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VIROLOGY
Viruses are NOT CELLS. They are very simple structures composed of a central core of nucleic acid surrounded
by a protein coat (called capsid). The capsid is made of protein subunits.
The nucleic acid present in a virus is either RNA or DNA.
A virus particle complete with a nucleic acid (DNA or RNA) and a protein coat can be called a virion.
Some viruses are enclosed with a glycoprotein membrane called an envelope.
Viruses are very small (20 – 300 nm in diameter). They cannot be seen using a light microscope. They can only
be observed by an electron microscope.
Viruses are non-cellular, have no organelles and are totally dependent on the host cell for replication. They are
therefore obligate intracellular parasites. One infectious virus particle enters a cell, and replicates to give rise
to hundreds of new virus particles. This often results in the death of the host cell, giving rise to disease. An
example; hepatitis virus kills cells of the liver and HIV kills cells of the immune system.
General properties of viruses
1. Viruses are acellular.
2. They are filterable (pass through bacteria proof filter).
3. Viruses are obligate intracellular parasites and infect all the major biological groups-animal, plants and
bacteria.
4. They are host specific i.e. a specific virus infects a specific host.
5. They are inactive molecules outside the host cell and active only inside host cells.
6. Each virus particle or virion is nucleoprotein in nature.
7. Nucleic acid is either DNA or RNA.
8. They lack enzymes and metabolic machinery for replication; they are therefore dependent on the host cell for
replication and protein synthesis.
9. They are resistant to chemicals, alcohols and environmental changes.
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Structure of viruses
Genome
- A core of DNA or RNA
- May be single-stranded (ss) or double stranded (ds)
- May be circular or linear.
Capsid
- Is the protein coat surrounding the genome
- Provides structural symmetry
- Participates in attachment to susceptible host
- Facilitates transfer of viral nucleic acid into host cell
- Protects the viral genome from nucleases in blood stream
Capsomeres: the structural units making up capsid: consist of one or several proteins
Nucleocapsid: The protein-nucleic acid complex.
Envelope
- A lipid bilayer surrounding the capsid of some viruses.
- May contain material of host cell as well as the virus’ material; the envelope is acquired as the virus buds out
through the host cell’s cell membrane.
- The envelope carries glycoprotein, which form projections or spikes (they are exposed on the surface of the
envelope). These proteins serve many purposes, such as binding to receptors on the host cell and playing a
role in membrane fusion and cell entry. They can also form channels in the viral membrane.
- Most human helical viruses are enveloped while icosahedral are either enveloped or non-enveloped.
Enveloped viruses are more unstable i.e. are more sensitive to heat, drying, detergents and alcohols. All viruses
transmitted by faecal-oral route like hepatitis A virus, poliovirus and rotavirus are non-enveloped (those have to
survive in environment). Enveloped viruses are often transmitted by direct contact as by blood, sexual contact
like HIV, HBV, HCV, rabies virus, measles, mumps, rubella viruses, etc.
Functions of the viral capsid and envelope;
- Protects the nucleic acid from the effects of various enzymes and chemicals when the virus is outside the
host.
- They help introduce the viral DNA or RNA into the suitable host cell, first by binding to the host cell surface
and then by assisting in penetration of the viral nucleic acid.
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- Parts of viral capsids and envelopes stimulate the immune system to produce antibodies that can neutralize
viruses and protect the host’s cells against future infections.
Virion: This term describes the complete infectious virus particle. In some cases the particles may lack nucleic
acids (are therefore empty particles), or may carry defective genomes (defective particles), which can interfere
with normal replication.
CLASSIFICATION OF VIRUSES
The following properties have been used as a basis for classification of viruses;
1) Virion morphology: size, shape, presence of envelope, etc.
2) Physicochemical properties: thermal stability, detergent stability, molecular mass, etc.
3) Genome: size, type of nucleic acid (DNA or RNA), strandedness (single/double, sense (positive/negative), etc.
4) Virus protein properties; number, size, sequence, etc.
5) Lipids; content, character, etc.
6) Carbohydrates; content, character, etc.
7) Genome organization and replication: strategy of replication, number and position of open reading frames,
transcriptional and translational strategies, site of virion assembly and release.
8) Antigenic properties: serological relationships.
9) Biological properties: Host range, mode of transmission, pathogenicity, tissue tropisms, geographic
distribution, etc.
However, with increased research and knowledge about viruses, classification is changing rapidly.
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SYMMETRY OF VIRUSES
Cubic/icosahedral symmetry - An icosahedron has 20 triangular faces. Example of viruses with icosahedral-
shaped capsids are adenovirus and picornaviruses.
Helical symmetry – Some viruses have hollow-tubed capsids surrounding the helical-shaped nucleic acid.
Example; Influenza and Measles viruses.
Complex symmetry – Some viruses have neither a helical/icosahedral structure; they are more intricate and
atypical. An example is the poxviruses, which are very large DNA viruses that lack a typical capsid and are covered
by a dense layer of lipoproteins and coarse fibrils on their outer surface.
Another atypical virus is the bacteriophage; Bacteriophages have a polyhedral capsid head and a helical tail and
fibers for attachment to the host cell.
REPLICATION OF VIRUSES IN A HOST CELL
Viruses cannot replicate without the machinery (enzymes, nutrients, energy, etc.) of the host cell.
All virus life cycles are different and are dependent on the virus type and the host.
The general steps are;
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Attachment: Viral proteins on the capsid or phospholipid envelope interact with specific receptors on the
host’s cell surface. This interaction is very specific and it determines which cells the virus can infect. Example;
HIV binds to receptors on the CD4 immune cells while the rabies virus affects infects the nerve cells of most
mammals. This tissue specificity is known as tropism.
Penetration: The process of attachment to a specific receptor induces changes in viral capsid proteins that
results in the fusion of viral and cellular membranes. Fusion occurs with enveloped viruses only. Both
enveloped and naked viruses can also enter the host cell through endocytosis; the virus is engulfed entirely
into a vesicle after its initial attachment.
Uncoating: The viral capsid (and vesicle, if present) is removed and degraded by viral enzymes or host
enzymes, thereby releasing the viral genomic nucleic acid.
Replication: Almost immediately upon entry, the viral nucleic acid alters the genetic expression of the host
and instructs it to synthesize the building blocks for new viruses (proteins, enzymes, etc.). Transcription and
translation of the viral genome is initiated. This results in the synthesis of viral proteins and genome.
Assembly: After the synthesis of viral genome and proteins, viral proteins are packaged with newly replicated
viral genome into progeny viruses that are ready for release from the host cell. This process can also be
referred to as maturation.
Virion release: There are two methods of viral release: lysis or budding. Lysis results in the death of an infected
host cell, these types of viruses are referred to as cytolytic. E.g. smallpox virus. Enveloped viruses, such as
Influenza A virus, are released from the host cell by budding. Budding of enveloped viruses causes them to
be shed gradually, without sudden destruction of the host cell. Enveloped viruses are not infectious until they
have acquired their envelopes.
The length of a multiplication cycle varies; from 8 to 72 hours. The number of virions released by infected cells
ranges from 3000 up to over 100,000 virions from a single infected cell.
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Routes of entry of pathogenic viruses
- Ingestion
- Inhalation
- Innoculation (bite or injection)
- Blood/organ transplant
- Congenital
- Sexual
- Broken skin
Pathogenesis of viral diseases
Viral pathogenesis refers to the interaction of viral and host factors that lead to disease production.
In order for host infection to occur, a virus must first attach to and enter cells of one of the body surfaces – skin,
respiratory tract, gastrointestinal tract, urogenital tract or conjunctiva. Viruses usually replicate at the primary
site of entry and do not spread further (are therefore local infections). These include rhinoviruses (respiratory
infection) and rotaviruses (gastrointestinal infection). Others produce disease at sites distant from their point
of entry e.g. enteroviruses (they enter through the GIT but may produce CNS disease). The result is systemic
infections. The most common route of viral spread is via the bloodstream or lymphatics. Presence of a virus in
the blood is called viremia.
Sub-clinical viral disease (asymptomatic illness) is very common. Both cellular and antibody immune responses
are produced in response to viral infections. Virus-infected cells may be lysed by cytotoxic T-cells and neutralizing
antibodies are directed against capsid proteins, thereby blocking the attachment and uncoating of the virus. In
acute infections, clearance of the virus from the body is associated with recovery.
Clinical illness from viral infection is the result of a complex series of events. General symptoms associated with
many viral infections, such as malaise and anorexia, may result from the host’s immune response, e.g. the
production of cytokines.
Viral infections are self-limiting. Sometimes, however, the virus persists for long periods in the host. This long-
term (persistent) infections may take several forms;
- Chronic infections are those in which the virus can be continuously detected, often at low levels. Mild or no
clinical symptoms may be evident. Infants infected with hepatitis B virus become chronic and asymptomatic
carriers.
- Latent infections are those in which the virus remains in an inactive or cryptic form over long periods. There
can be occasional flare-ups of clinical disease. Herpes simplex viruses (cold sores and genital herpes) and
herpes zoster viruses (chicken pox and shingles) enter the body and enter the nerve cells where they persist
in a noninfectious state. They are periodically reactivated to cause recurrent symptoms. Immunosuppression,
age and hormonal changes are a common cause of reactivation.
- Slow Infection: This type of virus-cell interaction is characterized by a prolonged incubation period, without
significant morphological and physiological changes of infected cells. A slow progression of cellular injury
may take years and is followed by extensive cellular injury and disease.
- Inapparent/sub-clinical infection – self-explanatory
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Virus shedding
Is the excretion of virus from the infected host. Once viral replication occurs, progeny viruses (virions) are
released into body fluids/secretions. At this point, the virions can be expelled from the body through various
routes. The infected individual is termed as ‘contagious’ because they can transmit the virus to others.
An individual infected with Influenza A virus sheds the progeny viruses by coughing. The shedding begins one
day before the appearance of symptoms and can continue for up to a week after the appearance of symptoms.
Norovirus, which causes the ‘stomach flu’ is shed through faeces and vomit, while Hepatitis A is shed in faeces
for 2 weeks before the appearance of symptoms. For some viruses, shedding can occur even if symptoms never
develop. For example, some people infected with Herpes Simplex Type 2 (genital herpes) can actively shed and
unknowingly infect their sexual partners. Virus shedding may also be present after vaccination with live,
attenuated viruses, e.g. the Oral Polio Vaccine. The virus may regain its pathogenicity and once shed, it may infect
others.
Transformation
Some animal viruses enter their host cell and permanently alter its genetic material, leading to cancers. These
viruses are termed oncogenic, and their effect is called transformation. Transformed cells generally have an
increased rate of growth, altered chromosomes, show changes in cell’s surface molecules and have the capacity
to divide for an indefinite period. Mammalian viruses capable of initiating tumors are called oncoviruses. They
include papillomas (associated with cervical and penile cancers), Epstein-Barr virus (cause Burkitt’s lymphoma)
and hepatitis B (liver cancer).
INCUBATION PERIOD
The time between infection and the appearance of symptoms of a viral infection appear is called the incubation
period. During this time, viral genomes are replicating and the host is responding, producing cytokines such as
interferon that can have global effects, leading to the classical symptoms of an acute infection (e.g., fever,
malaise, aches, pains, and nausea). These symptoms are called the prodrome.
Incubation period is variable, depending on the virus type and the site of entry. Common cold, caused by
Rhinoviruses, has a very short incubation period 0f 1-2 days. Chickenpox and poliomyelitis viruses have an
incubation period of 10-20 days, hepatitis B; 2 to 6 months. Slow viruses may have an incubation period of
years/decades.
Viral infections
Most types of viruses gain access to the human body via the respiratory tract mainly in the form of aerosolized
droplets or saliva. Successful infection occurs despite normal host protective mechanisms, such as the mucus
covering most surfaces, ciliary action, macrophages and secretory antibody (IgA). The severity of respiratory
infection can range from asymptomatic to severe. Acute viral respiratory infections are mostly caused by
Rhinovirus, Adenovirus, Influenza and Respiratory Syncytial virus (RSV).
Some viruses can initiate infection via the alimentary tract. Infections of the mouth can be brought on by herpes
simplex virus and Epstein-Barr virus. Rotaviruses, Norwalkviruses and calciviruses are major causes of acute
gastroenteritis in infants and children. Some other enteroviruses, such as polioviruses and hepatitis A virus, cause
systemic disease but do not produce intestinal symptoms.
The skin is a tough and impermeable barrier to the entry of viruses. However, a few viruses can penetrate this
barrier and initiate infection. Some obtain entry through small abrasions of the skin, e.g. papillomaviruses and
poxviruses, while others are introduced by the bite of arthropod/insect vectors (arboviruses) or infected
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vertebrate hosts (rabies, hepatitis B), or injected during body manipulations such as transfusions, tattooing and
acupuncture (hepatitis B and HIV). A few agents remain localized and produce lesions at the site of entry, e.g.
molluscum contagiosum, while most spread to other sites.
Invasion of the central nervous system (CNS) by viruses is always serious. Viruses gain access to the brain by two
routes; by the bloodstream and by peripheral nerve fibers. Many viruses can infect the CNS and cause meningitis
or encephalitis. E.g. herpesvirus, flaviviruses, enteroviruses and rhabdoviruses.
Few viruses produce disease in the human foetus. Most maternal viral infections do not cross into the foetus. If
the virus crosses the placenta and infection occurs, serious congenital defects may occur. Measles, Rubella,
Cytomegalovirus, Herpes and HIV can cause congenital infections. Many of these diseases can be transmitted to
the baby during delivery.
Human determinants of susceptibility to viruses
1. Mutations: It has been reported that some people have an RNA gene that increases the replication rate of
Influenza A virus. These individuals more often develop severe pneumonia, compared to the general population.
Some individuals can have a genetic variation in their co-receptor CCR5, which prevents HIV-1 from entering the
cell, making these individuals HIV- resistant.
2. Age: Very young and very old humans most susceptible to disease. Infants and young children have immature
immune response, while the elderly may have weaker immune responses. With respiratory viruses, the old have
less elastic alveoli, weaker respiratory muscles and diminished cough reflex (therefore contributing to higher
chances of acquiring infection)
3. Sex: Males slightly more susceptible to viral infections than females
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4. Pregnancy: Pregnancy weakens the immune system. Therefore, hepatitis A, B, E, influenza become more lethal in
pregnant women.
5. Malnutrition: Inadequate nutrients increase susceptibility because physical barriers and immune response are
compromised.
6. Environmental factors: Cigarette smoking increases susceptibility to respiratory infections, while air pollution
increases the incidence of respiratory disease.
7. Stress causes increased susceptibility.
VIRAL DISEASES AND VIRUSES CAUSING THEM
1) POXVIRUSES
- Are enveloped DNA viruses that produce eruptive skin pustules called pocks, which leave small, depressed scars
upon healing.
- Poxviruses are the largest and most complex of all animal viruses. They multiply in the cytoplasm of epidermal
cells.
Variola virus is the agent that causes smallpox. This disease, acquired through inhalation of droplets, was one of the
deadliest infectious diseases and the virus was highly virulent. Those who survived the disease always developed
lifelong immunity. Through vaccination, smallpox disease has been eradicated.
Molluscipox virus is another common pox virus that causes a skin disease known as molluscum contagiosum. It is
an infection of children and is transmitted by direct contact and fomites (inanimate object that has been in contact
with an infected individual). The infection can also be transmitted through sexual intercourse. Small, smooth skin
lesions are its main symptom, appearing on the face, trunk and limbs.
2) HERPES VIRUSES
- This is a family of viruses that produce a rash that spreads. They include:
a. Herpes Simplex 1 and 2 (HSV) that cause blisters, fever and genital infections. HSV 1 causes oropharynx
lesions and HSV-2, genital lesions. Both forms can cause severe neonatal herpes. Transmission of HSV involves
direct exposure to body secretions containing the virus. People with asymptomatic genital herpes
unknowingly transmit the disease to their sexual partners. In both forms of disease, the blisters have thin
walls and are very painful when they burst.
b. Varicella-Zoster Virus (VZV), the cause of chickenpox and shingles. VZV causes latent infections and their
main route of entry into the body is the respiratory epithelium.
- Varicella (chickenpox) initially produces no symptoms. After an incubation period of 10-20 days, fever and an
abundant rash appear. The rash progresses from small, red pimples to itchy blisters that dry off and heal
completely.
- Shingles (Herpes zoster), occurs when the varicella virus becomes latent in the sensory nerves (ganglia) and is
reactivated after many years, forming localized, painful rashes.
Reactivation of the virus may be caused by:
Fever
X-ray treatments
Immunosuppressive treatment
Surgery
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Declining immune function, e.g. with age
VZV cause self-limiting disease that requires no therapy
c. Cytomegaloviruses (CMV), which infect salivary glands and are transmitted in saliva, respiratory mucus, milk,
urine, semen and cervical secretions infected.
CMV results in giant infected, cells (hence the name ‘mega’) and remains latent in white blood cells. It causes
disease in fetuses, newborns and immunodeficient adults. Newborns are most affected by this opportunistic
disease and exhibit jaundice, capillary bleeding, hearing and visual disturbances and even mental retardation.
d. Epstein – Barr virus, which infects lymphoid tissue and salivary glands, resulting in infectious mononucleosis
(the kissing disease). The disease is marked by sore throat, high fever, skin rash and a gray-white exudate in
the throat. EBV can also transform lymphocytes into malignant (cancerous) cells, causing Burkitt lymphoma.
Burkitt lymphoma causes the swelling of the jaw and cheek, and is associated with chronic co-infections (such
as malaria) and a weakened immune system.
3. VIRAL AGENTS OF HEPATITIS
Hepatitis refers to the inflammation and necrosis of the liver:
- Hepatitis A Virus is a non-enveloped RNA enterovirus transmitted through contaminated food. It is a contagious
liver infection that causes symptoms such as fatigue, low appetite, stomach pain, nausea, and jaundice, which
usually resolve within 2 months of infection.
- Hepatitis B Virus is an enveloped DNA virus that causes chronic infection of the liver. It is transmitted through
sexual intercourse, sharing of dirty needles, blood transfusion and during the birth process. Virions in the blood
are in such high numbers that sharing a toothbrush can result in infection. Most people develop mild hepatitis,
while others develop chronic liver disease.
HBV has also been associated with hepatocellular carcinoma.
- Hepatitis C is caused by an RNA flavivirus. It is a chronic infection that is able to avoid the host’s immune detection
for a very long time. May also give rise to liver cancer. Most hepatitis infections occur with limited symptoms.
Common symptoms include Jaundice (yellowing of the skin or eyes), dark urine, fever and malaise.
- Hepatitis D virus infection occurs only in people with HBV.
- Hepatitis E virus is transmitted through the faecal-oral route, due to contamination of drinking water with faeces.
4. ORTHOMYXOVIRIDIAE – INFLUENZA VIRUSES
- Are 3 types; A, B, C. Influenza A is more virulent than the others.
- Influenza A undergoes many antigenic changes on its surface glycoproteins. Its two most important glycoproteins
are haemagglutinin (H) and neuraminidase (N). Both are virulence factors.
- H is needed to bind to the respiratory mucosal cells and induce viral entry.
- N is an enzyme that breaks down the mucus and keeps the virus from sticking together
- Influenza viruses cause a respiratory illness that causes inflammation of the respiratory epithelium, causing fever,
headache, cough and shortness of breath.
- Mode of transmission is inhalation of droplets. Infection is most common in school-going children. Poor ventilation
and crowding facilitates the spread of infection.
5. MORBILLIVIRUS
- Causes measles, an acute and highly contagious disease
- Transmitted principally by respiratory aerosols. After an incubation period of 2 weeks, an infected person develops
a sore throat, dry cough, headache, conjunctivitis and fever. Oval lesions called Koplik’s spots and a red rash
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develops over most of the body. The disease may progress into a neurological disease, resulting in coma and
death.
- Treatment relies on reducing fever, suppressing cough and replacing lost fluid.
6. RESPIRATORY SYNCYTIAL VIRUS
- Also called pneumovirus, it infects the respiratory tract and mostly infects children of 6 months and younger.
7. ARBOVIRUSES
- Refers to arthropod-borne viruses, which are viruses that are spread by arthropods; such as mosquitoes, ticks and
flies.
- Arboviruses include West Nile Fever Virus, Yellow Fever Virus, Rift Valley Fever Virus and Dengue Fever Virus. Most
arboviruses cause mild fevers, although some cause severe encephalitis and life-threatening haemorrhagic fevers.
8. RETROVIRUSES
- These are viruses that contain an enzyme that allows the virus to convert their single strand RNA to a double-
stranded DNA.
- An example is the Human Immunodeficiency Virus (HIV 1 and 2), the causative agent of acquired
immunodeficiency syndrome (AIDS).
- HIV attacks cells of the immune system, beginning with T-cells and macrophages.
9. PICORNAVIRUSES
- Are the smallest human viruses
- Include Poliovirus and Rhinovirus
- Poliomyelitis is an acute enteroviral infection of the spinal cord
- The poliovirus has a naked capsid that confers chemical stability and resistance to acid, bile and detergents. The
virus is therefore able to survive the gastric environment and other harsh conditions.
- The virus, when ingested, attaches itself to intestinal mucosa, where it multiplies in large numbers. Most infected
persons show mild symptoms of fever, fatigue, nausea, headache and stiffness. In a small percentage, the virus
travels to the spinal cord causing permanent paralysis of the limbs.
Mechanisms of cell injury by viruses
They result in the lysis of certain cells (cytolytic viruses)
Cytopathic effects: Cytopathic effects (CPE) are the virus-induced damages to the host cell that alters its microscopic
appearance. These cells can become disoriented, undergo changes in shape or size, or develop intracellular changes.
Microscopically, there may be appearance of inclusion bodies, which are compacted masses of viruses or
damaged cell organelles, in the nucleus and cytoplasm. Another common CPE is the fusion of multiple host cells
into single large cells (syncytia) containing multiple nuclei.
Viral inhibition of host protein and RNA synthesis, leads to loss of membrane integrity, leakage of enzymes from
lysosomes, cytoplasmic degradation, etc.
Proteins from several viruses (mumps, influenza) are toxic to cells and organisms.
Genotoxic Effects: Following virus infection, breakage, fragmentation, rearrangement and/or changes in the number
of chromosomes may occur.
Host cell can be transformed into a malignant cell.
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Techniques in cultivating and identifying animal viruses / viral infections
1. Cell culture techniques
The
in vitro
cultivation of cells results in a cell culture. Animal cell cultures can be grown in sterile environments in
special media that contains the correct nutrients required by the animal cells to survive. The cultured cells grow in a
monolayer
, or a single, continuous sheet of cells that can support viral multiplication. The cultures are then inspected
for signs of infection.
These signs include degeneration and lysis of infected cells in the monolayer. The areas where virus-infected cells have
been destroyed show up as clear, well-defined patches called plaques.
2. Using bird embryos
Embryos undergo rapid differentiation and are found in a sterile environment, making for a perfect virus replication
system. Chicken, duck and turkey eggs are the most common choice for inoculation of viruses. The virus sample is
injected through the shell, and then the egg is incubated. The signs of viral growth include the death of the embryo,
defects in the embryonic development and localized areas of damage in the embryonic membrane, forming opaque
spots called pocks.
3. Using live animals
Special strains of white mice, rats, hamsters, rabbits and primates can be used in animal cultivation of viruses. The virus
is injected into the brain, blood, muscle, body cavity or skin of the animal and the animal is monitored for signs of viral
infection.
4. Serological/molecular tests
Certain viruses can be identified by their ability to agglutinate red blood cells (form big clumps), such as Influenza
viruses. These tests are known as haemagglutination tests.
Others can be identified by their reaction with an antibody of known specificity that will bind with that specific virus, if
present.
Genetic tests can also be used to detect the presence of viral nucleic acids in a host.
5. Direct Observation
Use of microscopy (electron microscopy to identify the virus particle) and light microscope to identify CPE in infected
tissues or cells.
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VIRUS-LIKE AGENTS: Prions
The name comes from the term proteinaceous infections particle.
Prions are non-cellular infectious agents composed of a naked protein molecule only. Prions are the only biologically
active agents that lack any sort of nucleic acid (DNA or RNA).
Common prion diseases include bovine spongiform encephalopathy (AKA mad cow disease) in cattle and Creutzfeldt
Jakob syndrome in humans.
When they come in contact with a normal protein, prions cause spontaneous abnormal folding of the protein. The
abnormal protein accumulates in the cell, eventually killing it.
Viroids
Viroids are virus-like agents. They differ from ordinary viruses by being very small and lacking a capsid or any other
coating. Viroids mainly attack plants such as tomatoes, potatoes and citrus trees.
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ANTIVIRAL CHEMOTHERAPY
Most anti-viral agents have proved of little use therapeutically since the virus uses host-cell metabolic reactions and
thus, for the most part, anti-viral agents will also be anti-cell agents. Therefore, selective toxicity is a challenge.
Available drugs either suppress or inhibit viral growth. However, a limitation of these mechanisms is that many
rounds of virus replication occur during the incubation period and the virus has spread before symptoms appear,
making a drug relatively ineffective.
Types of antiviral agents
1. Nucleoside Analogs
These inhibit nucleic acid replication by inhibition of polymerases for nucleic acid replication. In addition, some
analogs can be incorporated into the nucleic acid and block further synthesis or alter its function.
The most effective analogs are those able to specifically inhibit virus-encoded enzymes, and minimally inhibit similar
(analogous) host cell enzymes.
Examples; acyclovir, lamivudine and zidovudine.
2. Nucleotide Analogs
Nucleotide analogs differ from nucleoside analogs in having an attached phosphate group. Their ability to persist
in cells for long periods of time increases their potency. Cidofovir is an example.
3. Nonnucleoside Reverse Transcriptase Inhibitors
It acts by binding directly to reverse transcriptase and disrupting the enzyme's catalytic site. It does not require
phosphorylation for activity. However, resistant mutants emerge rapidly. An example is nevirapine.
4. Protease Inhibitors
Protease inhibitors inhibit the viral protease that is required at the late stage of the replicative cycle to cleave the
viral gag and gag-pol polypeptide precursors to form the mature virion core. Inhibition of the protease yields
noninfectious virus particles. An example is saquinavir, a molecule designed to fit into the active site of the HIV
protease enzyme.
5. Fusion inhibitor
Fusion inhibitors block the virus and cellular membrane fusion. An example is fuzeon, which is a large peptide that
blocks the entry of HIV-1 into cells.
Other types of antiviral agents include;
Amantadine and rimantadine: These are synthetic amines that work against Influenza-A virus. They block viral
uncoating. They are used prophylactically.
Foscarnet: Also known as phosphonoformic acid, this molecule selectively inhibits viral DNA polymerases and
reverse transcriptases at the pyrophosphate-binding site.
Methisazone: It was the first antiviral agent to be described. It blocks late-stage viral replication, resulting in the
formation of immature, non-infectious particle. Used against poxviruses.
Interferons: Interferons (IFNs) are host-coded proteins which inhibit viral replication. They are produced very quickly
(within hours) in response to viral infection and are one of the body's first responders in the defense against viral
infection. IFN moves to other uninfected host cells and prompts the synthesis of proteins that inhibit viral replication.
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Target Drug Virus inhibited
1. Virus adsorption Soluble CD4 HIV
2. Penetration & uncoating Amantadine Influenza
Rimantadine
3. Viral nucleic acid synthesis Acylovir
Ganciclovir Herpes simplex, VZV
Penciclovir
Ribavirin RSV, Influenza A, RSV
Lamuvidine HIV, Hepatitis B
Interferon A range of viruses
Foscarnet HIV-1, Herpes
4. Binding to intact virus particle Disoraxic Rhinovirus
5. Virus release Saquinavir HIV
Zanamivir Influenza A & B
Osetamivir
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How viruses evade the immune system
Viruses have devised highly effective strategies for establishing infection, despite the presence of an active host
immune response;
1. Latency: Viruses can survive in a ‘silent’ or ‘dormant’ state without expressing any proteins that can be
recognized by the immune system. E.g. HIV in CD4 T-cells, EBV stays latent in B-cells and Varicella-zoster virus
in nerve cells.
2. Hiding in immune-privileged sites. Sites with immune privilege are anatomical regions that are naturally less
subject to immune responses than most other areas of the body. Immune privilege helps protect tissues in
which, for various reasons, an immune response could be harmful Immune-privileged sites include the brain,
behind the retina, the placenta and the testes. Eg. Ebola virus can stay hidden in eyes and testes of a recovered
person for months.
3. Viruses encode genes that produce molecules which block the effects of the antiviral immune responses, such
as interferons and cytokines.
4. They may inhibit apoptosis, which is an innate immune response that limits virus propagation. Viruses can
therefore block the production of host-induced molecules that signal for apoptosis. E.g. Adenoviruses and
Herpes-simplex viruses.
5. Viruses also have genes which inhibit antigen presentation on virus-infected cells. The cells can therefore, not
be recognized by the immune system. Example; human cytomegalovirus (HCMV) and HIV.
6. Antigenic variation; some viruses are able to rapidly evolve and change their antigenic composition, thus
avoiding the immune responses. E.g. Rhinovirus, Influenza A, HSV.
7. Some viruses, e.g. HIV and CMV, ‘borrow’ molecules that normally protect host cells from complement lysis,
and incorporate them into the viral envelope.
ONCOGENIC VIRUSES
Oncogenesis is the process through which normal cells are transformed into cancerous cells, which exhibit abnormal
and uncontrolled growth. This growth is as a result of genetic changes that alter the expression or function of
proteins that regulate cell growth and cell division.
Oncogene; a gene capable, when activated, of transforming a cell.
Some viruses can insert genetic material into normal cells, which alter the normal cell cycle, contributing to cancer
development.
The transformed cell has no CPE and does not produce new virions. The transformed cell continues to divide and
becomes immortal.
Approximately 20% of all human cancers are of viral origin.
Characteristics of transformed cells
1. Increased growth rate
2. Increased metabolic rate
3. Are growth factor-independent (do not rely on growth factors, like other cells. For example, DNA synthesis
continues, despite a lack of nutrients)
4. Continue to divide infinitely
5. They have inactivated tumor-suppressor genes. Tumor suppressor genes slow down cell division, repair DNA
mistakes and tell cells when to die.
6. Loss of contact inhibition: Cell growth is normally arrested/stopped when cells come into contact with each
other. This inhibition is lost in transformed cells.
See below image.
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