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33
Viruses

Concept Outline
33
...

The Discovery of Viruses
...

The Nature of Viruses
...

Able to reproduce only within living cells, viruses are not
themselves alive
...
2 Bacterial viruses exhibit two sorts of reproductive
cycles
...
Some bacterial viruses, called
bacteriophages, rupture the cells they infect, while others
integrate themselves into the bacterial chromosome to
become a stable part of the bacterial genome
...

Integrated bacteriophages sometimes modify the host
bacterium they infect
...
3 HIV is a complex animal virus
...
The animal virus HIV infects certain key cells of
the immune system, destroying the ability of the body to
defend itself from cancer and disease
...

The Future of HIV Treatment
...


33
...

Disease Viruses
...

Prions and Viroids
...


FIGURE 33
...
A virus has been referred to as “a piece of bad
news wrapped up in a protein
...
Viruses are genetic elements enclosed in
protein and are not considered to be organisms, as they
cannot reproduce independently
...
The virus particles you see in figure 33
...
Other viruses cause AIDS,
polio, flu, and some can lead to cancer
...
For more than four decades, viral studies
have been thoroughly intertwined with those of genetics
and molecular biology
...
Already,
viruses are being employed in the treatment of human genetic diseases
...
1

Viruses are strands of nucleic acid encased within a protein coat
...
Living organisms are cellular and able
to grow and reproduce independently, guided by information encoded within DNA
...
Even
simpler than bacteria are viruses
...
”
Viruses possess only a portion of the properties of organisms
...
They
cannot reproduce on their own, and for this reason they are
not considered alive by biologists
...
Earlier theories that viruses represent a kind
of halfway point between life and nonlife have largely been
abandoned
...

Viruses vary greatly in appearance and size
...
2)
...
Viruses are so
small that they are comparable to molecules in size; a hydrogen atom is about 0
...

Biologists first began to suspect the existence of
viruses near the end of the nineteenth century
...
Investigating the
agent further, the scientists found that it could not multiply in solution—it could only reproduce itself within living host cells that it infected
...

The true nature of viruses was discovered in 1933,
when the biologist Wendell Stanley prepared an extract of
a plant virus called tobacco mosaic virus (TMV) and attempted to purify it
...
This was surprising because
precipitation is something that only chemicals do—the
TMV virus was acting like a chemical off the shelf rather
than an organism
...

Within a few years, scientists disassembled the TMV
virus and found that Stanley was right
...
2
Viral diversity
...
At the scale these viruses are shown, a human
hair would be nearly 8 meters thick
...
Each particle of TMV virus is in
fact a mixture of two chemicals: RNA and protein
...
Later workers were able to separate the RNA from the protein and
purify and store each chemical
...
Further experiments carried out on other viruses
yielded similar results
...
They are not alive
...
Individual viruses contain
Capsid
only a single type of nucleic acid, either
Proteins
DNA or RNA
...

RNA
Viruses are frequently classified by the
(b) Tobacco mosaic virus
(c) Human immunodeficiency
(a) Bacteriophage
nature of their genomes
...

Nearly all viruses form a protein
FIGURE 33
...
(a) Bacterial viruses, called
bacteriophages, often have a complex structure
...
The capsid is composed of
2130 identical protein molecules (purple) that form a cylindrical coat around the single
one to a few different protein molecules
strand of RNA (green)
...
3) In
protected by the identical protein molecules packed tightly around it
...
Many animal
protein envelope
...
While some of the
material of the envelope is derived from the host cell’s
new program is not itself a computer and cannot make
membrane, the envelope does contain proteins derived
copies of itself when it is outside the computer, lying on
from viral genes as well
...
The introduced program, like a virus, is simply a
Viruses occur in virtually every kind of organism that
set of instructions
...
However, each
Viruses can reproduce only when they enter cells and
type of virus can replicate in only a very limited number
utilize the cellular machinery of their hosts
...
The suitable cells for a particular virus are
their genes on a single type of nucleic acid, either DNA or
collectively referred to as its host range
...
Viruses are able to reproduce beits potential hosts
...
These proteins lead to the production
African elephant to the Indian elephant, a situation made
of more viruses
...
Some viruses wreak havoc on the cells they infect;
Viral Shape
many others produce no disease or other outward sign of
their infection
...
A
or isometric
...

virus, have a rodlike or threadlike appearance
...

lions of them
...

ric viruses is the icosahedron, a structure with 20 equilateral triangular facets, like the adenovirus shown in figure
33
...
Most viruses are icosahedral in basic structure
...
It is
An infecting virus can be thought of as a set of instructhe most efficient symmetrical arrangement that linear
tions, not unlike a computer program
...

gram, just as a cell is directed by DNA-encoded
instructions
...
Most are icosahedral in structure
...
The
Chapter 33 Viruses

667

33
...


Bacteriophages
Bacteriophages are viruses that infect bacteria
...
Many of these
bacteriophages, called phages for short, are large and complex, with relatively large amounts of DNA and proteins
...
To illustrate the diversity of these viruses,
T3 and T7 phages are icosahedral and have short tails
...
4)
...
The other tail
fibers set the phage perpendicular to the surface of the bacterium and bring the base plate into contact with the cell
surface
...
The contents of the head, mostly DNA, are
then injected into the host cytoplasm
...
5)
...
However, they vary considerably as to when they become virulent within their host
cells
...
While residing there, it is
called a prophage
...
We know as
much about this bacteriophage as we do about virtually any
other biological particle; the complete sequence of its
48,502 bases has been determined
...

The integration of a virus into a cellular genome is
called lysogeny
...
This sort of reproductive cycle, involving a period of genome integration, is
called a lysogenic cycle
...

Bacteriophages are a diverse group of viruses that
attack bacteria
...


Head

DNA Capsid
(protein sheath)

Neck
Whiskers
Tail

Base
plate

(a)

668


...
4
A bacterial virus
...
(a)
Electron micrograph and
(b) diagram of the
structure of a T4
bacteriophage
...
5
Lytic and lysogenic cycles of a
bacteriophage
...
In the lysogenic cycle, the
bacteriophage DNA is integrated
into the large, circular DNA
molecule of the host bacterium
and is reproduced along with the
host DNA as the bacterium
replicates
...
Bacteriophages
are much smaller relative to their
hosts than illustrated in this
diagram
...
The RNA polymerase of the host cell reads the viral genes just as if they
were host genes
...
The genetic alteration of a cell’s genome by the introduction of foreign DNA is called transformation
...


Phage Conversion of the Cholera-Causing
Bacterium
An important example of this sort of phage conversion directed by viral genes is provided by the bacterium responsible for an often-fatal human disease
...
In this
latter form, the bacterium causes the deadly disease
cholera, but how the bacteria changed from harmless to
deadly was not known until recently
...
cholerae introduces into
the host bacterial cell a gene that codes for the cholera
toxin
...
The transfer occurs through bacterial pili (see chapter 34); in further experiments, mutant bacteria that did not have pili were resistant to infection by the
bacteriophage
...

Bacteriophages convert Vibrio cholerae bacteria from
harmless gut residents into disease-causing agents
...
3

HIV is a complex animal virus
...
A good
way to gain a general idea of what they are like is to look at
one animal virus in detail
...
AIDS was
first reported in the United States in 1981
...
Study of HIV revealed it
to be closely related to a chimpanzee virus, suggesting a
recent host expansion to humans in central Africa from
chimpanzees
...
Few who contract
AIDS survive more than a few years untreated
...
However, the transfer of body fluids,
such as blood, semen, or vaginal fluid, or the use of nonsterile needles, between infected and healthy individuals
poses a severe risk
...

The incidence of AIDS is growing very rapidly in the
United States
...
Many—perhaps all of
them—will eventually come down with AIDS
...
AIDS incidence is already very high in many
African countries and is growing at 20% worldwide
...


How HIV Compromises the Immune System
In normal individuals, an army of specialized cells patrols
the bloodstream, attacking and destroying any invading
bacteria or viruses
...
One special kind of white blood
cell, called a CD4+ T cell (discussed further in chapter
57) is required to rouse the defending cells to action
...
6)
...
AIDS patients die of infections that a healthy
person could fight off
...
During this long interval, carriers
of HIV have no clinical symptoms but are apparently fully in670

Part IX Viruses and Simple Organisms

FIGURE 33
...
HIV particles exit an infected CD4+ T cell
(both shown in false color)
...


fectious, which makes the spread of HIV very difficult to control
...
Eventually, however, a random mutational
event in the virus allows it to quickly overcome the immune
defense, starting AIDS
...
The way HIV infects humans
(figure 33
...
Most other viral infections follow a similar course, although the details of entry and replication differ in individual cases
...
When HIV is introduced into the human
bloodstream, the virus particle circulates throughout the
entire body but will only infect CD4+ cells
...

How does a virus such as HIV recognize a specific kind
of target cell? Recall from chapter 7 that every kind of cell
in the human body has a specific array of cell-surface glycoprotein markers that serve to identify them to other, similar
cells
...
Macrophages are
infected first
...
The viral
contents enter the cell by endocytosis
...
The host cell then synthesizes a complementary
strand of DNA
...


Complete HIV particles are assembled
...
In T cells, however, HIV ruptures the
cell, releasing free HIV back into the bloodstream
...
7
The HIV infection cycle
...
These free
viruses infect white blood cells called CD4ϩ T cells
...
After docking onto the CD4
receptor of a macrophage, HIV requires a second
macrophage receptor, called CCR5, to pull itself across the
cell membrane
...
The
current model suggests that after the conformational change,
the second receptor passes the gp120-CD4 complex through
the cell membrane, triggering passage of the contents of the
HIV virus into the cell by endocytosis, with the cell membrane folding inward to form a deep cavity around the virus
...
Once inside the macrophage, the HIV particle sheds its protective coat
...
This enzyme, called reverse transcriptase, synthesizes a double strand of DNA complementary to the virus RNA, often making mistakes and so introducing new mutations
...

HIV does not rupture and kill the macrophage cells it infects
...
HIV synthesizes large numbers of viruses in this
way, challenging the immune system over a period of years
...
During this time, HIV is constantly replicating and mutating
...

This new form of gp120 protein prefers to bind instead
to a different second receptor, CXCR4, a receptor that
occurs on the surface of T lymphocyte CD4+ cells
...

This has deadly consequences, as new viruses exit the cell
by rupturing the cell membrane, effectively killing the infected T cell
...
This destruction of the body’s T cells blocks
the immune response and leads directly to the onset of
AIDS, with cancers and opportunistic infections free to
invade the defenseless body
...
It is only able to gain entrance to those
cells possessing a particular cell surface marker
recognized by a glycoprotein on its own surface
...
For example, scientists are testing drugs and vaccines that act on HIV receptors, researching the possibility of blocking CCR5, and
looking for defects in the structures of HIV receptors in individuals that are infected with HIV but have not developed AIDS
...
8 summarizes some of the recent developments and discoveries
...
These include AZT and its analogs (which inhibit virus nucleic acid
replication) and protease inhibitors (which inhibit the
cleavage of the large polyproteins encoded by gag, poll, and
env genes into functional capsid, enzyme, and envelope segments)
...
A combination of a protease inhibitor and
two AZT analog drugs entirely eliminated the HIV virus
from many of the patients’ bloodstreams
...
Widespread use of this combination therapy has
cut the U
...
AIDS death rate by three-fourths since its introduction in the mid-1990s, from 49,000 AIDS deaths in
1995 to 36,000 in 1996, and just over 10,000 in 1999
...
While the virus disappears from the bloodstream, traces of it can still be detected in lymph tissue of
the patients
...
Because
of demanding therapy schedules and many side effects,
long-term combination therapy does not seem a promising approach
...
This led scientists to believe that the strain of virus transmitted to these
people has some sort of genetic defect that prevents it from
effectively disabling the human immune system
...
This gene is called nef, named
for “negative factor,” and the defective version of nef in the
HIV strain that infected the six Australians seems to be
missing some pieces
...

672

Part IX Viruses and Simple Organisms

This finding has exciting implications for developing a
vaccine against AIDS
...
The Australian strain with the defective nef gene has the potential to
be used in a vaccine that would arm the immune system
against this and other strains of HIV
...
It seems that the protein produced from
the nef gene is one of these critical HIV proteins, because
viruses with defective forms of nef do not reproduce, as
seen in the cases of the six Australians
...


Chemokines and CAF
In the laboratory, chemicals called chemokines appear to
inhibit HIV infection by binding to and blocking the
CCR5 and CXCR4 coreceptors
...

The search for HIV-inhibiting chemokines is intense
...
Researchers report that in
their tests, the levels of chemokines were not different between patients in which the disease was not progressing
and those in which it was rapidly progressing
...
Researchers have not yet succeeded in isolating CAF, which
seems not to block receptors that HIV uses to gain entry to
cells, but, instead, to prevent replication of the virus once it
has infected the cells
...
However, promising research on CAF suggests
that it may be an even better target for treatment and prevention of AIDS
...
The function of chemokines is to attract white blood cells to areas of infection
...
Injections of chemokines may hinder the immune system’s
ability to respond to local chemokines, or they may even
trigger an out-of-control inflammatory response
...


1

2

Combination Therapy

HIV
RNA

Replication

Vaccine or
Drug Therapy

Vaccine incorporating
defective nef

tat or rev

AZT

gag

pol

vif

vpr

vpu

nef

env

nef protein
inhibitor

Protease
inhibitors
Capsid
proteins

3

4

Blocking Receptors

Critical
protein

Envelope
proteins

Replication
proteins

5

Disabling Receptors

Blocking Replication with CAF

gp120

HIV

Viral
RNA

Mutated
coreceptor

CD4

Chemokine
blocking receptor

CCR5
or
CXCR4

CCR5
or
CXCR4

CD4+ cell

CD4

Replication
CAF

FIGURE 33
...
Among them are these five: (1) Combination therapy involves
using two drugs, AZT to block replication of the virus and protease inhibitors to block the production of critical viral proteins
...
Also, drug therapy that inhibits nef’s protein product
is being tested
...
(4) Producing mutations that will disable receptors may also be possible
...


Disabling Receptors
A 32-base-pair deletion in the gene that codes for the CCR5
receptor appears to block HIV infection
...
In one study of 1955 people,
scientists found no individuals who were infected and homozygous for the mutated allele
...
Treatment for AIDS involving disruption of CCR5 looks promising, as research indicates that
people live perfectly well without CCR5
...

A cure for AIDS is not yet in hand, but many new
approaches look promising
...
4

Nonliving infectious agents are responsible for many human diseases
...
Among the diseases that viruses
cause (table 33
...
In addition, viruses have
been implicated in some cancers and leukemias
...
In view of their
effects, it is easy to see why the late Sir Peter Medawar,
Nobel laureate in Physiology or Medicine, wrote, “A virus
is a piece of bad news wrapped in protein
...


Influenza
Perhaps the most lethal virus in human history has been
the influenza virus
...

Types
...
An individual flu virus resembles a rod studded with spikes composed of two kinds of protein (figure 33
...
There are
three general “types” of flu virus, distinguished by their
capsid (inner membrane) protein, which is different for

each type: Type A flu virus causes most of the serious flu
epidemics in humans, and also occurs in mammals and
birds
...

Subtypes
...
One of these proteins,
hemagglutinin (H) aids the virus in gaining access to the
cell interior
...
Parts of the H molecule contain “hot spots” that display an unusual tendency to
change as a result of mutation of the virus RNA during
imprecise replication
...
These highly variable segments of the H molecule are targets against which the
body’s antibodies are directed
...

Because of accumulating changes in the H and N molecules, different flu vaccines are required to protect
against different subtypes
...
Thus, the type A virus that
caused the Hong Kong flu epidemic of 1968 has type 3 H
molecules and type 2 N molecules, and is called
A(H3N2)
...
9
The influenza virus
...

(b) Diagram of an influenza virus
...


674

Part IX Viruses and Simple Organisms

Table 33
...
Over 33 million cases worldwide by 1998
...
No cure
...
Vaccine approved in U
...
in early 1995
...
The greatest problem
in combating flu viruses arises not through mutation, but
through recombination
...
Viral recombination of this kind seems to
have been responsible for the three major flu pandemics

Acute hemorrhagic fever; virus attacks connective tissue,
leading to massive hemorrhaging and death
...
Outbreaks
confined to local regions of central Africa
...

Approximately 1% of U
...
population infected
...
Can be fatal
...
Very prevalent worldwide
...

Exhibits latency—the disease can be dormant for
several years
...
The ducks are not affected by the flu virus, which
shuffles its antigen genes while multiplying within them,
leading to new flu strains
...
Vaccine available
...

Spread through contact with infected saliva
...
No cure
...

Spread through contact with infected saliva
...
No cure
...

Acute viral infection of the CNS that can lead to paralysis
and is often fatal
...
S
...

An acute viral encephalomyelitis transmitted by the bite of
an infected animal
...


Historically a major killer; the last recorded case of smallpox
was in 1977
...

Spread from individual to individual by mosquito bites; a
notable cause of death during the construction of the
Panama Canal
...


(that is, worldwide epidemics) that occurred in the last
century, by producing drastic shifts in H N combinations
...
The Asian flu of 1957, A(H2N2), killed over
100,000 Americans
...

Chapter 33 Viruses

675

It is no accident that new strains of flu usually originate
in the far east
...
Pigs are subject to infection by both bird and human strains of the
virus, and individual animals are often simultaneously infected with multiple strains
...
The Hong Kong flu,
for example, arose from recombination between A(H3N8)
[from ducks] and A(H2N2) [from humans]
...

A potentially deadly new strain of flu virus emerged in
Hong Kong in 1997, A(H5N1)
...
A(H5N1) was first
identified in chickens in 1961, and in the spring of 1997
devastated flocks of chickens in Hong Kong
...
Public health officials remain concerned that the genes of A(H5N1) could yet mix with those
of a human strain to create a new strain that could spread
widely in the human population, and to prevent this ordered the killing of all 1
...


FIGURE 33
...
This virus, with a fatality rate that can exceed
90%, appears sporadically in West Africa
...


associated with rodents
...
Although hantavirus has been known for
some period of time, this particular outbreak was attributed
to the presence of an unusually large rodent population in
the area following a higher than normal amount of rainfall
the previous winter
...
Often, this expansion is deadly to the new host
...

Influenza is fundamentally a bird virus
...

Among the most lethal of emerging viruses are a collection of filamentous viruses arising in central Africa that
cause severe hemorrhagic fever
...
One, Ebola virus (figure
33
...
The outbreak of Ebola
virus in the summer of 1995 in Zaire killed 245 people out
of 316 infected—a mortality rate of 78%
...

The natural host of Ebola is unknown
...
This highly fatal disease was soon
attributed to the hantavirus, a single-stranded RNA virus

Through epidemiological studies and research, scientists
have established a link between some viral infections and
the subsequent development of cancer
...
It has been suggested that viruses contribute to about 15% of all human cancer cases worldwide
...
Certain viruses can either activate host proto-oncogenes (see chapter 18) or
bring in viral oncogenes that become incorporated into the
host genome
...
The disease involves complex interactions with
cellular genes and requires a series of events in order to develop
...
Some of the most serious examples
are viruses that have transferred to humans from some
other host
...

Newly emerging viruses such as Ebola have received
considerable public attention
...
These diseases have the unusual property that it is years and often decades after infection before the disease is detected in infected individuals
...
Called transmissible spongiform encephalopathies
(TSEs), these diseases include scrapie in sheep, “mad cow”
disease in cattle, and kuru and Creutzfeldt-Jakob disease in
humans
...
TSEs can also spread via
tissue transplants and, apparently, food
...
Mad cow disease spread widely among
the cattle herds of England in the 1990s because cows were
fed bone meal prepared from cattle carcasses to increase
the protein content of their diet
...


A Heretical Suggestion
In the 1960s, British researchers T
...
Griffith
noted that infectious TSE preparations remained infectious
even after exposed to radiation that would destroy DNA or
RNA
...
Perhaps, they speculated, the protein usually preferred
one folding pattern, but could sometimes misfold, and then
catalyze other proteins to do the same, the misfolding
spreading like a chain reaction
...


Prusiner’s Prions
In the early 1970s, physician Stanley Prusiner, moved by
the death of a patient from Creutzfeldt-Jakob disease,
began to study TSEs
...
Try as he might, Prusiner
could find no evidence of nucleic acids or viruses in the infectious TSE preparations, and concluded, as Alper and
Griffith had, that the infectious agent was a protein, which
in a 1982 paper he named a prion, for “proteinaceous infectious particle
...
The scientific community resisted Prusiner’s renegade conclusions, but eventually experiments done in Prusiner’s and other
laboratories began to convince many
...
11
How prions arise
...
When prions
misfolded in different ways (blue) contact normal prion protein
(purple), the normal prion protein misfolds in the same way
...
11)
...
However, if brain tissue with the prion protein is
grafted into the mice, the grafted tissue—but not the rest
of the brain—can then be infected with TSE
...


Viroids
Viroids are tiny, naked molecules of RNA, only a few hundred nucleotides long, that are important infectious disease
agents in plants
...
It is not clear
how viroids cause disease
...
These sequences are capable
of catalyzing excision from DNA—perhaps the viroids are
catalyzing the destruction of chromosomal integrity
...
In
plants, naked RNA molecules called viroids can also
transmit disease
...
mhhe
...
biocourse
...
1 Viruses are strands of nucleic acid encased within a protein coat
...

• The simplest viruses use the enzymes of the host cell
for both protein synthesis and gene replication; the
more complex ones contain up to 200 genes and are
capable of synthesizing many structural proteins and
enzymes
...
Most
isometric viruses are icosahedral in shape
...
Why are viruses not
considered to be living
organisms?

• Characteristics of
Viruses

2
...
What is the approximate size
range of viruses and type of
microscope is generally required
to visualize viruses?

33
...

• Virulent bacteriophages infect bacterial cells by
injecting their viral DNA or RNA into the cell, where
it directs the production of new virus particles,
ultimately lysing the cell
...


4
...
What specific type of human
cell does the AIDS virus infect?
How does it recognize this
specific kind of cell?

• Bioethics Case Study:
AIDS Vaccine
On Science Articles:
• HIV’s Waiting Game
• Drug Therapy for
AIDS
• Curing AIDS Just Got
Harder
• HIV Delivery Protein

33
...

• AIDS, a viral infection that destroys the immune
system, is caused by HIV (human immunodeficiency
virus)
...

• Considerable progress has been made in the
treatment of AIDS, particularly with drugs such as
protease inhibitors that block cleavage of HIV
polyproteins into functional segments
...
How do many animal viruses
penetrate the host cell? How
does a plant virus infect its host?
How does a bacterial virus infect
its host?

33
...

• Viruses are responsible for many serious human
diseases
...

• Proteins called prions may transmit serious brain
diseases from one individual to another
...
Why is it so much more
difficult to treat a viral infection
than a bacterial one? Is this
different from treating bacterial
infections?
8

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