Viruses

Chapter 26

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 The History of Viruses / Virology
• Viral diseases such as rabies
have affected humans for many
centuries.
• Perhaps the first written record
of a virus infection consists of a
heiroglyph from Memphis, the
capital of ancient Egypt, drawn
in approximately 3700BC, which
depicts a temple priest called
Ruma showing typical clinical
signs of paralytic poliomyelitis.

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 The History of Viruses / Virology
• Smallpox was endemic in China by 1000BC. In response,
the practice of variolation was developed.
– What’s endemic?

• Recognized that survivors of smallpox outbreaks were

protected from subsequent infection.
– variolation involved inhalation of the dried crusts from

smallpox lesions, or in later modifications, inoculation of

the pus from a lesion into a scratch on the forearm of a
child.

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 The History of Viruses / Virology: Smallpox
• In 1717 the wife of an English ambassador to the
Ottoman Empire, observed local women
inoculating their children against Smallpox.
• In the late 18th century, Edward Jenner observed
and studied Miss Sarah Nelmes, a milkmaid who
had previously caught Cowpox and was
subsequently found to be immune to Smallpox, a
similar, but devastating virus.
• On 14th May 1796, Edward Jenner used cowpox-
infected material obtained from the hand of Sarah
Nemes, a milkmaid from his home village of
Berkley in Gloucestershire to successfully
vaccinate 8 year old James Phipps.

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 The History of Viruses / Virology: Smallpox
• On 1st July 1796, Jenner challenged the boy by
deliberately inoculating him with material from a
real case of smallpox !
He did not become infected !!!
• Jenner developed the first vaccine, based on these
findings, and smallpox is currently all but wiped
out. (Read the Demon in the Freezer)

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 The History of Viruses / Virology: Smallpox
• Although initially controversial, vaccination against
smallpox was almost universally adopted
worldwide during the 19th century.
• Cartoon by James Gillray, 1802.

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 The History of Viruses / Virology
• However, it was not until Robert Koch & Louis Pasteur jointly
proposed the 'germ theory' of disease in the 1880s that the significance
of these organisms became apparent.

Robert Koch (1843-1910) Louis Pasteur (1822-1895)

• Where should you be familiar with Pasteur’s name in your refrigerator?

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 The History of Viruses / Virology
Koch defined the four famous criteria now known as
Koch's postulates which are still generally
regarded as the proof that an infectious agent is
responsible for a specific disease:
• The agent must be present in every case of the
disease.
• The agent must be isolated from the host & grown in
vitro.
• The disease must be reproduced when a pure culture
of the agent is inoculated into a healthy susceptible
host.
• The same agent must be recovered once again from
the experimentally infected host.

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 The History of Viruses / Virology
• In the late 19th century Charles Chamberland
developed a porcelain filter. This filter was used to
study the first documented virus, tobacco mosaic virus.
• Shortly afterwards, Dimitri Ivanovski published
experiments showing that crushed leaf extracts of
infected tobacco plants were still infectious even after
filtering the bacteria from the solution.
• At about the same time, several others documented
filterable disease-causing agents, with several
independent experiments showing that viruses were
different from bacteria, yet they could also cause
disease in living organisms.
• These experiments showed that viruses are orders of
magnitudes smaller than bacteria. The term virus was
coined by the Dutch microbiologist Martinus Beijerinck.
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 The History of Viruses / Virology
• In the early 20th century, Frederick Twort
discovered that bacteria could be attacked by
viruses.
• Felix d'Herelle, working independently, showed
that a preparation of viruses caused areas of
cellular death on thin cell cultures spread on agar.
• Counting the dead areas allowed him to estimate
the original number of viruses in the suspension.
• The invention of Electron microscopy provided the
first look at viruses. In 1935 Wendell Stanley
crystallised the tobacco mosaic virus and found it
to be mostly protein.
• A short time later the virus was separated into
protein and nucleic acid parts.

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 Viruses: The Basics

• What are the “requirements” for life? Or how

do you know if something is alive?
• In small groups discuss
• Movement, sensitivity, death, complexity,
heredity, growth, cellular organization,
development, reproduction, regulation
• Are viruses alive?

• Class opinion
• Bruening / Rest of Science opinion
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 Viruses: The Basics
• Most virologists consider them non-living, as they do
not meet all the criteria of the generally accepted
definition of life.
• They are similar to obligate intracellular parasites as
they lack the means for self-reproduction outside a
host cell, but unlike parasites, viruses are generally
not considered to be true living organisms.
• A definitive answer is still elusive because some
organisms considered to be living exhibit
characteristics of both living and non-living particles,
as viruses do.
• For those who consider viruses living, viruses are an
exception to the cell theory as viruses are not made
up of cells. 12
 Viruses: The Basics
• A virus is a microscopic “particle” that can infect the
cells of a biological organism.
• Viruses can only replicate themselves by infecting a
host cell and therefore cannot reproduce on their own.
• At the most basic level, viruses consist of genetic
material contained within a protective protein coat
called a capsid. They infect a wide variety of
organisms: both eukaryotes and prokaryotes.
• A virus that infects bacteria is known as a
bacteriophage, often shortened to phage.
• The study of viruses is known as virology, and those
who study viruses are known as virologists.
• The word virus comes from the Latin, poison (syn.
venenum).
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 The Nature of Viruses
• Viral structure - core of nucleic acid surrounded by
protein
– classified by nature of genomes

 Either DNA or RNA

 RNA-based viruses – retroviruses (more later)

– Lack ribosomes and necessary enzymes for

protein synthesis
– nearly all form a protein sheath or capsid around

their nucleic acid core

 Many animal viruses form an envelope around

the capsid.
• Host range - suitable cells for a virus
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Viral Structure

15
 Bacterial Virus - Structure

• (a) Electron Micrograph

• (b) diagram of a T4 bacteriophage
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 Viral Replication

• Viruses can reproduce only when they enter

cells and utilize the host’s cellular machinery.
– viral genes translated into proteins by the

cell’s genetic machinery

– Compare to computer virus

Video – How does a virus enter a cell

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 Viral Shape
• helical - rodlike
• isometric - spiral
– Icosahedron

 structure with 20 equilateral

triangular facets
 most efficient symmetrical
arrangement that linear
subunits can form a shell with
maximum internal capacity
 basic design of geodesic
dome 

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 Viral Genome Structure

• Viral genomes types exhibit great diversity

• Some use DNA others RNA
• Some double stranded, others single stranded
• dsDNA, ssDNA, dsRNA, ssRNA
• In ssRNA, the genome can contain the same
base sequences as the mRNA used to
produce viral proteins. RNA strand can serve
as mRNA and is called a positive-strand virus
• Genome can contain bases complementary to
viral mRNA and is called negative-strand virus
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 Types of Viruses
• DNA Viruses RNA Viruses
• Adenoviruses Coronaviruses
• Iridoviruses Filoviruses
• Herpesviruses Orthomyxoviruses
• Papovaviruses Paramyxoviruses
• Parvoviruses Picornaviruses
• Poxviruses Retroviruses
• Viral Hepatitis Rhabdoviruses
• "Arboviruses" Arenaviruses, Bunyaviruses,
Flaviviruses, Togaviruses
• Diarrhoea Viruses Astroviruses, Caliciviruses,
Reoviruses (inc. Rotaviruses)
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 Important Human Viral Diseases – Table 26.1

• Molecular biologists call a DNA single strand or

sequence sense (or positive (+) sense) if an RNA
version of the same sequence is translated or
translatable into protein, and they call its
complement antisense (or negative (-) sense) 21
Important Human Viral Diseases – Table 26.1

22
 Types of Viruses - Adenoviruses
• Adenoviruses are viruses of the family
Adenoviridae.
• There are 2 genera, Aviadenovirus (avian) and
Mastadenovirus (mammalian) where they infect both
humans and animals.
• Adenoviruses are a frequent cause of acute upper
respiratory tract (URT) infections, i.e. "colds". In
addition, they also cause a number of other types of
infection; 5–10% of upper respiratory infections in
children, and many infections in adults as well
• Adenoviruses were first isolated in human adenoids
(tonsils), from which the name is derived.
• Widespread in nature, infecting birds, many
mammals and man. 23
 Types of Viruses - Adenoviruses
• Can undergo latent infection in lymphoid tissues,
becoming reactivated some time later.
• They're medium-sized (60-90 nm), nonenveloped
icosahedral viruses containing double-stranded
DNA.
• genome is linear, non-segmented double stranded
(ds) DNA which is between 26 and 45 Kbp. This
allows the virus to theoretically carry 22 to 40 genes
• Adenoviruses represent the largest nonenveloped
viruses, because they are the maximum size able to
be transported through the endosome (i.e. envelope
fusion is not necessary).
• Endosome? a membrane bound compartment inside
eukaryotic cells. It is a compartment of the endocytic
membrane transport pathway from the plasma
membrane to the lysosome. 24
 Types of Viruses - Adenoviruses

• Several types have oncogenic potential.

– What does this mean?

• In recent years, there has been considerable

interest in developing Adenoviruses as vectors
to carry and express foreign genes for
therapeutic purposes.
• One reason for this is that the Adenovirus
genome is relatively easily manipulated in vitro

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 Types of Viruses - Adenoviruses

Structure of
Adenovirus

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 Types of Viruses - Retroviruses
• Most of the retroviruses infect vertebrates, but as a
group, they have been identified in virtually all
organisms including invertebrates - evolutionarily
successful design!
• They are enveloped viruses possessing a RNA
genome, and replicate via a DNA intermediate.
• The virus itself stores its nucleic acid in the form of a
+mRNA genome and serves as a means of delivery of
that genome into cells it targets as an obligate parasite
• rely on the enzyme reverse transcriptase to perform
the reverse transcription of its genome from RNA into
DNA, which can then be integrated into the host's
genome with an integrase enzyme. 27
 Types of Viruses - Retroviruses
• Once in the host's cell, the RNA strands undergo
reverse transcription in the cytosol and are integrated
into the host's genome, at which point the retroviral
DNA is referred to as a provirus.
• It is difficult to detect the virus until it has infected the
host.
• Simply, the retrovirus enters a host cell and provokes
the RNA strands inside of the normally-functioning cell
to undergo reverse transcription, which is violating the
'central dogma of biology.' DNARNAProtein
• When a retrovirus is inside of a cell, the first two steps
of that process would be switched. (Rather than DNA -
-> RNA --> Protein, it would be RNA --> DNA) The
host cell would become a provirus as this has
occurred.
• Video How retroviruses work & Simpler Video & Book Video 28
 Types of Viruses - Retroviruses
• When retroviruses have integrated their genome
into the germ line, their genome is passed on to
a following generation.
• These endogenous retroviruses, contrasted with
exogenous ones, now make up surprisingly large
portion of the human genome. Most insertions
have no known function and are often referred to
as "junk DNA".
• However, many endogenous retroviruses play
important roles in host biology, such as control of
gene transcription, cell fusion during placental
development in the course of the germination of
an embryo, and resistance to exogenous
retroviral infection.
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 Types of Viruses - Herpesviruses
• Name comes from the Greek 'Herpein' - 'to
creep' = chronic/latent/recurrent infections.
Epidemiology of the common Herpesvirus
infections puzzled clinicians for many years.
• all herpesviruses are composed of relatively
large double-stranded, linear DNA genomes
encoding 100-200 genes encased within an
icosahedral protein cage.
• ~100 Herpesviruses have been isolated, at
least one for most animal species which has
been looked at. To date, there are 8 known
human Herpesviruses. 30
 Types of Viruses - Herpesviruses
• Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known as
Human herpes virus 1 and 2 (HHV-1 and -2), are two members of
the herpes virus family, Herpesviridae, that infect humans.
• ubiquitous and contagious. They can be spread when an infected
person is producing and shedding the virus.
• Symptoms of herpes simplex virus infection include watery blisters
in the skin or mucous membranes of the mouth, lips or genitals.
Lesions heal with a scab characteristic of herpetic disease.
• However, as neurotropic and neuroinvasive viruses, HSV-1 and -2
persist in the body for the life of the carrier by becoming latent and
hiding from the immune system in the cell bodies of nerves.
• After the initial or primary infection, some infected people
experience sporadic episodes of viral reactivation or outbreaks. In
an outbreak, the virus in a nerve cell becomes active and is
transported via the nerve's axon to the skin, where virus replication
and shedding occur and cause new sores.
• There is no known cure for HSV infection, but treatments can
reduce the likelihood of viral shedding and spread.

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 Bacteriophages

• Bacteriophages - viruses that infect bacteria

– Bacteriophages are among the most

common biological entities on Earth.

– The term is commonly used in its

shortened form, phage.

– some named as members of a “T” series

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 Bacteriophages
• One of the densest natural sources for phages and
other viruses is sea water, where up to 9×108
virions per milliliter have been found in microbial
mats at the surface, and up to 70% of marine
bacteria may be infected by phages.
• They have been used for over 60 years as an
alternative to antibiotics in the former Soviet Union
and Eastern Europe.
• They are seen as a possible therapy against multi
drug resistant strains of many bacteria.
• How would this work?

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 Bacteriophages
• Structure
– Picture on left is a real SEM image

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 Lytic Cycle
• tail fiber contacts lipoproteins of host bacterial

cell wall
– tail contracts and tail tube passes through

opening in base plate, piercing bacterial cell

wall
 contents injected into host cytoplasm

– will kill infected cell by lysis

– virulent viruses

Picture of phages on outside of cell


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36
 Lysogenic cycle
• Does not immediately kill the cell
• integrate their nucleic acid into the genome of
the infected host cell (prophage).
 prophage - phage genome inserted as

part of the linear structure of the DNA

chromosome of a bacterium
– The integration of a virus into a cellular

genome is termed lysogeny.

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 Lysogenic cycle
• prophage may exit genome and initiate virus

replication
 lysogenic cycle

 lysogenic (or temperate) viruses

Lytic and Lysogenic Cycle

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 Cell Transformation and Phage Conversion

• Transformation - genetic alteration of a cell’s

genome by the introduction of foreign DNA
– phage conversion - foreign DNA contributed

by bacterial virus
 disease-causing bacteria Vibrio cholerae

usually exists in harmless form

 bacteriophage that infects V. cholerae

introduces into the host bacterial cell a

gene that codes for the cholera toxin

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 AIDS

• Acquired Immunodeficiency Syndrome

(AIDS) was first reported in the US in 1981.
– estimated over 33 million people

worldwide are infected with Human

Immunodeficiency Virus (HIV)
• Infection cycle
– In normal individuals, white blood cells

patrol the bloodstream and attack invading

bacteria or viruses.

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 AIDS

• In AIDS patients, the virus hones in on CD4+

T cells, infecting and killing them.
– Without T cells, the body cannot defend

against invading bacteria or viruses.

 Each HIV particle possesses glycoprotein

(gp120) on its surface that precisely fits a

cell-surface marker protein (CD4) on
surfaces of macrophages and T cells.

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 AIDS
• After docking onto the macrophage CD4
receptor, HIV requires a second macrophage
receptor (CCR5) to cross the cell membrane.
– Once inside the macrophage, the HIV

particle sheds its protective coat.

 RNA and reverse transcriptase left

floating in cytoplasm
 double strand of DNA, complementary

to RNA, produced
 viruses released via exocytosis

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43
 The Future of HIV Treatment

• Combination drug therapy

– AZT and protease inhibitors

 keeps disease in check

• Vaccine therapy
– may reduce reproductive capability of HIV

• Blocking replication
– chemokines bind to and block receptors

– CAF prevents viral replication

• Disabling receptors
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45
 Disease Viruses
• Many human diseases are caused by viruses:
– influenza, smallpox , chicken pox, herpes

• Viruses may also play a role in autoimmune

diseases such as multiple sclerosis and
diabetes.
• Influenza
– Flu viruses are animal retroviruses

distinguished by their capsid.

 types A, B, and C

 subtypes differ in protein spikes

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 Disease Viruses

• Recombination
– Viral genes are readily re-assorted by

genetic recombination.
 novel combinations of H and N spikes

unrecognizable by human antibodies

 inability to make perfect vaccines

 flu pandemics

 How? And Why?

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 Disease Viruses
• Emerging viruses
– viruses that originate in one organism and then

pass to another and cause disease

 Ebola –one strain has 90% lethality

 Severe Acute Respiratory Syndrome (SARS) –

 coronovirus in 2003

 Unrelated to any previous coronovirus

 most likely came from civets (weasel-like

animals) in China eaten as delicacies

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 Viruses and Cancer

• Viruses are capable of altering growth

properties of human cells they infect by
triggering oncogene expression.
– Association between hepatitis B infections

and liver cancer

– Cervical cancer linked to certain strains of

HPV (human papilomaviruses)

 Why are some groups against vaccine?
– 15% of all cancers worldwide

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 Prions
• Prions – proteianceous infectious particle
 Nobel Prize in 1997

– infectious proteins that some believe may

be responsible for transmissible

spongiform encephalopathies (TSE’s)
 scrapie in sheep

 mad cow disease in cattle

 Humans

 Kuru in Fore people of New Guinea

 Creutzfeldt-Jakob disease

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How Prions Arise Shortcut to how_prions_arise.lnk

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TSE’s

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53
 Viroids
• tiny, naked molecules of RNA that are an
important infectious disease agent in plants
– recent outbreak killed 10 million coconut

palms in Phillipines
• Not clear how they cause disease
• Viroid nucleotide sequences resemble
sequences of introns within ribosomal RNA
genes
– capable of catalyzing destruction of

chromosome integrity??
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The Ebola Virus

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