Lytic Viral Growth Cycles Lead to Death of Host Cells

Although details vary among different types of viruses, those that exhibit a lytic cycle of growth proceed through the following general stages:

1. Adsorption—Virion interacts with a host cell by binding of multiple copies of capsid protein to specific receptors on the cell surface.

2. Penetration—Viral genome crosses the plasma membrane. For animal and plant viruses, viral proteins also enter the host cell.

3. Replication—Viral mRNAs are produced with the aid of the host-cell transcription machinery (DNA viruses) or by viral enzymes (RNA viruses). For both types of viruses, viral mRNAs are translated by the host-cell translation machinery. Production of multiple copies of the viral genome is carried out either by viral proteins alone or with the help of host-cell proteins.

4. Assembly—Viral proteins and replicated genomes associate to form progeny virions.

5. Release—Infected cell either ruptures suddenly (lysis), releasing all the newly formed virions at once, or disintegrates gradually, with slow release of virions.

Figure 4-40 illustrates the lytic cycle for T4 bacteriophage, a nonenveloped DNA virus that infects E. coli. Viral capsid proteins generally are made in large amounts because many copies of them are required for the assembly of each progeny virion. In each infected cell, about 100-200 T4 progeny virions are produced and released by lysis.

The lytic cycle is somewhat more complicated for DNA viruses that infect eukaryotic cells. In most such viruses, the DNA genome is transported (with some associated proteins) into the cell nucleus. Once inside the nucleus, the viral DNA is transcribed into RNA by the host's transcription machinery. Processing of the viral RNA primary transcript by host-cell enzymes yields viral mRNA, which is transported to the cytoplasm and translated into viral proteins by host-cell ribosomes, tRNA, and translation factors. The viral proteins are then transported back into the nucleus, where some of them either replicate the viral DNA directly or direct cellular proteins to replicate the viral DNA, as in the case of SV40 discussed in the last section. Assembly of the capsid proteins with the newly replicated viral DNA occurs in the nucleus, yielding hundreds to thousands of progeny virions.

Most plant and animal viruses with an RNA genome do not require nuclear functions for lytic replication. In some

► FIGURE 4-40 Lytic replication cycle of E. coli bacteriophage T4, a nonenveloped virus with a double-stranded DNA genome. After viral coat proteins at the tip of the tail in T4 interact with specific receptor proteins on the exterior of the host cell, the viral genome is injected into the host (step |1|). Host-cell enzymes then transcribe viral "early" genes into mRNAs and subsequently translate these into viral "early" proteins (step H). The early proteins replicate the viral DNA and induce expression of viral "late" proteins by host-cell enzymes (step |3|). The viral late proteins include capsid and assembly proteins and enzymes that degrade the host-cell DNA, supplying nucleotides for synthesis of more viral DNA. Progeny virions are assembled in the cell (step |4|) and released (step |5|) when viral proteins lyse the cell. Newly liberated viruses initiate another cycle of infection in other host cells.

Adsorption/injection

E. coli chromosome /

Adsorption/injection

E. coli chromosome /

Viral proteins

Replication of viral DNA Expression of viral late proteins

Viral proteins

Replication of viral DNA Expression of viral late proteins

Lipid bilayer. Genomic RNA

Rabies virus

♦ Nucleocapsid protein O Matrix protein

■A- Receptor-binding glycoprotein

• Viral RNA polymerase

Lipid bilayer. Genomic RNA

Rabies virus

♦ Nucleocapsid protein O Matrix protein

■A- Receptor-binding glycoprotein

• Viral RNA polymerase

Transport 8

Endocytosis

Transport 8

Matrix and nucleocapsid synthesis

Matrix and nucleocapsid synthesis

rriRNA

Transcription

Transcription

Endocytosis

Virus receptor Cell membrane

Fusion

Release

Virus receptor Cell membrane

Cytosol

Fusion

Release of these viruses, a virus-encoded enzyme that enters the host during penetration transcribes the genomic RNA into mRNAs in the cell cytoplasm. The mRNA is directly translated into viral proteins by the host-cell translation machinery. One or more of these proteins then produces additional copies of the viral RNA genome. Finally, progeny genomes are assembled with newly synthesized capsid proteins into progeny virions in the cytoplasm.

After the synthesis of hundreds to thousands of new virions has been completed, most infected bacterial cells and some infected plant and animal cells are lysed, releasing all the virions at once. In many plant and animal viral infections, however, no discrete lytic event occurs; rather, the dead host cell releases the virions as it gradually disintegrates.

As noted previously, enveloped animal viruses are surrounded by an outer phospholipid layer derived from the plasma membrane of host cells and containing abundant viral glycoproteins. The processes of adsorption and release of enveloped viruses differ substantially from these processes in nonenveloped viruses. To illustrate lytic replication of enveloped viruses, we consider the rabies virus, whose nu-cleocapsid consists of a single-stranded RNA genome surrounded by multiple copies of nucleocapsid protein. Like

^ FIGURE 4-41 Lytic replication cycle of rabies virus, an enveloped virus with a single-stranded RNA genome. The structural components of this virus are depicted at the top. Note that the nucleocapsid is helical rather than icosahedral. After a virion adsorbs to multiple copies of a specific host membrane protein (step 11), the cell engulfs it in an endosome (step 12). A cellular protein in the endosome membrane pumps H+ ions from the cytosol into the endosome interior. The resulting decrease in endosomal pH induces a conformational change in the viral glycoprotein, leading to fusion of the viral envelope with the endosomal lipid bilayer membrane and release of the nucleocapsid into the cytosol (steps 13 and 141). Viral RNA polymerase uses ribonucleoside triphosphates in the cytosol to replicate the viral RNA genome (step 15) and to synthesize viral mRNAs (step 16). One of the viral mRNAs encodes the viral transmembrane glycoprotein, which is inserted into the membrane of the endoplasmic reticulum (ER) as it is synthesized on ER-bound ribosomes (step 17). Carbohydrate is added to the large folded domain inside the ER lumen and is modified as the membrane and the associated glycoprotein pass through the Golgi apparatus (step 18). Vesicles with mature glycoprotein fuse with the host plasma membrane, depositing viral glycoprotein on the cell surface with the large receptor-binding domain outside the cell (step 19). Meanwhile, other viral mRNAs are translated on host-cell ribosomes into nucleocapsid protein, matrix protein, and viral RNA polymerase (step 10). These proteins are assembled with replicated viral genomic RNA (bright red) into progeny nucleocapsids (step 111), which then associate with the cytosolic domain of viral transmembrane glycoproteins in the plasma membrane (step 121). The plasma membrane is folded around the nucleocapsid, forming a "bud" that eventually is released (step 131).

▲ EXPERIMENTAL FIGURE 4-42 Progeny virions of enveloped viruses are released by budding from infected cells. In this transmission electron micrograph of a cell infected with measles virus, virion buds are clearly visible protruding from the cell surface. Measles virus is an enveloped RNA virus with a helical nucleocapsid, like rabies virus, and replicates as illustrated in Figure 4-41. [From A. Levine, 1991, Viruses, Scientific American Library, p. 22.]

other lytic RNA viruses, rabies virions are replicated in the cytoplasm and do not require host-cell nuclear enzymes. As shown in Figure 4-41, a rabies virion is adsorbed by endo-cytosis, and release of progeny virions occurs by budding from the host-cell plasma membrane. Budding virions are clearly visible in electron micrographs of infected cells, as illustrated in Figure 4-42. Many tens of thousands of progeny virions bud from an infected host cell before it dies.

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