The process of viral infection has two stages: sttachment and penetration. Viruses attach itself to the host cells by way of cellular receptors. A cell cannot be infected unless it expresses the molecule that serves as a receptor for that particular virus on its outer surface. These are usually protein but carbohydrates and lipids occasionally used. Receptors are molecules essential to the normal functioning of a cell and viruses have evolved to take advantage of these.

The precise details of how viruses enter animal cells by fusing after attaching to a cell receptor is not clear. However, it is clear that enveloped viruses can penetrate cells by fusing with the host cell membrance while both enveloped and naked viruses can penetrate by receptor-emdiated endocytosis. Fusion with the outer membrance results in the release of the viral genome in the cytoplasm. With endocytosis, the virus is contained in a vesicle of host cell membrance. Here uncoating is dependant on the acidic pH within the vesicle which is dependant upon fusion with an endosome. Acidic pH induces the escape of envoloped virus-genomes by fusion with the vesicle membrance and of non-envoloped viruses by permeabilizing the membrance.

Once the viral genome is released, it makes its way to the site of replication. This can be in the cytoplasm, in organelles, or in nucleus. Once the genome is there, early gene transcription begins. This transcription is either prompted by viral or cellular factors. The early gene products are normally regulatory proteins. These proteins regulate the transcription of later genes and the viral DNA replication. Later genes products are normally structural proteins required for the construction of new capsids. The late gene products accumulate in the replication site and eventually are assembled into empty neuclocapsids.

Viral DNA replication varies depending upon the neucleic acid involved. Circular DNA, both ds and ss, is replicated using a " rolling circle " mechanism. In it, the circular genome is transcribed over and over again along the circumference of the circle. This string produced is then spliced into single genomes. The transcription of RNA involves a complememtry intermediate. This intermediate is then transcribed into progeny genomes. In all cases, viral and cellualr proteins regulate nucleic acid replication. Following genome transcription, the progeny nucleic acid is packaged into the empty neucleocapsids. Then, if the virus is in a lytic state, the cell is deatroyed, releasing the viral progeny. If the virus is in a latent state, the progeny may stay in the cell untill activated.

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` Steps in Replication of Viruses

Step 1: The virus attach itself to its host cell

Step 2: The virus or its genetic information penetrates the cell.

Step 3: The nucleic acid is uncoated which frees the DNA or RNA from its capsomeres or lipid envelope and permits the host cell to read out ( express ) the genetic functions of the virus.

Step 4: At this stage in the life cycle if many viruses, only a portion of the viral genetic information is expressed, resulting in the synthesis of only the subset of viral-encoded proteins collectively called the early viral gene functions ( proteins ). These proteins may function in one of several ways. In some cases, they contribute directly to the replication of the viral chromosome. In some cases, these viral proteins turn off many of the host-cell activities, maximizing the cell's available resources for virus production. Alternatively, some viruses that can duplicate themselves only in actively dividing host cells produce proteins that stimulate host-cell division.

Step 5: The viral nucleic acid is then synthesized to produce hundreds or thousands of copies of viral chromosome.

Step 6: At this time, a second subset of the viral genetic information, commonly termed the late proteins, is expressed. These are the structural proteins including the capsomeres of the virus.

Step 7: The capsomeres are assembled to form a new shell around the nucleic acid of the virus.

Step 8: The mature virus having duplicated its new copies, is released from the infected cell to attack a new cell and repeat this process.

Going from step 1 to 8, a viral replication cycle displays temporal organization: specific events occur in sequence, each dependant upon the sucessful completion of the previous step. This development process which results in the synthesis of thousands of viral particles is formally similiar to the developement of a multicellular organism from a single fertilized egg cell. Both processes require quantiative and qualitative changes over time. Early viral proteins made from the somple genome of the infecting virus, are expressed at low levels while the late proteons are made from the newly replicated viral chromosomes produced in step 5. Quantitive changes are thus initiated and regulated chronologically.

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Attachment or Adsorption

A virus usues specific proteins on its coat to recgonize and attach to a specific receptors ona cell surface ( the plasma membrance ). These receptors may be proteins or other components that are located only on certain cells; in effect, a virus maybe able to attach only to a liver cell or to lung cell and to no other cell of the host body. This may result in specific disease states sucha s hepatitis or pneumonia caused by viruses that replicate only in liver or lung cells. Viruses are said to have a specific tissue preference ( tropism ) and in some cases this is due to tissue-specific receptors.

The human immunodeficiency virus ( HIV ), for example, attaches to a receptor called the CD4 proteon. The CD4 protein is found on the surface of certain lympocytes ( white blood cells ) that are critical for the vitality of the immune system in humans. By entering into and killing only cells that have the CD4 protein on the surfaces, Hiv kills the cells that maintain our ability to protect ourselves from infection thus causing AIDS ( acquired immune deficiency syndrome ). The tropism of HIV is determined by its adsorption to cells with the CD4 receptor. Few other animals contain the CD4 protein on their cell surfaces ( it is specific for some primates ), so the HIV agent grows only in these animals ( chimpanzees and humans ).

Thus the specific limitations of soem viruses amy be due to restrictions in their ability to attach to spefic cells. Other viruses replicate in many animals ( influenza virus, for example ) and this too can have profound consequences for the biology of the virus. There are also viruses that can replicate in many tissues or cekk types of an animal, which means they use receptors that are found on most cells. Such viruses may cause widely disseamted disease throughout the body of the host.

Bacteriophages infect and kill bacteria, which are single-cell organisms. Like all viruses, bacteriophages attach to a specific receptor on the surface of their host cell. Occasionally, a mutation ( a change so that genetic information ) occurs in the bacterium so that the host cell can no longer synthesize the receptor on its surface. In many cases, this is not detrimental to the bacterial host, which is then resistant to the virusthat normally uses that receptor. As might be expected, resistant host cells arise inpopulation under attack by virusrs----- and these resistant cells, without receptors, survive, replicate, and eventually take over as a majority type in the population. In this case, resistance to virus infection is selected for by the presence of a killer virus.

But it is not in the best interest of the virus to kill all its host cell, leaving only resistant bacteria; if there are no hosts, there can be no viruses. Some viruses have developed alternative strageties for a live-and-let-live viral life cycle. Others have taken advantage of rare mutations in the virtion coat protein, which may permit the virus to attach to a new receptor , even one found on the bacterial cell that was resistant to the original or parent virus. This rare virus is then selected for , by virture of its newly acquired ability to attach itself ot the otherwise resistant bacteria and duplicate itself in its new host. Host-range mutations, as they are called, that extend or restrict the ability of a virus to attach to susceptible host cells can thus occur in either the virus or the host cell. A virus evolves by altering its host range to be able to enter new enviroments. The attachment step provides a specificity and a selectivity that have profound consequences for the life cycle.

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Penetration

For those animal viruses with lipid envelopes, penetration of the nucleocapsod core of a virion into a cell occurs when the virion envelope fuses with the plasma membrance to which the virus is attached. The fusion of viral and cellular lipid membrances is usually mediated by proteins encoded by the information (chromosome) found in the viral particle. Fusion leaves the neucloprotein core of the virus on the inside of the cell; this penetration step is also part of the uncoating of such a virus.

Animal viruses without a lipid envelope ( the so-called naked virions, composed only of protein plus DNA or RNA ) are usually taken into cells to which the virus is attached by a process called phagocytosis, or endocytosis. AS we saw earlier in this chapter, many cells constantly produce cytoplasmic vesicles by pinching off portions of their yield spherical vesicles that sample the extracellular enviroment . When these endocyticvesicle migrate to the cytoplasm and fuse with the endosomes, they transport a virus to a cellular location where viral protein submits are removed and the viral nucleic acid becomes accesible to the cellular enviroment. Here too, penetation and uncoating of the nucleic acid are coupled steps. In some cases, viral necleocapsids are transported directly to the host-cell nucleus, where the viral chromosome resides during the entire life cycle.

Some bacteriophage are composed of a head, containing the nucleic acid, and a tail; they resemble sperm. At the base of the tail, the virus-specific attachments organs secure the virus to the cell wall of a sensitive bacterium with receptors. The tail then contracts, inserting a protein tube into the bacterium, just a needle and a syringe act to inject a substance. The bacteriophage's nucleic acid then moves from the head through the tube into the bacterium ----- effecting attachment, penetration, and uncoating in a single step.