The Poliovirus Life Cycle

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I. The Poliovirus Receptor (PVR)

Polio's first interaction with a host cell consists of binding to a specific cell surface protein, the poliovirus receptor (PVR). This protein, whose natural function is not known, is a member of a family of proteins called the immunoglobulin (Ig - pronounced as two letters, not as a one-syllable word) superfamily, the defining feature of which is a "loop" in the protein structure called the Ig domain. Different members of the family have different numbers of loops, and are frequently involved in communication between cells and the reception of external signals. PVR has three Ig loops (which are outside the cell), numbered 1-3 starting with the loop farthest from the cell surface. The protein extends through the cell membrane, with a short stretch of amino acids (protein sequence) inside the cell as well, as represented schematically in the figure above.

Polio appears to bind to its receptor on loop 1. This initial binding is followed by conformational changes in the virus's capsid which are believed to prepare it for uncoating. The receptor is taken into the cell by the process of endocytosis, which is most likely involved in PVR's natural function. In other words, the virus has evolved to take advantage of a naturally-occurring protein on the cell surface in order to gain entry and initiate an infection. This is a common tactic of many animal and plant viruses.

The poliovirus receptor is expressed in many human tissue types, apparently including some tissues, such as kidney, which are not normal sites of poliovirus replication in the host. Why doesn't polio replicate in these cells, if its receptor is available to let it in? There are two theories: either the virus's replication is blocked in these cells at some step after entry (replication, for example), or the virus is simply not exposed to those tissues during a normal infection. The tendency of a virus to replicate only in particular tissue types is called "tissue tropism," and is an active area of study for researchers working on many types of viruses. Polio ordinarily infects cells in the lining of the intestine and can migrate to nerve tissue, where it causes the characteristic pathology of paralytic poliomyelitis.

II. Uncoating

After binding to its receptor, poliovirus must get its genetic material into the cell's cytoplasm, where translation and replication will occur. In this respect, the viral capsid is something of a paradox, since it must be stable to harsh conditions in the environment (including the low pH of the host's stomach), but must be able to release its contents (the viral genome) easily and quickly when stimulated with the proper signal. At physiological temperatures, the virus can undergo a major structural change, called alteration, after binding to the receptor. The altered particle is easy to distinguish from the native virion, but it is unclear how - or even if - this altered stage leads to productive uncoating of the virus genome. For every 200 or so virus particles that encounter a cell, only one will successfully enter and replicate, so research in this area is often confounded by the rarity of successful entry.

There are two major models for poliovirus entry. In one, the virion, after binding to PVR, initiates entry directly from the cell surface, injecting its genome into the cell's cytoplasm. In the other model, the virus particle must be taken into the cell by a process called receptor-mediated endocytosis, a mechanism routinely employed by cells to take in food and signal proteins. According to this model, the virus then uncoats inside an compartment that forms in the cell, and the genome is released into the cytoplasm. There is little experimental data to support either model, so both are considered reasonable possibilities.

While the three-dimensional structure of the virus is known at high resolution, the events of entry are still obscure, as the preceding paragraphs indicate. Studying this phenomenon is important not only from the standpoint of understanding polio's pathogenesis, but also because similar mechanisms are undoubtedly employed by related viruses, such as rhinoviruses (which cause the common cold), hepatitis A virus, and foot-and-mouth disease virus (which infects cattle). Understanding how the virus enters the cell can lead to new therapies that target this vulnerable stage of its life cycle.

III. Protein Synthesis

In contrast to the human cells it infects, which have a genome made of deoxyribonucleic acid (DNA), the poliovirus genome is made of ribonucleic acid (RNA). In a cell, RNA is used as a "messenger" to carry genetic information from the nucleus into the cytoplasm, where it is translated into proteins that are the building blocks of the cell. Poliovirus skips the DNA step and simply carries a single RNA molecule inside its protective capsid. This RNA is "message sense," meaning that it can be translated directly into proteins in the cell's cytoplasm.

The entire poliovirus RNA molecule is translated into a single long "polyprotein." This large protein then cleaves itself into subsections and finally into the separate proteins involved in replication and packaging, including the virus capsid proteins. Some of the viral proteins also act to shut down the translation of the cell's messenger RNAs while still permitting the viral RNA to be translated, making the cell a more efficient virus factory.

IV. Protein Processing

The product of translation is the long viral polyprotein which contains all of the virus's proteins strung together into a single molecule. Some of these proteins are proteases, or enzymes which cut other proteins. In a series of cleavages, the proteases break down the polyprotein into its component parts, which then operate as separate gene products. Since the proteases are contained within the polyprotein initially, one of their most important functions is to cleave themselves out of the larger structure, freeing them to do the rest of their work.

In addition to its role in cutting up the polyprotein, one of the proteases is involved in shutting off most of the host cell's own protein synthesis. The protease does this by cleaving a component of the cell's translational machinery which is required for normal protein synthesis, but which the viral RNA does not need. Shutting down the host's RNA translation serves a dual function for the virus: first, it frees up more ribosomes to translate the viral genomes, and second, it insures that the cell will die and break down, releasing the progeny virus particles after they have been assembled.

V. RNA Replication

RNA viruses have a unique difficulty when it comes to replication, as the cell does not have the necessary machinery to reproduce an RNA molecule (the cell replicates DNA, which is transcribed to produce RNA, and RNA is translated to produce proteins). This means that the virus must carry its own RNA replication proteins or have a mechanism for producing them once inside the cell. For polio, the replication functions are carried out by a viral RNA-directed RNA polymerase. This means that it reads an RNA template and produces a new RNA molecule of the opposite polarity. Because RNA is single-stranded, the first round of replication produces a single antisense, or complementary, molecule, analogous to a printing plate where all of the letters are reversed. This antisense template is then used to produce a positive-sense copy of the original genome. As these new genomes accumulate, they can also act as additional messages for the cell's translation machinery, leading to higher levels of viral protein production.

VI. Packaging and Release

After the virus has translated its RNA to produce the necessary proteins and replicated its genome, it needs to package the newly synthesized RNA molecules inside capsids, or protein shells. A complete virus consists of the RNA packaged inside the capsid, which will be released from the cell for the next round of infection. The capsid proteins self-assemble into an immature capsid, a structure which contains all of the necessary proteins, but which has not finished cleaving them into their final form. The viral RNA enters the incomplete capsid and is secured inside when the viral proteases make the final cleavages. The processes which guide the RNA to the capsid are still poorly understood. Once the genomes have been packaged into mature virions, the virus particles await the cell's lysis (bursting), when they will be released to infect neighboring cells, starting the cycle over again.

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