Micro Chapter 31: Biology of Viruses
The main difference between viruses and other infectious agents is their way of reproducing
-
Unlike bacteria, viruses don’t just divide
Virus replication is done using host cell machinery, which makes copies of the viral genome and
viral proteins, which then assemble spontaneously in the host cell to form virus progeny
Viruses have no means to make energy, and contain few enzymes, so they are totally
dependent on host cells, which makes them an obligate intracellular parasite
Virus genome is either DNA or RNA, but never both
Virion – a virus particle
-
-
The virion has structural stuff used to survive in the environment, and bind to host cells
The virion also has the viral genome inside the structural stuff, and often has enzymes for the
first steps in virus replication
The viral nucleic acid is surrounded by a capsid, which is a single or double layered protein shell
o The nucleic acid and capsid together are called the nucleocapsid
o Capsids are made of subunits called caspomers arranged in a symmetric pattern
o Each capsid subunit can bind to other subunits in specific ways, allowing them to selfassemble to form the capsid
o Viral capsid proteins are arranged in one of two patterns – page 323
 Icosahedral – viruses in this shape all have the same # of subunits
 Usually spherical, and the nucleic acid is packed in the center of the
sphere, and tightly associated with viral capsid proteins
 Helical – the # of subunits varies from virus to virus
 Protein subunits of the capsid are bound in a regular periodic fashion
along the nucleic acid
Many viruses have an envelope that surrounds the nucelocapsid – called enveloped viruses
o The viral envelope is made of virus-specific proteins, plus lipids and carbs from the host
cell membrane
 Matrix (M) protein is sometimes a virus-specific envelope protein that lines the
inner surface of the envelope and touches the nucleocapsid
 M proteins stabilize the interaction between viral glycoproteins and the lipid
envelope, direct the viral genome to intracellular sites, and help the virus bud
Serotypes – different strains of species of virus, that differ in virulence and antigenic properties
Page 324 – classifying viruses, he said don’t need to know
Virus replication steps: infection of a cellreproduction of viral nucleic acid and proteinsassembly
and release of infectious progeny – page 326
-
-
-
-
Viruses can regulate cell enzymes, modify cell structures, and change metabolic and signaling
pathways in the cell
The first step in viral infection of target cells is attaching the virus to the host cell surface, called
adsorption
o Results from random collisions between virions and target cells
o Enveloped viruses attach with a spike protein on the outer surface of the envelope, like
hemagglutinin of flu virus
o Nonenveloped viruses attach with exposed parts of their capsid proteins that are made
to help attach the virus
o Viruses can attach to very specific protein receptors on host cells, or to very common
stuff like adhesion molecules, complement proteins, phospholipids, and carbs
o Some viruses use several receptors
Once adsorption happens, the entire virion, or just a part of it that has viral genome and
polymerases, must be translocated across the plasma membrane of the host cell
o Enveloped viruses fuse the envelope with the cell membrane, then release the
nucleocapsid into the cell
 Some viruses, like mumps, can fuse directly at the plasma membrane
 Other viruses are taken in by endocytosis, and then it fuses to the endosome
membrane inside the cell
 Flu virus is endocytosed at clathrin-coated pits, in vesicles, and then taken to
endosomes
o Nonenveloped viruses can’t fuse with cell membranes, they usually get endocytosed
and then escape the endosome
The next step is uncoating – the capsid is removed to make the viral genome accessible to
transcription and translation machinery
o For many viruses, penetration and uncoating happen simultaneously
o Some viruses, upon contact with the receptor, causes a shape change in the capsid that
releases the viral nucleic acid into the cytoplasm
o Other nonenveloped viruses need host cell enzymes to remove their capsids, or
proteases from endosomes and lysosomes
The making of all viral macromolecules first needs translation of viral mRNA into virus-specific
proteins
o Making viral mRNA – page 327
 Viruses with double-stranded DNA make mRNA the same way host cells do, by
using a DNA dependent RNA polymerase
 Viruses with RNA must make their mRNA from RNA
 Positive sense RNA can serve as mRNA to be read to make proteins
 Single-stranded positive-sense RNA viruses – the RNA genome serves directly as
the mRNA
 Picornaviruses and flaviviruses do this
 After entry into the host cell, the viral genomic RNA acts as mRNA and is
translated by cell ribosomes to make viral proteins



Some of these viruses are translated into a big polypeptide that the
virus uses viral enzymes to cleave into equal sized viral proteins
 Positive sense RNA viruses use virus encoded RNA dependent RNA
polymerase to make a complementary negative sense RNA using
genomic RNA as a template
o This negative sense RNA will then serve as a template for
making more copies of genomic positive-sense RNA
o The newly made genomic RNA may serve as mRNA or be packed
into progeny virions
 Translation: the positive sense genomic RNA is used as the mRNA to
make proteins
 Replication: the positive sense RNA is first converted by viral RNA
polymerase into a negative sense single strand RNA and then again by
viral RNA polymerase into a replicated positive sense single stranded
RNA
Single-stranded negative sense RNA viruses:
 The RNA of negative sense viruses doesn’t carry instructions for
making viral proteins, only its complementary positive sense strand will
 So instead, these viruses use the genomic negative sense RNA as a
template to make mRNA transcrpits corresponding to each viral gene
o Each transcript is made according to how much of it the virus
wants to make
 The genome is replicated by making a full length single stranded
positive sense RNA intermediate, which then serves as a template to
make new copies of single stranded negative sense genomic RNA
 Mammal cells don’t have enzymes to use RNA as a template to make
RNA, so these viruses must have an RNA dependent RNA polymerase in
the virion that’s introduced into the host cell
 So translation: the genomic negative sense RNA is converted by viral
RNA polymerase to a positive sense single strand mRNA and then
translated into proteins
 Replication: it’s replicated using viral RNA polymerase into a single
stranded positive sense RNA, and then again with viral RNA
polymerase into a replicated single stranded negative sense RNA
Double stranded RNA viruses:
 The info encoded in double stranded RNA must first be copied into a
positive sense single strand of RNA to act as mRNA
o Since it’s double stranded, the genome RNA can’t directly be
the mRNA, even though it does have a positive strand
 Double-stranded RNA viruses have a virus encoded RNA dependent RNA
polymerase that transcribes single stranded positive sense RNAs using
-
the negative sense strands of the double strand RNA segments as
templates
 Double stranded RNA genome is always found as segments, each of
which is transcribed to form a unique mRNA
 So double stranded RNA viruses use their own RNA polymerase to
take the negative strand part of their double strand of their RNA, and
copy it into positive sense to be the mRNA
 DNA viruses – make mRNA similar to host cells
 Transcription of viral DNA into mRNA happens in the host cell nucleus,
and depends on host cell enzymes
 Both early and late mRNA transcripts are made
o Early transcrpits encode regulatory proteins and proteins
needed for DNA replication
o Late transcrpits encode structural proteins of the virion
 Many DNA viruses induce cells to express host proteins needed for viral
DNA replication, by stimulating cell cycle progression
 The mRNAs for early and late viral proteins often correspond to
sequences of viral DNA called exons (which are separated from each
other by introns)
 Transcription then makes RNA molecules with sequences identical to
those of the DNA
 The immature mRNA is then cut and spliced back together to remove
introns
 Poxviruses are the most complicated
o Transcription starts in the cytoplasm – so it can’t use host RNA
polymerase, found in the nucleus
o So poxviruses have their own DNA-dependent RNA
polymerase to initiate transcription
o Then one of the early proteins made will do a second stage of
uncoating, so the that the viral DNA is fully accessible for
transcription and replication
 Virus replication, transcription, and assembly all happen in virus-initiated
organelles called “factories” in the host cytoplasm
 As infection progresses DNA replication starts, the making of early nonstructural
proteins stops, and late proteins are made
 Many late proteins are structural proteins, but some are enzymes
 Page 329
DNA viruses replicate in the nucleus of the host – need host RNA polymerase
RNA viruses replicate in the cytoplasm of the host – brought their own RNA polymerase
Now that the proteins have been made, virions are made and released from host cells
o
-
Nonenveloped viruses and nucleocapsids of enveloped viruses are often made
spontaneously, forming crystalline arrays of viral capsids
o Once the capsid is formed, it becomes filled with viral nucleic acid, resulting in the
production of viable virions
o Nonenveloped viruses are usually released when the cell lyses
 Viruses cause lysis by inhibiting making of macromolecules, disorganizing the
cytoskeleton, and changing the host cell membrane structure
o Enveloped viruses are usually released from infected cells by budding
 This may or may not be lethal to the cell
 Virus-encoded proteins inserted into the host cell membrane displace out
normal proteins, causing restructuring of the membrane
 Viral capsids then bind to virus-encoded M proteins on the cytoplasmic side of
the membrane
o Many viruses causes apoptosis, where the host cell shrinks, the membrane blebs, the
nuclear chromatin condense, and the DNA is cleaved
 Apoptosis can be used by the host to kill the infection, or by the infection to kill
the cell and be released
Some viruses cause disease even though they can’t replicate autonomously, called defective
viruses, and they need a coinfection with a helper virus
o Ex: HDV needs HBV, causing fulminant hepatitis
If you were to graph the viral titer in the blood – page 329
-
After the virus adsorbs and begins to be disassembled, titer decreases
The titer then stays constantly low during replication
The viral titer then increases as progeny virions are made
The point right before viral titer increases, is called the eclipse
Once a virus reaches its target organs, it must infect and successfully replicate in a population of host
cells
One of 3 things happens after infection of a host organism by a virus:
-
-
Acute infection – virus does multiple rounds of replication, which causes the host cell to die
o The host cell is used as a factory for virus production
Latent infection – no progeny virus is made
o Caused by DNA viruses or retroviruses
o The viral DNA persists, either as an extrachromosomal element (like in herpesvirus) or as
an integrated sequence within the host genome (retroviruses)
o During cell growth, the genome of the virus is replicated along with the chromosomes of
the host cell
Chronic infection – virus particles continue to be shed after the period of acute illness
o
o
o
o
o
The mark of chronic infection is release of virus particles, sometimes without death of
the host cell or cell injury
Chronic infection is usually done by RNA viruses
The amount of virus made is usually less than in acute infections
The viruses are often altered or mutated from the original one
Chronic infections are allowed by an insufficient immune response that isn’t enough
to clear the infection
Table 31-2 page 331
Respiratory viral infection takes place with aerosol droplets, nasal secretions, or saliva
-
Respiratory aerosolization usually happens from coughing or sneezing, which produce lots of
aerosols
Small particles stay airborne longer, and can escape filtering in the nose easier, making them
very contagious
The common cold is spread by contaminated hands to body orifices, which can be prevented
by washing your hands
Respiratory epithelial cells are covered by a thick glycocalyx, and mucus in the respiratory tree
traps virus particles
Ciliated respiratory epithelial cells continually sweep mucus up from the lower respiratory tract
into the upper respiratory tract, where it is usually swallowed
In the lung, there is secreted IgA, NK cells, and alveolar macrophage
GI viral transmission happens when viruses shed in feces contaminate food or water that is then
ingested (fecal-oral spred)
-
Stool-tainted hands are another way to spread too
Stomach acidity kills a lot of viruses, but activates a few of them that can stand it
Bile salts in the small intestine can destroy the lipid envelopes of many viruses, which is why
most GI viruses are nonenveloped
Proteolytic enzymes and secreted IgA also protect the GI
Some enteric viruses are transported across gut mucosa by microfold (M) cells in peyer patches
The stratum corneum of the skin is both a physical and biologic barrier against entry of viruses
Viremia – lots of virus in the bloodstream
Horizontal spread – transmission of viruses between members of a susceptible host population
Vertical spread – fetus is infected in utero
Some viruses infect and replicate right where they enter you, while others need to spread somewhere
else to cause disease
Incubation period – time of viral replication but no symptoms of clinical illness
Viruses that infect the nervous system use a neuron’s fast axonal transport
-
Rod processes of olfactory receptor cells are exposed in the olfactory mucosa, and are the only
place in the body where the nervous system is in direct contact with the environment
Hematogenous spread – through blood
-
Usually starts with a period of primary replication, and may be asymptomatic or show
prodromal symptoms
Enteric viruses usually do primary replication in peyer patches and peritonsillar lymphatic tissue
Respiratory viruses do primary replication in epithelial or alveolar cells
Spread through the blood often brings the virus to the liver or spleen, leading to replication
there that causes a second viremia
The most important adaptive immune defense against viruses is cell-mediated immunity
-
Vaccines though work by antibodies, which neutralize viruses
Neutrophils aren’t involved much in fighting viruses, but macrophage are a lot
Extrinsic protective mechanisms – defense outside the cell; includes anatomic barriers, innate immunity,
and adaptive immunity
Intrinsic protective mechanisms – intracellular defenses
-
Cells can respond to a virus infection by activating apoptosis to prevent completion of the virus
life cycle
Autophagosomes can sequester and eat the virus
Innate immunity recognizes things likely to be expressed by microbial pathogens, but not by host cells
(pathogen-associated molecular patterns)
-
Toll-like receptors (TLRs) and sensors in the cytoplasm (like RIG-1) are activated by viral stuff like
viral glycoproteins and RNA, triggering inflammation, cytokine and interferon secretion, and
activation of adaptive immunity
Cell mediated immunity recognizes viral antigens bound to MHC proteins on the host cell surface
-
NK cells get there before T cells and antibodies
o NK cells are large granular lymphocytes that recognize and kill virus-infected cells
TC cells will recognize antigens bound to MHC1s
Antibodies aren’t big in terminating acute viral infections, but are important in preventing reinfection
-
Neutralizing antibodies – end the infectivity of the virus
o Usually directed against epitopes on viral proteins on the surface of the virus
o
-
If two isolates of a virus are neutralized by the same antibody, they’re said to be part of
a single serotype
o Neutralizing antibodies against one member of a serotype, will protect against
reinfection by other members of the same serotype, but not against viruses of another
serotype
Antibodies also help lyse virus infected cells, through antibody-dependent cell-mediated
cytotoxicity (ADCC)
o Virus specific antibodies bind to antigens on the surface of infected cells, and then
interact with receptors on NK cells, activating it to kill the infected cell
 Macrophage, lymphocytes, and neutrophils can do ADCC too
Viral infections elicit interferons as well
-
-
Host cells make interferons in response to viruses, to inhibit virus replication indirectly by
inducing other cell proteins to inhibit protein synthesis
Three main kinds of interfeorns:
o Interferon-α – made by WBCs
o Interferon- β – made by fibroblasts and epithelial cells
o Interferon-γ – made by T cells
Interferon acts locally and not systemically
Binding of interferon to its receptor cause expression of lots of genes that do antiviral stuff
o Ex: interferon induces expression of the protein kinase PKR, which phosphorylates a
viral protein synthesis initiation factor, so with it phosphorylated, it can no longer work
in protein synthesis, inhibiting viral protein synthesis
Virus-antibody complexes can circulate and deposit in tissues, causing injury by attracting and activating
inflammatory mediators
Page 335 – ways to diagnose a virus
Taking a specimen to isolate a virus, you then culture it and look for a cytopathic effect
Detecting IgM antibodies to specific agents are good ways to diagnose viral infections
PCR is commonly used to diagnose viruses