T/F. Viruses divide in order to reproduce.
False, they are obligate intracellular parasites
In general, how do viruses replicate
they use host cell machinery to copy their genome and make viral proteins for their viral progeny
Do enzymes have the ability to produce energy?
What type of virus infects bacteria only?
What is the genomic nucleic acid of a virus?
either DNA or RNA, not both
What is a virion?
a virus particle
What can a virion be schematically represented as?
a delivery system surrounded by a payload. Delivery system serves as structural component to protect virus and bind to host cells, payload contains viral genome and enzymes needed
T/F. The viral genome is very diverse.
True, some genomes may encode 3 or 4 proteins while others code for hundreds
T/F. The number of proteins encoded by viral genome may be more than predicted.
True, because of the arrangement of the genome. By having multiple open reading frames or overlapping regions that can be transcribed into multiple mRNA's
What is the capsid?
a single or double layer protein shell that surrounds viral nucleic acid
What is the nucleocapsid?
the nucleic acid and the capsid
What are capsids composed of?
protein subunits known as capsomers arranged in symmetrical patterns
What are the two structures of capsid patterns?
icosahedral and helical
How many subunits are in icosahedral capsids?
defined number of subunits, 20 triangular faces and 12 vertices
How many subunits are in helical capsids?
no defined number and varies with virus type
Where is the nucleic acid located in icosahedral capsids?
packed inside the spherical core of the capsid, the nucleic acid is tightly associated with viral capsid proteins
How are the proteins of helical capsids arranged?
the subunits of the capsid are bound in a regular, periodic fashion along the nucleic acid
What type of genome is always found with helical capsid viruses?
What is the composition of a viral envelope?
virus specific proteins and lipids and carbohydrates derived from host cell membranes
What is a matrix (M) protein?
a protein that lines the inner envelope of an enveloped virus and is in contact with the nucleocapsid
What is the function of M proteins?
stabilize interaction between viral glycoprotein and lipid envelope, direct viral genome to intracellular sites, help in virus budding
What are spikes?
virus specific envelope glycoproteins that protrude from the surface of enveloped viruses
What is hemagglutination?
carried out by some enveloped viruses, the spikes bind to red blood cell receptors and agglutinate RBC
What is the enzyme(s) that make viral specific mRNA?
RNA-dependent RNA polymerase if the virus has RNA genome, and DNA-dependent RNA polymerase if the virus has a DNA genome
What is the enzyme used for virus mRNA production in retroviruses?
RNA dependent DNA polymerase known as reverse transcriptase
What are capping enzymes?
viral mRNA processing enzymes that modify viral mRNA by adding a methylguanosine cap at the 5' or a polyadenylate at the 3'
T/F. Some viruses have enzymes on their surface involved in progeny release.
True, in influenza virus there are neuraminidase on the virus surface
What is a serotype?
the antigenic properties of a virus, different serotypes within a species
What are the three general steps of viral replication?
infection of susceptible cell, reproduction of nucleic acid and proteins, and release of infectious progeny
How do viruses enter host cells?
through a process known as adsorption, results from random collisions between cells and virions
Does host/virion collision require energy? Temperature? Ph? Ionic conditions?
doesn't require energy or temperature, but requires pH and ionic conditions
What part of the virus mediates attachment to host cell receptors?
in enveloped viruses it is a spike protein, in non-enveloped viruses it is exposed capsid protein
Can some viruses have more than one attachment protein on their surface?
yes, such as the herpes and poxviruses
Viral receptors are very specific for only one type of cell receptor?
no, sometimes they may be very specific but they can also be very ubiquitous (example is HIV only binds to CD4 receptor)
T/F. Viruses of the same species, but different serotype may bind to the same or different receptors?
Once the virus has attached to a host cell what can be transported across the membrane?
the entire virion or a part of the payload containing the viral genome and viral associated polymerases
How do some nonenveloped viruses (adenovirus) get inside host cells?
via receptor-mediated endocytosis, end up in cytoplasm in endocytic vesicles
Can enveloped viruses cross the host cell plasma membrane directly?
yes, some of them may appear in the cytoplasm directly and free of any vesicle formation
What are the two strategies used by enveloped viruses to penetrate host cells?
(1)virus binds to clathrin-coated pits on host cell surface, endocytosed within clathrin coated vesicles and are delivered to endosomes, the viral envelope and endosomal membrane fuse and release nucleocapsid into the cytoplasm (2) fuse directly with the plasma membrane
What method of penetration does the influenza virus use?
clathrin coated pit method
What method of penetration do the paramyxoviruses use?
fusion with plasma membrane
What is uncoating?
the process in which the viral delivery system is removed to make viral genome accessible
When does uncoating occur?
usually simultaneously with the penetration step, some viruses are uncoated when they bind with host cell receptors
What do some non-enveloped viruses require in order to be uncoated?
host cell enzymes, such as the proteases found in endosomes and lysosomes
What is the first step in viral macromolecule production?
synthesis of viral mRNA and then translation into viral specific proteins
What direction does the positive-sense and negative-sense strands run in?
positive sense strands run from 5' to 3', negative sense strands run from 3' to 5'
What is at the 5' end and what is at the 3' end?
5' is the 5th sugar in the carbon ring of deoxyribose, 3' is the hydroxyl group at the 3rd carbon of sugar ring
In what viruses do the nucleic acids act directly as mRNA (single strand positive sense RNA)?
picornaviruses (polio) and flaviviruses (west nile)
How is genome replication carried out in single stranded positive sense RNA viruses?
the genomic RNA acts as mRNA and is translated by cellular ribosomes to make viral proteins
For some viruses, like polioviruses, why are the proteins made in one long strand?
the large polyprotein is cleaved by virus encoded proteases to release individual proteins - leads to viral proteins in equimolar amounts
How does the single strand positive sense RNA viruses maintain its positive strand when it is continually used as mRNA?
a virus encoded RNA dependent RNA polymerase makes a complementary negative sense RNA strand that serves as a template to make copies of the positive sense RNA strand the virus uses. The positive strand can then be used as RNA to be packaged into progeny or as mRNA
How do single strand negative sense RNA viruses make mRNA?
they use a viral RNA polymerase to make a positive RNA strand that is used as its mRNA
How does the single strand negative sense RNA replicate its strands?
uses a viral RNA polymerase to make a positive RNA strand that serves as a template for the synthesis of the negative strand
Does the single strand negative sense RNA carry instructions for viral protein synthesis?
no only its complementary strand does
By making viral proteins in individual transcripts what does this allow (single strand, negative sense RNA)?
the synthesis of each viral protein to be regulated independently
Single stranded RNA viruses have to utilize a RNA dependent RNA polymerase, where do they get this?
Not from host cell, it must be present in the virion and transferred into host cells during infection
What are segmented genomes?
found in single strand, negative sense RNA viruses like influenza and consist of more than one RNA molecule
How do double stranded RNA viruses make mRNA?
a copy of the positive strand is made and then it acts like mRNA
Can virion double stranded RNA function directly as mRNA?
no because of its double-stranded character
How does double stranded RNA viruses replicate?
they use the positive strand as a template and use RNA polymerase to make new double stranded RNA
What type of viruses are double stranded RNA?
reoviruses and rotaviruses
T/F. Double stranded RNA viral genomes are always found as segments?
What type of genome do retroviruses have?
single stranded, positive sense RNA
How do rotaviruses replicate?
they use their positive sense strand as a template for DNA via virion made RNA dependent DNA polymerase (reverse transcriptase). The DNA is then integrated into host cell DNA for the life of the host cell. The viral DNA is transcribed like the host cell genes via host cell DNA dependent RNA polymerase
How do DNA viruses make mRNA?
occurs in host cell nucleus and uses host cell enzymes
What types of viruses have genomic DNA?
adenoviruses, polyomarviruses, papillomaviruses, herpesviruses
What two type of transcripts are synthesized in DNA viruses?
early and late mRNA transcripts - early are regulatory proteins and for DNA replication, late are the structural proteins of the virion
What viruses induce host cells to make proteins needed for DNA replication, and how?
adenoviruses and human papillomavirus stimulate cell cycle progression
What is the HPV E7 protein and what does it do?
E7 binds the retinoblastoma gene product pRB and liberates transcription factor E2F. E2F drives a cell to progress through the cell cycle. To prevent programmed cell death in response to E7, the virus also makes E6 protein that causes the degradation of p53 (tumor suppressor protein).
Why is the mRNA made in DNA viruses initially immature?
because it contains exons separated by introns, the mRNA must be spliced to remove the introns and then put back together
How are the poxviruses method of replication different from other DNA viruses?
transcription and translation occur in the cytoplasm so they can't use host enzymes. They use their own DNA dependent RNA polymerase to start the process and make early proteins. The early proteins are needed to further uncoat the DNA for complete replication. All takes place in virus initiated organelles called factories in the host cytoplasm.
How are non-enveloped viruses and nucelocapsids assembled?
spontaneously, resulting in crystalline arrays of viral capsids. The capsid becomes filled with viral nucleic acid.
When/how are non-enveloped viruses released from host cells?
when host cell lyses
Why do host cells sometimes lyse in the presence of a virus?
inhibition of host cell macromolecule synthesis, disorganization of host cytoskeleton, alteration of cell membrane structure, increased cell permeability, release of preteolytic enzymes, inhibited function of ion transport pumps disrupting transport of essential nutrients and waste products
How are enveloped virus progeny released from host cells?
Is budding lethal to host cells?
may or may not be lethal, but in every case virus encoded proteins are inserted into cell membranes and some of the normal protein components may be disrupted
(1) M proteins become associated with host cell membrane (2) glycoprotein spikes are incorporated into host cell membrane (3) Viral capsids bind to the M proteins lining the cytoplasmic surface of the host cell membrane (4) budding occurs until the virion is free from host cell
T/F. Many viruses are capable of inducing apoptosis in host cells
What are cellular characteristics of cell death?
cell shrinkage, membrane blebbing, condensation of nuclear chromatin, cleavage of cellular DNA
What are defective viruses?
viruses that can't replicate autonomously, but can still cause disease. In order to replicate they require coinfection with a helper virus
In order for hepatitis delta infection to occur what must also occur?
coinfection with hepatitis B virus, causes fulfillment hepatitis infection by allowing increased multiplication of HBV
What are prions?
infectious proteins that are devoid of nucleic acid
What type of diseases are prions known to cause?
neurological diseases known as transmissible spongiform encephalopathies
What is PrPsc and PrPc?
PrPsc is the prion protein that has the same amino acid sequence as that of PrPc which is a normal cellular protein
What is the difference between viral and cellular PrP?
their conformational folding - in the PrPsc conformation the protein is highly resistant to degradation by enzymes, protein denaturing agents and temperature
How does prion cause disease?
the PrPsc and PrPc combine to form the infectious agent. The PrPsc can also function as a template forcing the PrPc to assume the PrPsc conformation. Once PrPsc transformation occurs it continues rapidly converting all the PrPc found in neural tissues. The collection of nondegradable PrP in brain and spinal cord leads to neurological degradation
T/F. Prions don't transmit sequence information, but serve as a template for improper molecular folding?
How are prions spread?
direct inoculation into the CNS, percutaneous exposure, ingestion
How was the disease kuru spread?
prion disease spread through the ritualistic cannibalism of human brains among new guinea natives
Recent epidemic of BSE (bovine spongiform encephalopathy) was caused how?
by feeding younger cows the offal including neural tissue of slaughtered cows
How does transmission of Creutzfeldt-Jakob disease occur?
via corneal transplants, dura mater grafts, human pituitary gland extracts
T/F. Transmission of prions from animals to humans is common.
False, the transfer is not very efficient
What is the pathobiological process of viruses?
virus enters host cell, virus undergoes primary replication in cell, spreads to final target tissue, infects and successfully replicates in susceptible target tissue
What are the three possible outcomes following infection with a virus?
acute infection, latent infection, chronic infection
What is an acute infection?
virus undergoes multiple rounds of replication resulting in death of host cell
What is a latent infection?
no progeny virus are produced, viral DNA exist as extra chromosomal elements or as an integrated sequence in host genome, progeny aren't produced but viral DNA is replicated when host cells replicate
What type of viruses cause latent infections? Example?
DNA viruses and retroviruses, an example is herpes simplex virus 1
What is transformation?
latent infections caused by retroviruses that may change cells leading to cancer formation
What is chronic infection?
virus particles are continually shed from host cells after the latent period, typically there isn't overt host cell injury and cell death may not occur, the amount of virus produced is usually less than in acute infections and the viruses are usually altered from the original infecting virus
What type of viruses typically cause chronic infections?
Can pregnant women transfer viruses to their fetuses?
Is a large number of virus particles always needed to cause disease?
no, in adenovirus and influenza a virus as little as 10 particles are needed
In respiratory spread of a virus what conditions effect the fate of aerosol droplets?
environmental like humidity and wind currents, particle size
What routes are considered respiratory?
aerosol, nasal secretions, saliva
What does particle size difference in respiratory spread effect?
small droplets remain airborne longer and are more likely to escape the filtering capabilities of the nose (6um or larger)
T/F. Viruses transmitted in small particles are highly contagious?
How are rhinoviruses spread?
through contaminated hands to eyes/nose/mouth
What are the immunological defenses of the lungs against viruses?
secretory IgA, NK cells, macrophages
How are viruses spread via the GI route?
when viruses shed in feces contaminate food or water and are then ingested by an individual (fecal-oral)
How is GI transmission of viruses limited?
the virus must be able to withstand the harsh environment of the various parts of the GI system - stomach acidity inactivates viruses, bile salts break down lipid envelopes
What cells in the GI tract appear to facilitate transport of viruses across mucosal epithelium?
microfold (M) cells which overlie peyer patches
How are viruses spread via the transcutaneous route?
insect or animal bites, needles
What is viremia?
high titer of virus in the bloodstream
In some arthropod diseases why are humans considered dead end hosts?
degree of viremia in infected individuals is insufficient to transmit the infection toa new group of insect vectors
How is dengue fever spread?
an infected mosquito transmits the virus via its saliva when it bites a human host, viremia occurs in human allowing mosquitos that subsequently bite to pick up the virus
Other than vertebrate intermediate hosts how do some arthropods transmit viruses?
transovarian fashion to the progeny of infected individuals (allows viral survival through winter months), sexual transmission
What is iatrogenic inoculation?
transmission of disease caused by diagnostic or therapeutic procedures
What viruses can be present in contaminated blood products?
HIV, HBV, CMV
T/F. The use of live-attenuated viruses for vaccination is an example of iatrogenic inoculation?
Are most viral infections due to exogenous or endogenous viruses?
Can endogenous viruses be reactivated to cause disease? Example?
yes, reactivated varicella causes shingles, recurrent oral/genital infections
Are viral infections typically spread in vertical or horizontal manners?
What is horizontal spread?
between members of a susceptible host population
What is vertical spread?
fetus infected in utero through a virus carried in the germ cell line, virus infecting placenta, virus in birth canal
Do all viruses enter and cause disease at their site of entry?
no, URI and LRI tend to but many other viruses spread to distant sites and cause infection
What are primary and secondary replication?
primary occurs at the site of virus entry, secondary occurs at the target organ or tissue
What are the primary and secondary replication sites of enterovirus?
primary the intestines, secondary is CNS to cause meningitis/encephalitis/poliomyelitis
What is incubation period?
the period of time when the virus is replicating but no signs or clinical symptoms are present
T/F. Viral infections always lead to overt disease?
False, some who become inoculated don't get the disease
What pathways of the human body are used by viruses to travel to their target tissue?
hematogenous, lymphatic, neural
What are three viruses that are spread through nerves?
HSV, rabies, varicella zoster
How does neural spread of viruses occur?
interneuronal mechanisms involved in fast axonal transport, infection of Schwann cells, dissemination to CNS
What is the only place in the body where the nervous system is in direct contact with environment?
in the nose - the olfactory receptors in the nasal mucosa
Where does primary replication for enteroviruses typically occur?
in peyers patches and peritonsilar lymphatic tissue
Where does primary replication of respiratory viruses usually occur?
epithelial or alveolar cells
When viremia occurs where do most of the viruses go?
the liver and spleen where continued replication in parenchymal cells occurs
T/F. Bloodborne viruses can travel freely or in connection with a cell.
How does varicella zoster spread through the human body?
hematogenous spread to the skin, then spreads along nerves from the skin to neurons in the dorsal root ganglion where it becomes latent
What does reactivation of varicella zoster cause?
spread of virus along sensory nerves to their dermatomal location producing shingles
What population is especially vulnerable to HSV infections?
T/F. Specific host genes may help determine susceptibility to a virus.
How does inadequate nutritional status effect virus susceptibility?
may cause a depressed cell mediated immunity (seen in measles)
Can stress trigger reactivation of viruses, such as those that cause fever blisters?
What is the most important defense mechanism against viruses?
cell mediated immunity
What type of people usually have prolonged viral infections?
those with defective cell mediated immunity but normal ability to make antibodies - AIDS patients, bone marrow transplant patients
What type of chronic virus can occur in people who are antibody-deficient?
Does antibody deficiency usually change the outcome of a viral infection?
no because host defense mechanisms mainly rely on cell mediated immunity
Does phagocytosis by neutrophils play an important role in host defense against viruses?
no, cell mediated immunity does
Are macrophages involved in host defense against viruses?
yes they typically limit the spread of the virus within the host
What type of cell receptor on host cells are activated by viral components?
What does activation of TLR's lead to?
inflammatory responses, cytokine and interferon secretion, adaptive immunity activation
Why is cell mediated immunity needed to kill viruses?
because they are intracellular, so WBC's are able to recognize viral antigens bound to MHC receptors on host cells
What is the earliest host defense against virally infected host cells?
natural killer cells have peak activity at 2-3 days (detect stressed cells don't necessarily need MHC)
What two viruses are natural killer cells especially important for destruction?
herpesvirus and CMV
Other than NK cells what other tactics are used by the host for defense against viruses?
cytotoxic t lymphocytes and antibody responses
How do CTL's function in host defense against viruses?
an APC with a MHC class I protein presents protein viral antigen to a CTL, CTL's initiate cell lysis of infected host cell
What is the difference between CTL's and antibody defense mechanism?
CTL's recognize protein fragments from a virus attached to a MHC, antibodies recognize epitopes on intact viral surface proteins
T/F. Most viruses are sufficiently antigenic enough to elicit an antibody response?
Are antibodies important in controlling acute viral infections?
No, they are important in preventing reinfection
What are neutralizing antibodies?
antibodies that protect the host by destroying the infectivity of the virus by inhibiting early steps of the replication cycle. They may also produce aggregations of virions, increase virus degradation in phagosomes, and enhance opsinization
If two isolates of a virus are neutralized by the same antibody what are they called?
Do antibodies of different serotypes protect against one another?
no, Ab are serotype specific
What is antibody-dependent cell-mediated immunity?
virus antibodies bound to antigens interact with the Fc receptor portion of IgG located on the surface of NK cells, binding of the IgG to the antibody leads to targeted cell killing
What is the inducible defense mechanism elicited by viruses?
What are interferons?
proteins encoded by host cells who synthesis is induced by viruses and proinflammatory agents
How do interferons effect viruses?
they block virus replication indirectly by inducing cell synthesis of proteins that inhibit protein synthesis machinery
What are the three kinds of interferons and their locations?
alpha known as leukocyte interferon, beta known as fibroblast interferon is made by fibroblasts and epithelial cells, gamma known as immune interferon and is induced by T cell activation
What are interferon alpha and beta induced by?
viable and inactivated viruses, double stranded RNA
What happens when interferon is made?
released into extracellular fluids, binds to specific interferon receptors on neighboring cells, induces genes to be expressed in cell that create an antiviral state, causes PKR to be expressed which is a protein that phosphorylates a protein synthesis factor, the phosphorylated factor can't function in the initiation of proteins synthesis complex and viral protein synthesis can't occur
Do interferons act locally or systemically?
What pathways of the complement system can be activated by viruses?
alternative and classical pathways, even in absence of antibody
Is complement essential for combating viral infection?
How does immunological injury occur in viral infections?
cell lysis elicited by one or more of the antiviral host defense mechanisms
What is an example of virus induced immunopathology?
children vaccinated with inactivated measles virus experience severe disease when infected with the live virus later in life
What is responsible for much of the damage caused to myocardial tissue after viral infections?
T/F. Viruses may combine with Ab to produce antigen-antibody immune complexes that circulate.
True, the complexes can become trapped in basement membranes resulting in tissue injury by attracting inflammatory mediators
What is molecular mimicry?
stimulation of B lymphocytes that can result in the production of cross-reacting antibodies to host structures that contain antigenic regions similar to those of virus
How does HIV avoid the immune system?
replicates within T cells and macrophages of the immune system
How do viruses avoid destruction by CTL's?
blocking antigen processing or inhibiting MHC expression
How do viruses avoid NK cells?
encode an MHC like protein that engages inhibitory receptors on NK cells
T/F. Viruses have the ability to produce glycoproteins that interfere with complement activation, interferons and apoptosis
How are viral infections diagnosed?
some based on clinical presentation but most require isolation and culture of virus, virus specific antigen or nucleic acid detection in fluids, or specific serological responses
T/F. Certain viruses grow better in certain cell lines.
T/F. Isolation into allantoic cavity of embryonated chicken eggs is useful for influenza virus isolation
Once a cell culture is inoculated with a virus, what is the specimen examined for next and why?
cytopathic effect because some viruses exert their toxic effect more rapidly
What does the presence of syncytia in a culture suggest?
herpesvirus, measles, mumps, respiratory syncytial.
What does the presence of cytomegaly in a culture suggest?
CMV, HSV, VZV
What is hemadsorption and what viruses do it?
ability to absorb red blood cells in culture, orthomyxoviruses and paramyxoviruses
T/F. Scrapings of virus can be useful in identification, example is measles or VZV.
What is considered diagnostic of an acute infection?
a fourfold or greater increase in antibody titer to a specific viral agent in serum of patient compared with that taken in the acute phase
What virus is the cause of roseola?
human herpesvirus 6 (HHV-6)