Influenza Virus

Subjects: virology, microbiology · Systems: virology, microbiology · Tags: virology, microbiology

Influenza Viruses

Influenza viruses are enveloped, negative-sense, single-stranded RNA viruses belonging to the Orthomyxoviridae family. They are notable for their segmented genomes: influenza A and B viruses contain eight RNA segments, while influenza C and D contain seven. Each segment encodes one or more proteins, giving the virus a modular architecture that enables genetic reassortment when multiple strains infect the same cell. This feature underlies the phenomena of antigenic drift and antigenic shift, which drive seasonal epidemics and occasional pandemics. The viral genome is encapsidated by nucleoprotein (NP) and associated with the viral RNA-dependent RNA polymerase complex composed of PB1, PB2, and PA, forming ribonucleoprotein particles (RNPs).

The viral envelope contains two major glycoproteins: hemagglutinin (HA) and neuraminidase (NA). HA mediates binding to sialic acid residues on host cell surface glycoproteins and glycolipids, initiating entry. After binding, the virus is internalized by endocytosis, and acidification triggers a conformational change in HA that promotes fusion of the viral envelope with the endosomal membrane. The M2 ion channel protein allows protons to enter the virion, uncoating the RNPs. NA functions later in the cycle, cleaving sialic acids from host cell surfaces and from newly formed virions, preventing viral aggregation and facilitating release. Because HA is essential for receptor binding and membrane fusion, and NA for viral egress, these proteins are primary targets for neutralizing antibodies and antiviral drugs.

Replication takes place in the nucleus, an unusual feature for an RNA virus. The viral polymerase uses a process called “cap snatching,” whereby PB2 binds capped 5′ ends of host pre-mRNAs and cleaves short fragments that serve as primers for viral mRNA synthesis. This ensures that viral transcripts are efficiently translated by host ribosomes. In addition to transcription, the polymerase also synthesizes complementary RNA intermediates that serve as templates for replication of the genome segments. The viral NS1 protein suppresses host antiviral responses by inhibiting interferon induction and antagonizing host RNA processing. After assembly in the nucleus, RNPs are exported to the cytoplasm via the nuclear export protein (NEP), and virions assemble at the plasma membrane, where HA, NA, and M2 are inserted. Budding occurs, followed by NA-mediated release.

The classification of influenza viruses rests on their internal proteins and their surface glycoproteins. Influenza A viruses are further subtyped by HA (18 known subtypes) and NA (11 subtypes) proteins, yielding designations such as H1N1 or H3N2. Influenza B viruses lack subtypes but are divided into lineages, notably Victoria and Yamagata. Influenza C viruses cause mild disease and lack NA, instead having a single glycoprotein called hemagglutinin-esterase-fusion (HEF). Influenza D viruses infect cattle and are not currently of major human importance. Influenza A viruses infect multiple species, including birds, swine, horses, and humans, and serve as the source of pandemics through reassortment between animal and human strains.

Antigenic drift and shift are central to influenza epidemiology. Drift refers to the gradual accumulation of point mutations in the HA and NA genes due to the error-prone viral polymerase, leading to new strains that partially evade existing immunity and cause seasonal epidemics. Shift, in contrast, refers to the sudden acquisition of novel HA and/or NA genes through reassortment between human and animal strains, potentially creating viruses to which humans have little or no preexisting immunity. Pandemics such as the 1918 H1N1, 1957 H2N2, 1968 H3N2, and 2009 H1N1 pandemics reflect antigenic shift.

Clinically, influenza presents with abrupt onset of fever, chills, headache, myalgias, malaise, cough, and sore throat. Unlike many common respiratory viruses, systemic symptoms are prominent and reflect both viral replication and host cytokine responses. Complications include viral pneumonia, secondary bacterial pneumonia (especially by Streptococcus pneumoniae, Staphylococcus aureus, and Haemophilus influenzae), exacerbation of underlying conditions, and in rare cases myocarditis, encephalitis, or Reye syndrome (associated with aspirin use in children with influenza B or varicella infection). High-risk groups include the very young, the elderly, pregnant women, and those with chronic cardiopulmonary disease or immunosuppression.

Diagnosis is typically clinical during influenza season, but laboratory confirmation can be achieved with rapid antigen tests, direct or indirect immunofluorescence, nucleic acid amplification tests (RT-PCR), or viral culture. RT-PCR offers the highest sensitivity and specificity and is now the standard in many settings. Viral culture retains utility for surveillance and vaccine strain selection.

Treatment includes supportive care and, in selected cases, antiviral therapy. Neuraminidase inhibitors (oseltamivir, zanamivir, peramivir) block NA activity, limiting release of new virions and shortening illness if started early. The M2 inhibitors (amantadine, rimantadine) target the M2 ion channel, but resistance in influenza A strains is now nearly universal, rendering them obsolete. Baloxavir marboxil, a newer agent, inhibits the viral endonuclease responsible for cap snatching and is active against both influenza A and B. Antiviral therapy is especially important for hospitalized patients, those with severe disease, and those at high risk for complications. For otherwise healthy outpatients, the benefit is greatest when treatment is initiated within 48 hours of symptom onset.

Prevention relies heavily on vaccination. Inactivated influenza vaccines are produced annually, typically as trivalent or quadrivalent formulations including two influenza A subtypes (currently H1N1 and H3N2) and one or two influenza B lineages. Live attenuated intranasal vaccines are also available for certain populations. Because of antigenic drift, vaccine composition must be updated yearly based on global surveillance coordinated by the World Health Organization. Vaccine effectiveness varies year to year depending on the match between vaccine strains and circulating viruses, but even when imperfect, vaccination reduces severity, hospitalization, and mortality.

Influenza remains a paradigmatic example of the interplay between viral genetics, host immunity, and public health. Its capacity for rapid change necessitates continuous surveillance, annual vaccination, and preparedness for pandemics. For medical students and clinicians, understanding influenza requires integrating molecular virology, immunology, clinical medicine, and epidemiology, as the virus continually tests the boundaries of both individual immunity and societal defenses.

Disclaimer: For education only. Not medical advice; always follow your institution's guidance.