These lecture notes will provide an outline of information from the lectures. They are not complete. They should be used to help follow the lecture and as a guideline for information I think is important. You will need to fill in the gaps.

CHAPTER 11 - VIRUSES

These notes were updated February 4, 2001, and are ready for printing by Spring 2001 Med Micro. students.

I.   Overview of Viruses

A.   Viruses are nonliving agents that can infect all forms of life 1.   The infected form is called the HOST B.   Size range is 20 nm-250 nm 1.   Recall that bacteria range from 0.2-2 micrometers a)   Which is 200-2000 nm C.   Called a VIRION when it is on the outside of its host cell and a virus inside the host cell 1.   The reality is, virion and virus are often used interchangeably II.   Structure of the Virion A.   Composed of two or three parts 1.   A core of nucleic acid, called the GENOME a)   This is a segment of one type of nucleic acid ONLY (DNA or RNA, but NEVER both)
b)   This segment may be single-stranded OR it may be double-stranded
c)   This segment may be linear or circular
d)   This segment is folded and condensed or coiled 2.   A protein coat, called the CAPSID a)   The capsid protects the nucleic acid
b)   It resists temperature, pH, and other environmental changes
c)   It may also contain enzymes that assist cell penetration
d)   This is what will stimulate an immune response in humans during the infectious process
e)   This also is responsible for the shape of the virus
f)   The capsid is made up of capsomeres (1)   The number of capsomeres is characteristic for each type of virus g)   The capsid and genome are called the nucleocapsid 3.   An envelope in some instances a)   Composed of lipids and protein
b)   It is VERY SIMILAR TO THE CELL MEMBRANE OF ITS HOST (1)   That's because the virus acquires part of the host's cell membrane during replication c)   The envelope may have spikes (1)   Spikes contain enzymes that assist with attachment to host cells d)   Enveloped viruses are only infectious when their envelopes are attached
e)   Viruses are either enveloped or naked B.   Various shapes of the virion (which may be obscured if virus is enveloped) 1.   Helical symmetry a)   Resembles a corkscrew or spring 2.   Icosahedral symmetry a)   Polyhedron with 20 triangular faces and 12 corners 3.   Complex symmetry a)   This is a combination of helical and icosahedral symmetry
b)   This is the most common type of bacteriophage symmetry
c)   This type does not occur in animal and plant viruses 4.   Pleomorphic a)   Having an irregular shape C.   Classification of Virions 1.   Because there is much yet to learn, it is expected that classification systems will change
2.   Today, animal viruses are classified based on three of the above-mentioned characteristics: a)   Genome structure (1)   DNA or RNA
(2)   Single-stranded or double-stranded b)   Virion particle structure (1)   Icosahedral
(2)   Helical
(3)   Pleomorphic c)   Presence or absence of viral envelope 3.   In addition, viruses infecting humans are loosely classified based on their route of transmission: a)   Enteric viruses
b)   Respiratory viruses
c)   Zoonoses
d)   Sexually transmitted 4.   OR based on the tissue they infect a)   Pneumotropic (respiratory system)
b)   Dermotropic (skin/subcutaneous tissues)
c)   Viscertotropic (blood/visceral organs)
d)   Neurotropic (central nervous system) III.   Replication A.   Viruses can only multiply within living cells that are actively metabolizing 1.   Viruses use structures and enzymes of these cells to support their own reproduction B.   Viruses do not have the ability to generate energy 1.   So, we cannot classify them as being "phototrophic" or "chemotrophic"
2.   They do not have mitochondria C.   Viruses do not have the ability to synthesize proteins 1.   They do not have ribosomes D.   A virus MUST be able to do (encode for) three things 1.   Contain genes on its nucleic acid that encode the viral protein coat
2.   Contain genes on its nucleic acid that encode for replication of the viral nucleic acid
3.   Contain genes on its nucleic acid that encode for movement into and out of the host cell E.   How the virion takes over the metabolism of the host cell occurs in one of several ways 1.   Some virions take over the metabolism of the host cell, destroying (through lysis) the cell in the process a)   These are called lytic phage infections 2.   Others only take over some of the host cell's metabolism and the host cell continues to multiply while the virions leak out of the cell
3.   Still others live in harmony with the host cell and multiply as the host cell multiplies a)   These are called temperate phage infections IV.   A Model of Replication in a Lytic Bacteriophage, the T-Even Group A.   Attachment 1.   There must be a chemical interaction between the virion and the host cell
2.   There must be a receptor site on the host cell that matches to the virion a)   For example, a site upon the flagellum, cell wall, or fimbriae in bacteria
b)   In human cells, it would be the upon the plasma membrane B.   Penetration 1.    The tail of the phage releases lysozyme a)    This dissolves part of the bacterial cell wall 2.    Then the tail sheath contracts a)    The tail core drives through the cell wall 3.    The nucleic acid of the virus passes into the bacterial cytoplasm C.    Biosynthesis 1.    Phage DNA uses bacterial nucleotides and enzymes to synthesize multiple copies of the DNA
2.    Then transcription and translation of viral proteins occur, using bacterial ribosomes D.    Maturation 1.    Assembly of virions from the synthesized DNA and capsids a)    This is when generalized transduction may occur
b)    Recall this is the process of inserting bacterial DNA into the new phage instead of phage DNA (1)   This abnormal phage particle is called a transducing particle, and it can attach to another bacterium and inject bacterial DNA into it
(2)   The result is a genetic exchange: DNA from the bacterial cell where the transducing particle was formed is introduced into another cell
(3)   The DNA fragment that the phage injects persists in the host cell ONLY if it becomes integrated by recombination into the host's genome E.   Release 1.   Cell membrane of bacterium lyses, releasing the virons to infect other bacteria
2.    Burst time is the time from phage attachment to release of new viruses a)    Averages 20-40 minutes for bacteriophages
b)    Releases 50-200 bacteriophages per host cell (1)   This is the burst size V.    How Does This Model Compare to Replication of Viruses Infecting Animal Cells? A.    Attachment 1.    Animal virus receptor sites are found on host cell membrane, not cell wall (as in bacteria)
2.    Animal viruses have no tails a)    Their attachment sites are distributed over the entire surface of the capsid
b)    Animal viruses may use spikes, capsid, or envelop to attach 3.    The irony of it all: a)   The host cell inherits viral receptor sites for the virion to attach to (we are programmed for viral infection)
b)    This accounts for differences in susceptibility to viral infections among people B.    Penetration 1.    The whole animal virus enters into the animal cytoplasm a)    Recall that the bacteriophage only injects its DNA into the bacterial cytoplasm 2.    If the animal virus is enveloped, one of two entries: a)    Membrane fusion method (1)    Its lipid envelope blends with animal membrane lipids
(2)    The envelope remains outside and the nucelocapsid passes into the host cell's cytoplasm
(3)    Nucleic acid is released b)    Endocytosis (1)    Interaction between viral spikes and host cell receptor sites occurs
(2)    A membrane vesicle forms around the virus
(3)    This vesicle pinches off INTO the animal cell cytoplasm
(4)    The viral envelope blends with the vesicle membrane, causing the liberation of the nucleocapsid into the cytoplasm 3.    Naked virions enter by endocytosis a)    The difference is that, since there is no envelope, there is no fusing with the vesicle
b)    Instead, once engulfed and surrounded by the vesicle, the virus dissolves inside of it, resulting in the release of the nucleocapsid into the cytoplasm 4.    Only after entry does the animal virus release its nucleic acid a)    This is called UNCOATING C.    Biosynthesis 1.    In animal cells, biosynthesis differs from virus to virus
2.    The difference is based on whether the virus contains DNA or RNA as its nucleic acid a)    If it is DNA (1)    Some may replicate entirely in the host cell cytoplasm
(2)   Others may replicate the DNA in the host cell nucleus and then synthesize the protein capsids in the cytoplasm
(3)    These proteins then move back to the nucleus to join with the DNA for assembly b)    If it is RNA (1)    Some viruses use their RNA as messenger RNA and begin protein synthesis immediately (a)    These are called "sense" viruses or positive-stranded RNA viruses (2)    Other viruses use their RNA as the template to synthesize a COMPLEMENTARY strand of RNA, which is then used as the mRNA for protein synthesis (a)    These viruses are called antisense or negative-stranded RNA viruses (3)    The retroviruses are the most interesting (a)    They use their RNA as a template to synthesize single-stranded DNA, which then serves as a template to form its complementary DNA strand (i)    Reverse transcriptase is the viral enzyme that synthesizes DNA using the genetic message contained in the RNA (b)    The viral RNA is destroyed, and the two DNA strands form a double helix and move into the cell nucleus where they INTEGRATE into one of the host cell's chromosomes
(c)    This integrated piece is called a PROVIRUS (i)    Recall that temperate bacteriophages insert their DNA into the bacterial chromosome and are called PROPHAGES (d)    This is called lysogeny in both animal and bacterial viruses
(e)    From here, it will encode new retroviruses D.    Maturation 1.   Synthesis and assembly may occur entirely in the cytoplasm
2.    Synthesis may occur in the cytoplasm and nucleus, followed by assembly in the nucleus E.   Release 1.   Naked viruses leave the cell after the cell membrane has ruptured a)   This causes cell death 2.   Enveloped viruses leave in a process called budding, which does not necessarily kill the cell a)    Once its envelope proteins are synthesized, they are incorporated into the cell membrane
b)   The virus pushes through the membrane
c)   This forces a part of the membrane to surround it, resulting in an envelope VI.   Lysogeny A.    Lysogeny occurs when viral infection of a cell results in the INTEGRATION of the viral DNA or RNA (via DNA) into a chromosome of the cell 1.    If a bacteriophage is involved, the phage DNA is called a prophage
2.    If an animal virus is involved, the viral DNA is called a provirus
3.    In both cases, the viral nucleic acid is encoding a repressor protein that prevents the activation of the genes necessary for viral replication B.    During lysogeny: 1.    The virus cannot be reached by the host cell's antibodies
2.    The virus is replicated each time the cell's chromosome is reproduced
3.    New properties are conferred by the prophage or provirus on the infected cell a)    E.g., toxin-encoding prophages (C. botulinum, E. coli O157:H7, C. diptheria) in bacteria
b)   E.g., Human T-lymphocytes that harbor the HIV in the provirus form 4.    Specialized transduction can occur during lysogeny a)    Recall this is when a particular fragment of DNA from one cell is transferred to a second cell in combination with the bacteriophage DNA (the fragment found on either side of the bacteriophage DNA) 5.    Another possible result of lysogeny may be cancer a)    This occurs when a lysogenic virus' genome encodes for proteins that can bring about cancerous changes VII.    Viruses and Cancer A.    How are cancer cells different from normal cells? 1.    They undergo mitosis more frequently than normal cells
2.    They do not adhere to each other normally a)    Consequently, they overgrow one another to form a mass
b)    They become invasive
c)    They may metastasize (spread) 3.    They undergo DEDIFFERENTIATION a)    This is a return to an early developmental stage (immature form of the cell) B.    How do viruses transform normal cells? 1.    Oncogene theory a)    Proto-oncogenes are the fore-runners of oncogenes
b)    Proto-oncogenes regulate growth and mitosis of the cell
c)    They can be converted to oncogenes by carcinogens (1)    Certain viruses
(2)    Radiation
(3)    Chemicals
(4)    Chromosomal breakage and rearrangement d)    Once converted, tumor formation may begin 2.    Certain viruses may transform cells into tumor-forming cells a)    This transformation is not the same as the transformation of bacteria by naked DNA
b)    This transformation causes cells to demonstrate the properties of cancer cells (above) 3.   Retroviruses are the most common viral cause of tumors in animal cells (but NOT the most common cause of tumors!) a)    They transform cells by inserting transforming genes (of the virus) into the genome of the host cell
b)    This means the genetic information in the viral RNA is converted into a double-stranded DNA molecule by reverse transcriptase, integrated into the host DNA, and expressed
c)    These transforming genes are oncogenes (1)    Oncogenes are mutant forms of the normal cells proto-oncogenes
(2)    The latest theory on these oncogenes is that they originated from the animal proto-oncogenes that were "captured" by the retrovirus (specialized transduction!) in the course of being excised from the host's chromosome
(3)    Recall that in bacteria, the temperate phage that is integrated into the bacterial host chromosome may incorporate a specific piece of bacterial DNA during its excision
(4)    This bacterial DNA is then transferred to other bacteria by transduction
(5)    In a similar fashion, retroviruses, which also integrate into animal chromosome, may carry a proto-oncogene from the host during their excision
(6)    Once inside the virus, the proto-oncogene underwent mutations that converted it into an oncogene VIII.    Subviral Particles A.    Viroids 1.    Not viruses
2.    Consist of a single-stranded RNA molecule and no protein coat
3.    All viroids identified thus far are plant pathogens
4.    Do they have counterparts in animals? B.    Prions 1.    Not viruses
2.    These are proteinaceous infectious particles
3.    These are very resistant, surviving heat, radiation, and chemical treatments
4.    Composed only of protein
5.    Are deviant versions of a harmless protein found on the membrane surfaces of most mammalian cells, especially brain cells
6.    This protein is called prion protein (PrP)
7.    In the normal state, PrP protects its cell
8.    Once converted to the abnormal form, PrP not only cannot protect the cell, it leads to the cell's death
9.    The symptoms of disease soon follow
10.   Brain tissues develop a spongelike appearance with empty areas of dead tissue a)     Examples are Mad Cow Disease and Creutzfeldt-Jakob disease (CJD)

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