunological Implications

A person's immunity to surface antigens, particularly hemagglutinin, reduces the likelihood of infection and severity of disease if infection occurs. 1

• Antibody against one influenza virus type or subtype confers limited or no protection against another type or subtype 1
• Antibody to one antigenic variant might not protect against a new antigenic variant of the same type or subtype 1
• Anti-hemagglutinin antibodies play a fundamental role in protection against infection 4
• Anti-neuraminidase antibodies limit virus spreading and contribute to milder disease 4
• Cytotoxic T lymphocytes kill infected cells in early replication phases before progeny virions form 4

Transmission Characteristics

Influenza viruses spread from person to person primarily through respiratory droplets from coughing and sneezing of infected persons. 1, 7

• The incubation period ranges from 1-4 days, with an average of 2 days 1, 4
• Adults are typically infectious from the day before symptoms begin through approximately 5 days after illness onset 1
• Children can be infectious for longer periods, up to 10 days or more 1
• Severely immunocompromised persons can shed virus for weeks or months 1