The replication cycle of influenza virus is summarized in Figure 1. The viral multiplication cycle proceeds rapidly. There is the shut-off of host cell protein synthesis by about 3 hours postinfection, permitting selective translation of viral mRNAs. New progeny viruses are produced within 8–10 hours.

Fig1. Schematic diagram of the life cycle of influenza virus. After receptor-mediated endocytosis, the viral ribonucleoprotein complexes are released into the cytoplasm and transported to the nucleus, where replication and transcription take place (1). Messenger RNAs are exported to the cytoplasm for translation. (2) Early viral proteins required for replication and transcription, including nucleoprotein (NP) and a polymerase protein (PB1), are transported back to the nucleus. RNA polymerase activity of the PB1 protein synthesizes positive single-stranded RNA (ssRNA) from genomic negative single-stranded RNA (–ssRNA) molecules. (3) These +ssRNA templates are copied by the RNA polymerase activity of the PB1 protein. (4) Some of these new genome segments serve as templates for the synthesis of more viral mRNA. Later in the infection, they become progeny genomes. Viral mRNA molecules transcribed from some genome segments encode structural proteins such as hemagglutinin (HA) and neuraminidase (NA). These messages are translated by endoplasmic reticulum-associated ribosomes and delivered to the cell membrane (5). Viral genome segments are packaged as progeny virions bud from the host cell (6). ER, endoplasmic reticulum. (Reproduced with permission from Willey JM, Sherwood LM, Woolverton CJ (eds): Prescott, Harley, & Klein’s Microbiology. McGraw-Hill, 2008, p. 457. © McGraw-Hill Education.)

A. Viral Attachment, Penetration, and Uncoating

The virus attaches to cell-surface sialic acid via the receptor site located on the top of the large globule of the HA. Virus particles are then internalized within endosomes through receptor-mediated endocytosis. The next step involves fusion between the viral envelope and cell membrane, triggering uncoating. The low pH within the endosome is required for virus-mediated membrane fusion that releases viral RNPs into the cytosol. Acid pH causes a conformational change in the HA structure to bring the HA2 “fusion peptide” in correct contact with the membrane. The M2 ion channel protein present in the virion permits the entry of ions from the endo some into the virus particle, triggering the conformational change in HA. Viral nucleocapsids are then released into the cell cytoplasm.

B. Transcription and Translation

Transcription mechanisms used by orthomyxoviruses differ markedly from those of other RNA viruses in that cellular functions are more intimately involved. Viral transcription occurs in the nucleus. The mRNAs are produced from viral nucleocapsids. The virus-encoded polymerase, consisting of a complex of the three P proteins, is primarily responsible for transcription. Its action must be primed by scavenged capped and methylated 5′ terminals from cellular transcripts that are newly synthesized by cellular RNA polymerase II. This explains why influenza virus replication is inhibited by dactinomycin and α-amanitin, which block cellular transcription, but other RNA viruses are not affected because they do not use cellular transcripts in viral RNA synthesis.

Six of the genome segments yield monocistronic mRNAs that are translated in the cytoplasm into six viral proteins. The other two transcripts undergo splicing, each yielding two mRNAs that are translated in different reading frames. At early times after infection, the NS1 and NP proteins are preferentially synthesized. At later times, the structural proteins are synthesized at high rates. The two glycoproteins, HA and NA, are modified using the secretory pathway.

The influenza virus nonstructural protein NS1 has a posttranscriptional role in regulating viral and cellular gene expression. The NS1 protein binds to poly(A) sequences, inhibits pre-mRNA splicing, and inhibits the nuclear export of spliced mRNAs, ensuring a pool of donor cellular molecules to provide the capped primers needed for viral mRNA synthesis. The NS2 protein interacts with M1 protein and is involved in nuclear export of viral RNPs.

C. Viral RNA Replication

 Viral genome replication is accomplished by the same virus encoded polymerase proteins involved in transcription. The mechanisms that regulate the alternative transcription and replication roles of the same proteins are related to the abundance of one or more of the viral nucleocapsid proteins.

As with all other negative-strand viruses, templates for viral RNA synthesis remain coated with NPs. The only completely free RNAs are mRNAs. The first step in genome replication is production of positive-strand copies of each segment. These antigenome copies differ from mRNAs at both terminals; the 5′ ends are not capped, and the 3′ ends are neither truncated nor polyadenylated. These copies serve as templates for synthesis of faithful copies of genomic RNAs.

Because there are common sequences at both ends of all viral RNA segments, they can be recognized efficiently by the RNA-synthesizing machinery. Intermingling of genome segments derived from different parents in coinfected cells is presumably responsible for the high frequency of genetic reassortment typical of influenza viruses within a genus. Frequencies of reassortment as high as 40% have been observed.

D. Maturation

The virus matures by budding from the surface of the cell. Individual viral components arrive at the budding site by different routes. Nucleocapsids are assembled in the nucleus and move out to the cell surface. The glycoproteins, HA and NA, are synthesized in the endoplasmic reticulum; are modified and assembled into trimers and tetramers, respectively; and are inserted into the plasma membrane. The M1 protein serves as a bridge, linking the nucleocapsid to the cytoplasmic ends of the glycoproteins. Progeny virions bud off the cell. During this sequence of events, the HA is cleaved into HA1 and HA2 if the host cell possesses the appropriate proteolytic enzyme. The NA removes terminal sialic acids from cellular and viral surface glycoproteins, facilitating release of virus particles from the cell and preventing their aggregation.

Many of the particles are not infectious. Particles sometimes fail to encapsidate the complete set of genome segments; frequently, one of the large RNA segments is missing. These noninfectious particles are capable of causing hemagglutination and can interfere with the replication of intact virus.

Reverse-genetics systems that allow the generation of infectious influenza viruses from cloned cDNAs of viral RNA segments are available and allow for mutagenesis and functional studies.

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Antigenic Drift and Antigenic Shift

Structure and Function of Neuraminidase

Complications of COVID-19

Clinical Features of SARS-CoV-2 and COVID-19

Modes of Transmission SARS-CoV-2 and COVID-19

Papillomaviruses

Arenaviruses

Adenoviruses

Viral Serology: Immune Status Testing

Structure and Function of Hemagglutinin

Structure and Composition of influenza viruses