7.3.6A: The Productive Life Cycle of Animal Viruses
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- Ying Liu
- City College of San Francisco
Learning Objectives
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When given information about a virus in terms of how it penetrates the host cell, whether it has a DNA or RNA genome, and how it is released, describe how an enveloped virus accomplishes each of the steps of the productive life cycle listed below.
(Tailor the life cycle to that virus.)
- viral attachment or adsorption to the host cell
- viral entry into the host cell
- viral movement to the site of replication within the host cell
- viral replication within the host cell
- viral assembly or maturation within the host cell
- viral release from the host cell
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When given information about a virus in terms of how it penetrates the host cell, whether it has a DNA or RNA genome, and how it is released, describe how a naked virus accomplishes each of the steps of the productive life cycle listed below. (Tailor the life cycle to that virus.)
- viral attachment or adsorption to the host cell
- viral entry into the host cell
- viral movement to the site of replication within the host cell
- viral replication within the host cell
- viral assembly or maturation within the host cell
- viral release from the host cell
For many animal viruses, the details of each step in their life cycle have not yet been fully characterized, and among the viruses that have been well studied there is great deal of variation. What follows is a generalized productive life cycle for animal viruses consisting of the following steps: adsorption, viral entry, viral movement to the site of replication and release of the viral genome from the remainder of the virus, viral replication, viral assembly, and viral release.
Viral Attachment or Adsorption to the Host Cell
Adsorption (Figures 1) involves the binding of attachment sites on the viral surface with receptor sites on the host cell cytoplasmic membrane.
For a virus to infect a host cell, that cell must have receptors for the virus on its surface and also be capable of supporting viral replication. These host cell receptors are normal surface molecules involved in routine cellular function, but since a portion of a molecule on the viral surface resembles the chemical shape of the body's molecule that would normally bind to the receptor, the virus is able to attach to the host cell's surface.
For example:
- Most human rhinoviruses that cause the common cold bind to intercellular adhesion molecules (ICAM-1) found on cells of the nasal epithelium. These ICAM-1 molecules are used normally for the recruitment of leukocytes into the respiratory tract.
- The human immunodeficiency viruses (HIV) adsorbs to first CD4 molecules and then chemokine receptors found on the surface of human T4-lymphocytes and macrophages . CD4 molecules are normally involved in immune recognition while chemokine receptors play a role in initiating inflammation and recruiting leukocytes.
- Human cytomegaloviruses (CMV) adsorb to MHC-I molecules . MHC-I molecules on human cells enable T8-lymphocytes to recognize antigens during adaptive immunity.
- The hepatitis B virus (HBV) adsorbs to IgA receptors on human cells. These receptors normally bind the antibody isotype IgA for transport across cells.
Viral Entry into the Host Cell
a. Enveloped viruses
Enveloped viruses enter the host cell in one of two ways:
1. In some cases, the viral envelope may fuse with the host cell cytoplasmic membrane and the nucleocapsid is released into the cytoplasm (see Figs. 2A , Figure \(\PageIndex{2}\)B and Figure \(\PageIndex{2}\)C) .
2. Usually they enter by endocytosis , whereby the host cell cytoplasmic membrane invaginates and pinches off, placing the virus in an endocytic vesicle (see Figure \(\PageIndex{3}\)A , Figure \(\PageIndex{3}\)B , Figure \(\PageIndex{3}\)C , and Figure \(\PageIndex{3}\)D) .
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3D animation illustrating adsorption and penetration of the dengue fever virus. Janet Iwasa, Gaël McGill (Digizyme) & Michael Astrachan (XVIVO). This animation takes some time to load. |
b. Naked viruses
Naked viruses enter the cell in one of two ways:
1. In some cases, interaction between the viral capsid and the host cell cytoplasmic membrane causes a rearrangement of capsid proteins allowing the viral nucleic acid to pass through the membrane into the cytoplasm (see Figure \(\PageIndex{4}\)A , Figure \(\PageIndex{4}\)B , Figure \(\PageIndex{4}\)C , and Figure \(\PageIndex{4}\)D ).
2. Most naked viruses enter by receptor-mediated endocytosis whereby the host cell cytoplasmic membrane invaginates and pinches off, placing the virus in an endocytic vesicle (see Figure \(\PageIndex{5}\)A , Figure \(\PageIndex{5}\)B , Figure \(\PageIndex{5}\)C , and Figure \(\PageIndex{5}\)D) .
3. Viral Movement to the Site of Replication within the Host Cell and Release of the Viral Genome from the Remainder of the Virus.
In the case of viruses that enter by endocytosis, the endocytic vesicles containing the virus move within the host cell. During this process the pH of the endocytic vesicle typically decreases and this enables the virus to leave the endocytic vesicle. Viruses exit the endocytic vesicle through a variety of mechanisms, including:
a. Fusion of the viral envelope with the membrane of the endocytic vesicle enabling the viral nucleocapsid to enter the cytoplasm of the host cell (see Figure \(\PageIndex{7}\)A , Figure \(\PageIndex{7}\)B , and Figure \(\PageIndex{7}\)C) .
b. Lysis of the endocytic vesicle releasing the viral nucleocapsid into the cytoplasm of the host cell (see Figure \(\PageIndex{7}\)D , and Figure \(\PageIndex{7}\)E) .
c. The viral capsid undergoing conformational changes that forms pores in the endocytic vesicle enabling the virial genome to enter the cytoplasm of the host cell (see Figure \(\PageIndex{9}\)A , Figure \(\PageIndex{9}\)B, and Figure \(\PageIndex{9}\)C).
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Flash animation showing viral capsid undergoing conformational changes that forms pores in the endocytic vesicle and enable the virial genome to enter the cytoplasm.
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html5 version of animation for iPad showing viral capsid undergoing conformational changes that forms pores in the endocytic vesicle and enable the virial genome to enter the cytoplasm.
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Before viruses can replicate within the infected host cell, the viral genome needs to released from the remainder of the virus. This process is sometimes referred to as uncoating.
In the case of most viruses with an RNA genome, the viral RNA genome is released from the capsid and enters the cytoplasm of the host cell (see Figure \(\PageIndex{8}\)A , and Figure \(\PageIndex{8}\)B) where replication generally occurs.
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Flash animation showing release of the viral genome from the capsid (uncoating).
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html5 version of animation for iPad showing release of the viral genome from the capsid (uncoating).
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In the case of most viruses with a DNA genome, the viral genome enters the nucleus of the host cell through one the mechanisms shown below. Most larger DNA viruses use either a or b to enter the nucleus. Method c is used by some very small DNA whose capsid is small enough to be carried through the nuclear pores.
a. The viral DNA genome is released from the capsid, enters the cytoplasm of the host cell, and subsequently enters the nucleus of the host cell through the pores in the nuclear membrane (see Figure \(\PageIndex{9}\)D and Figure \(\PageIndex{9}\)E).
b. The capsid of the viruses interacts with the nuclear membrane of the host cell enabling the viral DNA genome to enter the nucleus of the host cell via the pores in the nuclear membrane (see Figure \(\PageIndex{9}\)F and Figure \(\PageIndex{9}\)G) .
c. The nucleocapsid of a small DNA virus enters the nucleus of the host cell and the capsid is subsequently removed releasing the viral DNA genome into the nucleoplasm (see Figure \(\PageIndex{9}\)H and Figure \(\PageIndex{9}\)I) .
This uncoating begins the eclipse period , the period during which no intact virions can be detected within the cell. After uncoating and during the replication stage the virus is not infectious.
4. Viral Replication within the Host Cell
The viral genome directs the host cell's metabolic machinery (ribosomes, tRNA, nutrients, energy, enzymes, etc.) to synthesize viral enzymes and viral parts. The viral genome has to both replicate itself and become transcribed into viral mRNA molecules. The viral mRNA can then be translated by the host cell's ribosomes into viral structural components and enzymes need for replication and assembly of the virus.
As mentioned earlier under Viral Classification, viruses can store their genetic information in six different types of nucleic acid which are named based on how that nucleic acid eventually becomes transcribed to the viral mRNA:
a. (+/-) double-stranded DNA (see Figure \(\PageIndex{10}\)A). To replicate the viral genome, DNA-dependent DNA polymerase enzymes (usually provided by the cell) copy both the (+) and (-) DNA strands producing dsDNA viral genomes. To produce viral mRNA molecules, host cell-DNA-dependent RNA polymerase enzymes copy the (-) DNA strand into (+) viral mRNA. The (+) viral mRNA can then be translated into viral proteins by host cell ribosomes. Examples include most bacteriophages, Papovaviruses, Adenoviruses, and Herpesviruses.
b. (+) single-stranded DNA (see Figure \(\PageIndex{10}\)B). To replicate the viral genome, DNA-dependent DNA polymerase enzymes (usually provided by the cell) copy the (+) DNA strand of the genome producing a dsDNA intermediate. DNA-dependent DNA polymerase enzymes (again, usually provided by the cell) then copy the (-) DNA strand into ss (+) DNA genomes. To produce viral mRNA molecules, host cell-DNA-dependent RNA polymerase enzymes copy the (-) DNA strand into (+) viral mRNA. The (+) viral mRNA can then be translated into viral proteins by host cell ribosomes. Examples include Phage M13 and Parvoviruses.
c. (+/-) double-stranded RNA (see Figure \(\PageIndex{10}\)C) . To replicate the viral genome, viral RNA-dependent RNA polymerase enzymes (replicase) copy both the (+) RNA and (-) RNA strands of the genome producing a dsRNA genomes. To produce viral mRNA molecules, viral RNA-dependent RNA polymerase enzymes (transcriptase) copy the (-) RNA strand into (+) viral mRNA. The (+) viral mRNA can then be translated into viral proteins by host cell ribosomes. Reoviruses are an example.
d. (-) RNA (see Figure \(\PageIndex{10}\)D). To replicate the viral genome, viral RNA-dependent RNA polymerase enzymes (transcriptase) copy the (-) RNA genome producing ss (+) RNA. Transcriptase must be carried into the cell with the virion. Viral RNA-dependent RNA polymerase enzymes (replicase) then copy the (+) RNA strands producing ss (-) RNA viral genome. The (+) mRNA strands also function as viral mRNA and can then be translated into viral proteins by host cell ribosomes. Examples include Orthomyxoviruses, Paramyxoviruses, Rhabdoviruses.
e. (+) RNA (see Figure \(\PageIndex{10}\)E). To replicate the viral genome, viral RNA-dependent RNA polymerase enzymes (replicase) copy the (+) RNA genome producing ss (-) RNA. Viral RNA-dependent RNA polymerase enzymes (replicase) then copy the (-) RNA strands producing ss (+) RNA viral genome. To produce viral mRNA molecules. RNA-dependent RNA polymerase enzymes (replicase) copy the (-) RNA strand into (+) viral mRNA. The (+) viral mRNA can then be translated into viral proteins by host cell ribosomes. Examples include Picornaviruses, Togaviruses, and Coronaviruses.
f. (+) RNA Retroviruses (see Figure \(\PageIndex{10}\)F) . To replicate the viral genome, viral reverse transcriptase enzymes (RNA-dependent DNA polymerases) copy the (+) RNA genome producing ss (-) DNA strands. Viral reverse transcriptase can also function as a DNA-dependent DNA polymerase enzymes and will copy the (-) DNA strands to produce a dsDNA intermediate. Reverse transcriptase must be carried into the cell with the virion. The viral DNA will move to the nucleus where it integrates into the cell’s DNA using the viral enzyme integrase which also must be carried into the host cell with the virion. Once in the host cell’s DNA, host cell DNA-dependent RNA polymerase enzymes then copy the ds (-) DNA strands to produce ss (+) RNA genomes. To produce viral mRNA molecules, host cell DNA-dependent RNA polymerase enzymes copy the ds (-) DNA strand into (+) viral mRNA. The (+) viral mRNA can then be translated into viral proteins by host cell ribosomes. Retroviruses, such as HIV-1, HIV-2, and HTLV-1 are examples.
As the host cell's ribosomes attach to the viral mRNA molecules, the mRNAs are translated into viral structural proteins and viral enzymes. During the early phase of replication, proteins needed for the replication of the viral genome are made and the genome makes thousands of replicas of itself. During the late phase of replication, viral structural proteins (capsid and matrix proteins, envelope glycoproteins, etc.) and the enzymes involved in maturation are produced.
Some viral mRNAs are monocistronic, that is, they contain genetic material to translate only a single protein or polypeptide. Other viral mRNAs are polycistronic. They contain transcripts of several genes and are translated into one or more large polyproteins. These polyproteins are subsequently cut into individual functional proteins by viral enzymes called proteases.
In the case of most RNA viruses, replication and assembly occurs in the host cell's cytoplasm. With DNA viruses, most replication and assembly occurs in the nucleus of the host cell. The viral genome enters the nucleus of the host cell and here is transcribed into viral mRNA. The viral mRNA molecules then leave the nucleus through the pores in the nuclear membrane and are translated into viral proteins by the host cell's ribosomes in the cytoplasm. Most of these viral proteins then re-enter the nucleus where the virus assembles around the replicated genomes.
- Transmission electron micrograph of Herpes simplex viruses in the nucleus of an infected host cell ; courtesy of CDC.
Also during replication, viral envelope proteins and glycoproteins coded by the viral genome are incorporated into the host cell's cytoplasmic membrane (see Figure \(\PageIndex{11}\)A and Figure \(\PageIndex{11}\)B) or nuclear membrane.
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Flash animation showing viral replication.
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Whether a virus has an RNA or a DNA genome is significant when it comes to developing antiviral agents to control viruses. In the case of RNA viruses, all of the enzymes used in genome replication and transcription are viral encoded enzymes different from those of the host cell so these enzymes can potentially be targeted. On the other hand, DNA viruses use the host cell's RNA transcription machinery and DNA replication machinery so these enzymes, shared by the virus and the host cell, cannot be targeted without killing the host cell. Since all viruses use the host cell's translation machinery regardless of genome type, translation can not be targeted in any viruses.
5. Viral Assembly or Maturation within the Host Cell
During maturation, the capsid is assembled around the viral genome .
- Maturation of an enveloped virus: see Figure \(\PageIndex{12}\)A .
- Maturation of a naked virus: see Figure \(\PageIndex{12}\)B .
Viral Release from the Host Cell
a. Naked viruses
Naked viruses are predominantly released by host cell lysis (see Figure \(\PageIndex{13}\) C) . While some viruses are cytolytic and lyse the host cell more or less directly, in many cases it is the body's immune defenses that lyse the infected cell.
b. Enveloped viruses
With enveloped viruses, the host cell may or may not be lysed. The viruses obtain their envelopes from host cell membranes by budding. As mentioned above, prior to budding, viral proteins and glycoproteins are incorporated into the host cell's membranes. During budding the host cell membrane with incorporated viral proteins and glycoproteins evaginates and pinches off to form the viral envelope. Budding occurs either at the outer cytoplasmic membrane, the nuclear membrane, or at the membranes of the Golgi apparatus .
1. Viruses obtaining their envelope from the cytoplasmic membrane are released during the budding process (see Figure \(\PageIndex{14}\)A and Figure \(\PageIndex{14}\)B) .
- Transmission electron micrograph of Rubella viruses budding from an infected host cell ; courtesy of CDC.
2. Viruses obtaining their envelopes from the membranes of the nucleus, the endoplasmic reticulum, or the Golgi apparatus are then released by exocytosis via transport vesicles (see Figure \(\PageIndex{15}\)A and Figure \(\PageIndex{15}\)B) .
- Transmission electron micrograph of Coronaviruses in the endoplasmic reticulum of an infected host cell ; courtesy of CDC.
Some viruses, capable of causing cell fusion, may be transported from one cell to adjacent cells without being released, that is, they are transmitted by cell-to-cell contact whereby an infected cell fuses with an uninfected cell (see Figure \(\PageIndex{16}\)A , Figure \(\PageIndex{16}\)B , and Figure \(\PageIndex{16}\)C ).
Reinfection
As many as 10,000 to 50,000 animal viruses may be produced by a single infected host cell.
- Transmission electron micrograph showing envelope and glycoprotein spikes Coronaviruses ; courtesy of CDC.
Exercise: Think-Pair-Share Questions
- Animal viruses adsorb to receptors on the cytoplasmic membrane of host cells.
Why would our cells possess receptors that viruses could adsorb too?
- When we vaccinate against viral infections such as measles, mumps, rubella, poliomyelitis, and chickenpox, we inject an attenuated or inactivated form of the virus. The body responds by making antibodies that coat the surface of that virus by binding to its surface proteins or glycoproteins.
Briefly describe two ways this may prevent future infections with this virus.
| Flash Animation showing a summary animation of the life cycle of an enveloped virus. |
| Flash Animation showing a summary animation of the life cycle of a naked virus. |
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Flash Animation Showing All Viral Life Cycle Animations
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Nice Animation with Simplistic Explanation of the Replication of Influenza Viruses. created for NPR by medical animator, David Bolinsky |
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The dengue virus is an RNA virus that enters by endocytosis, gets its envelope by budding into the endoplasmic reticulum, and is packaged by the Golgi apparatus and released by exocytosis. Dengue fever is a mosquito-borne viral infection found mainly in tropical areas. Often asymptomatic and self-limiting but when symptoms do appear, they can include joint and muscle pain, headache, and a rash that may become hemorrhagic. The virus replicates in macrophages. Courtesy of HHMI's Biointeractive . |
Summary
- For a virus to infect a host cell, that cell must have receptors for the virus on its surface and also be capable of supporting viral replication.
- Adsorption involves the binding of attachment sites on the viral surface with receptor sites on the host cell cytoplasmic membrane.
- Once adsorbed, many viruses enter the host cell by endocytosis, whereby the host cell cytoplasmic membrane invaginates and pinches off, placing the virus in an endocytic vesicle. Some viruses enter by a fusion process whereby part of the virus fuses with the host cell enabling the remainder of the virus to enter the host cell’s cytoplasm.
- Following entry, the virus moves to the site of replication within the host cell. Most RNA viruses replicate in the host cell’s cytoplasm; most DNA viruses replicate in the host cell’s nucleus.
- During replication, the viral genome directs the host cell's metabolic machinery (ribosomes, tRNA, nutrients, energy, enzymes, etc.) to synthesize viral enzymes and viral parts. The viral genome has to both replicate itself and become transcribed into viral mRNA molecules. The viral mRNA can then be transcribed by the host cell into viral structural components and enzymes need for replication and assembly of the virus.
- During maturation, the capsid is assembled around the viral genome.
- Prior to or during release, enveloped viruses obtain their envelopes from host cell membranes by budding. Budding occurs either at the outer cytoplasmic membrane, the nuclear membrane, or at the membranes of the Golgi apparatus.
- Viruses obtaining their envelopes from the membranes of the nucleus, the endoplasmic reticulum, or the Golgi apparatus are then released by exocytosis via transport vesicles; viruses obtaining their envelope from the cytoplasmic membrane are released during the budding process.
- Naked viruses are predominantly released by host cell lysis.
- As many as 10,000 to 50,000 animal viruses may be produced by a single infected host cell.
Questions
Study the material in this section and then write out the answers to these questions. Do not just click on the answers and write them out. This will not test your understanding of this tutorial.
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An enveloped virus enters by fusion, has an RNA genome, and is released by budding. Describe how it accomplishes each of the following steps during its productive life cycle.
- viral attachment or adsorption to the host cell (ans)
- viral entry into the host cell (ans)
- viral movement to the site of replication within the host cell (ans)
- viral replication within the host cell (ans)
- viral assembly or maturation within the host cell (ans)
- viral release from the host cell (ans)
- When a virus infects the body, the body responds by producing antibodies that coat the virion. Discuss briefly how this might offer protection to the body. (ans)
- Why are viruses generally very specific as to the types of hosts, tissues, and cells they are able to infect? (ans)
- Multiple Choice (ans)