The influenza virus, categorized into types A, B, and C, is a significant pathogen responsible for seasonal epidemics and occasional pandemics. Understanding the organization and function of its unique genetic blueprint is central to comprehending how the virus operates and why it remains a persistent public health challenge. The virus’s ability to replicate and adapt lies within its genetic material, which is highly specialized.
The Segmented RNA Architecture
The influenza genome is composed of single-stranded, “negative-sense” RNA. This means the RNA strand cannot be directly read by host cell machinery; it must first be copied into a complementary positive-sense strand. The genome’s physical organization is characterized by segmentation, a trait consequential for viral evolution. Influenza A and B viruses, which cause most human illness, each possess eight distinct RNA segments.
Each segment exists as a tightly packaged ribonucleoprotein complex (RNP), not a naked strand. The viral RNA within the RNP is heavily coated by numerous copies of the Nucleoprotein (NP), forming a rod-like, helical structure. Attached to one end of this complex is the viral RNA-dependent RNA polymerase, a multi-component enzyme made up of three different protein subunits: PB1, PB2, and PA.
The RNP complex is the fundamental unit of the influenza genome, used for transcription and replication. The Nucleoprotein binds tightly to the RNA, protecting the fragile strand. The attached polymerase complex ensures the machinery required for copying the genome is immediately available upon cell entry. Influenza C viruses are similar but possess only seven RNA segments.
The Gene Blueprint: Coding for Viral Proteins
Despite having only eight genomic segments, the influenza A virus genome codes for 10 to 12 distinct proteins. This efficiency is achieved because some segments use mechanisms like alternative splicing of messenger RNA (mRNA) or ribosomal frameshifting to encode more than one protein. This allows the virus to maximize the genetic information within its limited genome size. The proteins produced fall into two main categories: structural proteins that form the virus particle and non-structural proteins that aid in replication and immune evasion.
Two of the most recognized proteins are the surface glycoproteins: Hemagglutinin (HA) and Neuraminidase (NA). HA binds the virus to sialic acid receptors on the host cell surface, initiating infection. NA functions later in the cycle, cleaving sialic acid to release newly formed virus particles from the host cell. The polymerase complex proteins (PB1, PB2, and PA) are crucial for synthesizing both mRNA and new genomic RNA.
Other proteins perform structural or regulatory roles:
- Matrix protein 1 (M1) forms a layer beneath the viral envelope, providing structural integrity to the virion.
- Matrix protein 2 (M2) forms an ion channel in the viral envelope essential for uncoating the virus inside the host cell’s endosome.
- Non-structural protein 1 (NS1) is an immune antagonist, interfering with the host’s innate immune response.
- The Nuclear Export Protein (NEP), also known as NS2, transports newly synthesized RNP complexes out of the nucleus and into the cytoplasm for assembly.
The Replication Cycle: Copying the Genome
Replication begins when the Hemagglutinin protein binds to sialic acid receptors on the host cell surface. The host cell internalizes the virus via endocytosis, enclosing it within an endosome. As the endosome matures, its internal environment becomes acidic, triggering two simultaneous events: the low pH causes a conformational change in the HA protein, leading to the fusion of the viral envelope with the endosomal membrane.
The M2 ion channel opens in response to the acidity, allowing protons to enter the viral core. This acidification causes the M1 protein shell to disassemble, releasing the eight RNP complexes into the cytoplasm. These RNP complexes are then actively transported into the host cell’s nucleus, which is unusual for an RNA virus. Once there, the viral polymerase complex associated with each RNP segment begins its work.
The polymerase first synthesizes viral messenger RNA (mRNA) from the negative-sense genomic RNA template, a process requiring “cap-snatching” from host cell mRNAs to prime transcription. These viral mRNAs are exported to the cytoplasm for translation into viral proteins. The polymerase also synthesizes a full-length, positive-sense complementary RNA (cRNA), which acts as a template for producing new copies of the negative-sense genomic RNA (vRNA). New vRNA, NP, and polymerase proteins form new RNP complexes.
The new RNP complexes are exported from the nucleus, mediated by the NEP protein. In the cytoplasm, these complexes travel to the cell membrane where the surface proteins (HA and NA) and the M1 protein have already been trafficked. The final stage involves assembling the eight RNP segments into a new virion particle at the plasma membrane. The new virus buds off, acquiring its lipid envelope, and Neuraminidase cleaves the sialic acid receptors, ensuring the release of the progeny virus.
Genetic Change and Viral Evolution
The structure and replication dynamics of the influenza genome underpin its remarkable ability to evolve and evade host immunity. The viral RNA polymerase is notoriously error-prone because it lacks the proofreading function found in host cell DNA replication machinery. This frequent introduction of mistakes leads to small, continuous changes in the genes for surface proteins like Hemagglutinin and Neuraminidase. This steady accumulation of mutations is known as antigenic drift.
Antigenic drift is why people can be infected multiple times and why the seasonal flu vaccine must be updated annually. Minor changes to the HA and NA proteins mean that antibodies from a previous infection or vaccine may no longer recognize the altered virus effectively. The segmented nature of the genome, however, allows for a more dramatic and sudden genetic change called antigenic shift.
Antigenic shift occurs when a single host cell is simultaneously infected by two different strains of influenza A virus (e.g., a human strain and an avian strain). As new virus particles assemble, they can package a mix of RNA segments from both parental viruses, effectively swapping entire genes. This reassortment results in a completely novel virus subtype with HA or NA proteins that have never circulated in the human population. Because the human immune system has no pre-existing defense against this new combination, antigenic shift events are the main cause of influenza pandemics.