The influenza A virus uses several proteins to infect host cells and replicate, including the Polymerase Basic 1 protein (PB1). The genetic instructions for PB1 are encoded in one of the virus’s eight RNA segments. As a multi-functional component of a larger complex, PB1 works with other viral proteins to ensure the continuation of the viral life cycle. Its proper function is necessary for the virus to propagate within a host.
The Function of PB1 in Viral Replication
The primary role of the PB1 protein is to serve as the catalytic core of the influenza virus’s RNA-dependent RNA polymerase (RdRp), a complex that acts as a viral copy machine. The RdRp is a heterotrimer composed of three subunits: PB1, Polymerase Basic 2 (PB2), and Polymerase Acidic (PA). PB1 forms the structural backbone of this complex and contains the active site for adding nucleotides to a growing RNA strand.
During replication, PB1 initiates RNA synthesis, copying the original viral RNA (vRNA) segments into complementary RNA (cRNA) templates. The polymerase complex then uses these cRNA templates to produce large quantities of new vRNA. This new vRNA is packaged into newly assembled virus particles, allowing the infection to spread.
PB1 also participates in a mechanism called “cap-snatching” to transcribe viral genes into messenger RNA (mRNA). The PB2 subunit binds to the 5′ cap of host cell mRNAs, and the PA subunit cleaves it. This capped RNA fragment is then used by PB1 as a primer to initiate the synthesis of viral mRNA, hijacking the host’s machinery to produce viral proteins.
The Accessory Protein PB1-F2
Encoded within the same RNA segment as the main PB1 protein is a smaller, accessory protein known as PB1-F2, produced from an alternative reading frame. Discovered in 2001, this protein is not required for viral replication but instead modulates how the virus interacts with the host’s immune system. Its function is distinct from the polymerase activity of the larger PB1 protein.
The primary role of PB1-F2 is the induction of apoptosis, or programmed cell death, in immune cells. By causing the death of these cells, the protein helps the virus evade clearance by the host’s immune system. This allows the infection to persist for longer and contributes to the virus’s ability to cause more severe disease.
PB1-F2 localizes to the mitochondria, where its presence disrupts cellular functions and contributes to the cell death process. The length and amino acid sequence of the PB1-F2 protein vary between influenza strains, influencing its potency. While many seasonal flu viruses have a truncated version, many avian and pandemic strains express the full-length, active protein.
Influence on Influenza Pathogenicity
The characteristics of the PB1 protein and its accessory product, PB1-F2, directly influence the severity of an influenza infection. Variations in the PB1 subunit can affect the efficiency of the viral polymerase. A more efficient polymerase leads to faster viral replication and a higher viral load in the host, which often correlates with more severe symptoms.
The presence of a full-length, functional PB1-F2 protein is associated with the high virulence of certain influenza strains. For example, the 1918 Spanish flu pandemic virus contained a PB1-F2 protein that is thought to have contributed to its lethality. Studies show that viruses with a functional PB1-F2 can delay viral clearance from the lungs in animal models, leading to prolonged infection and increased tissue damage.
The introduction of a new PB1 gene segment into a circulating human influenza virus, a process known as reassortment, was a hallmark of past pandemics, including those in 1957 and 1968. This suggests that the PB1 gene, along with the PB1-F2 protein it encodes, can provide an advantage to a new virus in a naive population. The combination of the polymerase’s replication efficiency and the immune-disrupting functions of PB1-F2 can determine how dangerous a particular flu strain is.
Targeting PB1 for Antiviral Therapies
The function of the PB1 protein in viral replication makes it a target for antiviral drugs, as inhibiting the polymerase complex can stop the infection. The high degree of conservation in the amino acid sequences of the polymerase proteins across different influenza strains means a drug targeting this complex could be effective against a wide range of viruses, including seasonal, avian, and pandemic variants.
Several modern antiviral medications interfere with the influenza polymerase. For instance, drugs like favipiravir function as PB1 antagonists. These nucleoside analogues are incorporated into the growing RNA chain by the PB1 subunit, which halts further synthesis. Other drugs target the interaction between the polymerase subunits, preventing the complex from assembling correctly.
Ongoing research is focused on creating new inhibitors of the polymerase. One strategy involves targeting the interface where the PB1 and PA subunits connect. By developing small molecules that block this connection, scientists hope to create next-generation antivirals that can combat drug-resistant influenza strains and prepare for future pandemics.