Influenza Virus: A Comprehensive Review of Structure, Pathogenesis, Variability, and Control Strategies
Abstract
Influenza viruses are major pathogens of global significance, causing seasonal epidemics and occasional pandemics. This review synthesizes current understanding of influenza virus biology including structural components, the replication cycle, genetic variability, host immune responses, pathogenesis, transmission dynamics, and therapeutic and preventive strategies. We especially emphasize recent advances in structural studies of viral proteins, molecular mechanisms of host adaptation, antiviral drug development, and vaccine innovations, including universal influenza vaccine efforts. Remaining challenges and future research directions are also discussed.
1. Introduction
Influenza viruses (family Orthomyxoviridae) represent one of the most important causes of acute respiratory infection in humans as well as in many animal species. Seasonal influenza leads to substantial morbidity and mortality each year, while pandemics—arising from novel strains—can have even more dramatic impact. Understanding influenza virus structure, life cycle, genetic variability, and host interactions is critical for designing better vaccines and antivirals. This review aims to provide an updated summary of influenza virus biology and current control efforts, drawing upon recent literature.
2. Classification and Basic Virology
2.1 Influenza Types, Subtypes, and Hosts
There are four genera of influenza viruses infecting mammals and birds: influenza A, B, C, and D. Influenza A viruses infect a broad range of host species, including birds, pigs, horses, dogs, and humans, and are the primary cause of pandemics. Influenza B is largely human-restricted (with some reports in seals), causes seasonal disease but not pandemics. Influenza C causes mild disease in humans; influenza D is primarily a pathogen of cattle.
Influenza A viruses are further classified by their hemagglutinin (HA) and neuraminidase (NA) surface glycoproteins. To date, 18 HA subtypes (H1–H18) and 11 NA subtypes (N1–N11) have been identified, many in avian reservoirs. Only some HA/NA combinations have adapted to efficient human-to-human transmission (e.g. H1N1, H2N2, H3N2).
2.2 Morphology and Genome Organization
Influenza A virus particles are enveloped, pleomorphic (spherical and filamentous forms), roughly 80-120 nm in diameter for spherical virions, and containing a lipid envelope derived from the host cell membrane. Embedded in the envelope are two major glycoproteins: hemagglutinin (HA) and neuraminidase (NA), along with the “M2” ion channel protein (in influenza A) plus M1 matrix protein lining the inside of the envelope.
The genome consists of eight negative-sense, single-stranded RNA segments. Each RNA segment is associated with multiple copies of nucleoprotein (NP), and a heterotrimeric RNA-dependent RNA polymerase (RdRp) complex (subunits PB1, PB2, and PA) to form ribonucleoprotein (RNP) complexes. The polymerase complex performs both transcription and replication of viral RNA.
3. Influenza Virus Structure: Molecular Insights
Recent structural biology has yielded high‐resolution images of vital viral components, improving understanding of function, antigenicity, and mechanisms of adaptation.
3.1 Hemagglutinin (HA)
HA is the principal viral surface glycoprotein responsible both for binding to host cell receptors (sialic acid-linked glycoproteins) and mediating membrane fusion during viral entry. Structural analyses (e.g. H2 subtype HA from the 1957 H2N2 pandemic) have elucidated how small changes, such as residue substitution at critical positions (e.g. residue 226), shift receptor specificity from avian types (α2,3-linked sialic acids) to human types (α2,6).
Glycosylation sites on HA, the lengths of receptor binding sites, and antigenic variation via drift (mutation) and shift (reassortment) are important in determining infectivity, immune evasion, and host range.
3.2 The Polymerase Complex and Ribonucleoprotein (RNP)
The influenza A polymerase complex (PA, PB1, PB2) associated with NP and viral RNA forms the RNP, a critical unit for transcription (mRNA synthesis) and replication (generation of antigenome and progeny vRNA). Recent high-resolution studies (cryo-EM and X-ray crystallography) have elucidated the architecture of the polymerase both bound and unbound to RNA promoters, revealing promoter binding, cap-snatching, template and product channels, dynamics of subunit interfaces, and conformational states associated with transcription versus replication.
For example, the Cusack group’s work (“Structure of Influenza A Polymerase Bound to the Viral RNA Promoter”) has provided atomic resolution detail of promoter interactions and conformational transitions relevant to both viral replication and potential antiviral targeting.
3.3 Other Accessory Proteins: NS1 and Others
Non-structural protein 1 (NS1) is multifunctional and plays roles in antagonizing host innate immunity, particularly by interfering with interferon responses and other host antiviral defenses. Structure-function analyses of NS1-host protein interactions are valuable for identifying virulence determinants and therapeutic targets.
Other proteins (e.g. PA-X, PB1-F2 in some strains) modulate virulence and immune interactions, often in strain- and host-dependent manners.
4. Life Cycle and Replication Cycle
This section outlines the influenza A virus replication cycle, with emphasis on recent research updates.
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Attachment and Entry.
HA binds to sialic acid receptors on host cell surfaces; specificity influences tropism (avian vs. human vs. other mammals). After binding, the virus is internalized via endocytosis. Acidification in the endosome triggers HA conformational changes, fusion of viral and endosomal membranes, and release of RNPs into the cytoplasm/nucleus. -
Cap-Snatching and Transcription.
The viral RdRp (PB1, PB2, PA) translocates to the nucleus, where PB2 binds capped host pre-mRNA transcripts; PA provides endonuclease activity to cleave them. These fragments serve as primers for transcription of viral mRNAs. Transcription yields spliced and unspliced viral mRNAs, which are exported to the cytoplasm for translation. -
Replication.
For replication of full-length vRNA, a complementary RNA (cRNA) is synthesized without the cap-snatching primer requirement. The cRNA serves as template for progeny vRNA. NP and polymerase subunit interactions and nuclear/nucleoprotein environment influence regulation of these processes. Recent studies describe structural rearrangements of polymerase in different functional states (promoter-bound, elongation, etc.). -
Assembly and Budding.
Newly synthesized vRNA segments are complexed with NP and polymerase to form RNPs; these are transported from nucleus to cytoplasm. Viral structural proteins (HA, NA, M2) are inserted into the host cell membrane, M1 associates with inner leaflet and RNPs, virus assembles and buds off, acquiring envelope with HA and NA. NA enzymatic activity cleaves sialic acids to release virions, preventing aggregation at the cell surface and facilitating spread. -
Host Cell Shutdown and Immune Evasion.
Host gene expression is suppressed; NS1 plays a role. Interferon response is antagonized; various viral proteins modulate apoptosis, cell signaling, etc.
5. Genetic Variability, Evolution, and Host Adaptation
Influenza’s capacity for evolution is central to its success as a pathogen.
5.1 Antigenic Drift and Shift
- Drift: Accumulation of point mutations in HA, NA, or other antigenic proteins over time, leading to reduced recognition by preexisting host immunity. This is the cause of seasonal influenza variation.
- Shift / Reassortment: Exchange of entire gene segments when two different influenza viruses co-infect a cell (e.g. human and avian). This can lead to novel HA or NA combinations to which the human population has little immunity; such events underlie pandemics (e.g. 1957 H2N2, 1968 H3N2, 2009 H1N1).
5.2 Host Adaptation
For avian influenza viruses to infect and cause disease in humans (or other mammals), they must adapt through changes in receptor binding, polymerase activity at different temperatures, evasion of innate immunity, etc. Key changes in HA that shift receptor specificity (e.g. from avian α2,3 to human α2,6 sialic acid linkage) are critical. Additional determinants include mutations in polymerase subunits (e.g. PB2 E627K, D701N) that enhance replication in mammalian cells; modulation of viral accessory proteins to counteract host immunity.
5.3 Rapid Evolution: Quasispecies, Population and Selective Pressures
Genetic variation arises due to error-prone polymerase lacking proofreading. Influenza viruses exist as quasispecies within hosts. Selection pressures include host immune response, prior immunity (vaccination or natural infection), antiviral drugs, and inter-species transmission barriers. Studies such as hydropathicity scaling of HA/NA under vaccination and migration pressures reveal punctuated evolution patterns.
5.4 RNA Secondary Structures and Non-Coding Regions
Elements beyond coding sequences also matter. For example, secondary structure in non-coding regions (5ʹ and 3ʹ UTRs), the NS segment RNA secondary structure, influence packaging, replication efficiency, and host interactions. Variation in these regions may affect strain fitness.
6. Pathogenesis and Transmission
6.1 Innate Immune Response, Early Events
After entry, influenza virus triggers host innate immunity via detection of viral RNAs, activation of pattern recognition receptors (e.g. RIG-I, MDA5). Subsequent interferon (IFN) responses, production of proinflammatory cytokines and chemokines, infiltration of innate immune cells (macrophages, neutrophils) are early hallmarks. The virus's ability to inhibit or evade these responses influences disease severity. Studies such as Pathogenesis Induced by Influenza Virus Infection: Role of the Early Events of the Infection and the Innate Immune Response (2025) clarify the dynamics of these early interactions.
6.2 Clinical Disease versus Host Species Differences
In humans, influenza often causes respiratory symptoms (fever, cough, sore throat, muscle aches), but in some cases (especially in pandemics or with highly pathogenic avian strains) severe disease including pneumonia, multi-organ failure, death. Severity influenced by age, comorbidities, immune status. In animal models (pigs, birds, mice, ferrets), disease manifestations vary; these models are crucial for studying pathogenesis and transmission. For example, in pigs experimentally infected with a pandemic swine-origin H1N1, virus shedding and mild symptoms were observed; transmission to contact animals was efficient.
6.3 Transmission Routes
Influenza spreads primarily through respiratory droplets, aerosols, and contact with contaminated surfaces (fomites). The efficiency of transmission depends on viral load in respiratory secretions, stability of virion in the environment, host behavior and immunity. Secondary attack rates in households are high; children often serve as index or amplifiers. Vaccination of household contacts reduces secondary infection risk.
6.4 Seasonal versus Pandemic Behavior
Seasonal influenza circulates with predictable periodicity in temperate regions (winter peaks) and more continuously in tropical/subtropical zones; pandemics arise when a novel subtype emerges with sufficient transmissibility, to which population has minimal immunity, often via zoonotic origin. The transition from avian/swine virus to one capable of sustained human-to-human transmission involves multiple genetic barriers.
7. Control Strategies: Vaccines, Antivirals, and Other Interventions
7.1 Vaccines
7.1.1 Seasonal Vaccines
Currently used vaccines include inactivated influenza vaccines (IIV), live attenuated influenza vaccines (LAIV), recombinant HA vaccines, etc. These are updated annually based on predictions of circulating strains. Challenges include antigenic drift, mismatches between vaccine strains and circulating viruses, variability in immunogenicity (especially in elderly, immunocompromised).
7.1.2 Universal Influenza Vaccine Efforts
Because of the limitations of seasonal vaccines, a major goal is vaccines that protect broadly across influenza A (and possibly B) subtypes, and ideally across emerging strains. Strategies under investigation include:
- Vaccination with more conserved regions (e.g. the stem region of HA, conserved epitopes in NP, M1).
- Use of broadly neutralizing antibodies.
- Novel platforms (mRNA, viral vectors, nanoparticle vaccines) that allow rapid updates or multi-valent coverage.
7.1.3 Recent Advances
A recent study showed Moderna’s experimental influenza vaccine mRNA-1010 demonstrated significantly better efficacy in older adults compared to a licensed vaccine.
Other research has explored needle-free or mucosal delivery (e.g. nasal spray, possibly even non-traditional routes), as well as efforts to improve antigen stability, cross-protection to highly pathogenic avian strains (H5N1 etc.).
7.2 Antiviral Therapies
Several approved antivirals exist:
- Neuraminidase inhibitors: oseltamivir, zanamivir, peramivir, etc.—act by blocking NA, thereby preventing release of progeny virions.
- Cap-dependent endonuclease inhibitors: e.g. baloxavir marboxil, which inhibit the PA subunit function.
- Other experimental agents: polymerase inhibitors, host factor antagonists, broadly neutralizing antibodies.
Recent reviews (2023) have summarized advances in influenza A virus drug options, including new molecules, combination therapies, and strategies for circumventing resistance.
7.3 Non-Pharmaceutical Interventions and Public Health Measures
Hand hygiene, respiratory etiquette, isolation of sick individuals, mask use, ventilation, and surveillance are all important. Seasonal vaccine campaigns, rapid diagnostics, and antiviral stockpiling help manage outbreak and pandemic risk.
Surveillance in animal populations (wild birds, domestic poultry, swine) is crucial to detect zoonotic spillover risk and emergent strains with pandemic potential.
8. Recent Research Highlights
Some of the especially noteworthy recent findings:
- Detailed structures of RNP complexes, polymerase promoter bound/unbound states, which may allow drug design targeting conserved functional regions.
- Studies on the Na+ hydropathic properties of HA and NA showing “punctuated evolution” under combined migration and vaccination pressures.
- Improved understanding of RNA secondary structure in non-coding regions (e.g. NS segment) influencing viral replication and possibly virulence.
- Epidemiological work quantifying household transmission risk and vaccine effectiveness in preventing secondary infections.
9. Challenges, Gaps, and Future Directions
Despite progress, many challenges remain.
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Antigenic Mismatch and Drift
Prediction of circulating strains remains imperfect. Mismatches between vaccine strain and circulating viruses reduce effectiveness. -
Host Adaptation and Zoonotic Risk
Many avian influenza viruses currently infect humans only sporadically; the mutations necessary for efficient human transmission are still under study. Early detection systems and genetic/structural markers of adaptation are needed. -
Antiviral Resistance
Resistance to current antivirals (especially neuraminidase inhibitors) can emerge. Continuous monitoring and development of agents targeting conserved, essential functions are required. -
Immune Response Variability
Differences in immune responses due to age, comorbidity, immune history (prior infection or vaccination), and possibly genetic factors. Understanding correlates of protection, and how to elicit more durable immunity, remains a priority. -
Delivery and Accessibility of Vaccines
Particularly in low- and middle-income countries, logistical issues (cold chain, vaccine production capacity, cost, distribution) are major barriers. -
Universal Vaccine Development
While promising candidates exist, none have yet achieved full clinical implementation. Key challenges include balancing breadth of protection with immunogenicity, and safety. -
Pandemic Preparedness
Surveillance systems in animals and humans, rapid vaccine production platforms (e.g. mRNA), stockpiling of broad antivirals, and strategies for rapid response remain essential.
10. Conclusion
Influenza viruses continue to pose a significant public health burden due to their high variability, zoonotic potential, and capacity to evade immunity. Advances in structural biology, molecular virology, immunology, and vaccine technology offer promising avenues to improve prevention and treatment. However, many challenges persist, particularly in universal vaccine development, antiviral resistance, and rapid detection of emergent strains. A multidisciplinary approach combining virology, immunology, structural biology, epidemiology, and public health is essential for future progress.
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References
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- Carter, T., & Iqbal, M. (2024). The Influenza A Virus Replication Cycle: A Comprehensive Review. Viruses, 16(2), 316.
- Márquez-Bandala, A. H., Gutierrez-Xicotencatl, L., & Esquivel-Guadarrama, F. (2025). Pathogenesis Induced by Influenza Virus Infection: Role of the Early Events of the Infection and the Innate Immune Response. Viruses, 17(5), 694.
- Other sources as cited above.
