Moffat Flashcards
(78 cards)
1
Q
What is a virus?
A
Definition: a capsid-encoding organism associated with all life forms (can only replicate in cells and are “filterable agents”)
Capsid: protein shell that encapsulates the nucleic acid genome
Virion: the particle encoded by a virus genome
Viruses are obligate intracellular parasites
2
Q
Why are virus genomes modular?
A
All viruses have 3 basic gene modules:
1) capsid proteins (“structural” because they form the vision)
2) the “replicon” (encodes the nucleic acid polymerase and accessory proteins to copy the genome
3) multifunctional proteins that interact with the host (usually “non-structural” because they are left behind in the infected cell and not packaged into the vision)
* Some replication proteins may also be included in the virion, but this is optional
3
Q
What is the structure of the virion?
A
Genome + Capsid ± Envelope = Virion
- Capsid shape is independent of the genome type
- Some virions are “naked” (not enveloped)
- Some virions have a lipid bilayer envelope
4
Q
How do we classify a virus?
A
Host Cell (Kingdom):
- Eukaryotic or Prokaryotic
- Plant, insect, animal
Genome type:
- RNA or DNA
- Single or double stranded
Virion Structure:
- Enveloped or naked
- Helical, icosahedral, or complex
5
Q
What are the unifying principles of virology?
A
All viruses follow a simple three-part general
strategy to ensure their survival:
- The genome encodes a capsid that protects it outside the cell
- The genome contains information for infecting a cell, replicating the genome, intracellular survival, and assembling virions
- Transmission to a new host is required to maintain the virus as a species
6
Q
How big is a virus?
A
~ 10-7m
skin cell>nucleus>bacterium>naked virion>ribosome>DNA molecule
7
Q
What does a virus need to replicate successfully?
A
- The right host (tropism)
- Cells with the right receptors (susceptible)
- Appropriate intracellular environment (permissive)
- Biosynthesis machinery
- Abundant building blocks
- Nucleotides (RNA, DNA)
- Amino acids
- ATP, lipids, sugars, etc.
- Time to finish replication
8
Q
What are the steps in virus replication?
A
- Recognition of the target cell
- Interactions between virions and tissues
- Attachment
- Binding of a virion surface molecule to its specific cellular receptor
- Entry: Penetration or Fusion
- Virions may use multiple routes to enter cells (varies by cell type & may have consequences for disease outcome
- Penetration: engulfment of entire virion into cell (receptor-mediated endocytosis, pinocytosis & phagocytosis)
- Fusion: virion envelope fuses with plasma membrane, leaving parts of the virion behind
- Uncoating: Release of the genome into the cell
- For infection to begin, capsids must open to release the genome into the cytoplasm or nucleus
- Uncoating marks the beginning of the “eclipse phase”Transcription of mRNA
- Uncoating can occur at the plasma membrane, within endosomes and at the nuclear membrane
- Transcription of mRNA
- All viruses must make mRNA
- Viral genome is the template for transcription
- Viral and host transcription factors regulate mRNA synthesis
- mRNA is made by viral or host polymerases
- Protein synthesis
- Viral mRNAs are translated into protein by the host machinery (ribosomes, tRNAs, amino acids)
- Viral proteins are sorted to site of vision assembly (capsid proteins interact with the newly made genomes; membrane proteins traffic through the secretory pathway; cytosolic proteins accumulate next to the membrane)
- Replication of the genome
-Viral genomes come in many types
RNA: double or single-stranded, (+) or (-) sense; DNA: double or single-stranded, (+) or (-) sense; linear, circular, segmented, sealed ends, etc…
-Polymerases make new genomes using host cell nucleotides [viral RNA-dependent RNA polymerase (RDRP); viral DNA polymerase; host cell DNA polymerase; host cell RNA Pol II (RNAP II)] - Assembly of visions
- Marks the end of the “eclipse phase”
- Capsid proteins first form an empty shell
- Viral DNA is then inserted into the capsids, making them appear dark on this TEM
- Egress: lysis, budding, exocytosis
- Virions are released by: budding from the cell, exocytosis, lysis of the cell, cell-to-cell spread
- Virions may transfer to new cells by fusion (syncytium)
9
Q
Describe capsid assembly
A
• Capsid proteins are usually made late during infection • Icosahedral and helical capsids self-assemble
• Complex capsids are made of genomes coated with
nucleoproteins
• Some capsids mature outside of the cell
- Capsid assembly can occur at the same time as envelopment.
- All virion components accumulate at the site of capsid formation, genome incorporation, matrix, glycoproteins, and envelopment.
10
Q
Describe virion envelopment
A
• Enveloped viruses acquire a membrane from a cellular source
– ER
– Golgi
– Plasma membrane
• Viral and cellular proteins are sorted to site of envelopment
– Membrane proteins traffic through the secretory pathway
– Cytosolic proteins accumulate next to the membrane
- Capsid assembly can occur at the same time as envelopment
- All virion components accumulate at the site of capsid formation, genome incorporation, matrix, glycoproteins, and envelopment
11
Q
Measuring the virus life cycle (single-step virus growth curve)
A
- Eclipse: no virus is recovered during the replication and assembly phases
- Maturation and release: virus particles are made and can infect other cells
- Burst size: the number of infectious viral progeny from a single round of replication
12
Q
What happens when cells lyse due to viral egress?
A
- Cells die
- Lysed cells appear clear when cell monolayers are stained with dye
- Infectious virions are measured in PFUs (Plaque Forming Units)
13
Q
Why are RNA viruses relevant?
A
- Huge medical burden: flu, colds, diarrhea, hepatitis C, AIDS, etc - High mutation rates: Resistance to antivirals Barriers to vaccines Reassortment of genome segments Pandemics
14
Q
What are some common features of RNA viruses?
A
RNA is the genetic material AND the template for protein synthesis
The dual purpose of replication is to copy the genome and make mRNA
Diverse strategies have evolved to accomplish these dual goals
15
Q
How do viruses make RNA from RNA?
A
- Viruses use a special enzyme: RNA-dependent RNA Polymerase (since cells don’t have the enzymes to transcribe RNA from RNA, all RNA viruses encode and RNA polymerase)
- “RDRP” allows RNA viruses to copy their RNA genomes and to synthesize mRNA from RNA templates
- (+) strand = sense strand = mRNA
- (-) strand = antisense strand = template for mRNA
16
Q
Describe RNA-dependent RNA polymerase (RDRP)
A
- RDRP is highly efficient; poliovirus makes 50K copies in 8 hours!
- RDRP does not proofread (error rates = 1 in 103-104 nucleotides)
- all RNA virus stocks are mixtures of wild type and mutant forms
- RDRP does it job in the cytoplasm (except in the case of influenza virus)
- Replication often occurs on cell membranes (endosomes, lysosomes, ER vesicles); RNA, RDRP, nucleoproteins, and accessory proteins are not floating free in the cytoplasm
- this mechanism improves efficiency!
- All RNA viruses encode RDRP (retroviruses encode reverse transcriptase)
- (-)RNA and dsRNA viruses must package RDRP in the virion
- (+)RNA viruses may or may not package RDRP in the virion
- If RDRP is not present in the virion, then protein synthesis is necessary to make RDRP before replication can begin
17
Q
Why are viruses referred to as quasispecies?
A
Viruses are not pure populations
Mutants arise frequently
New variants may cause new diseases
Drugs and vaccines lose effectiveness
18
Q
Explain recombination and reassortment in viruses
A
Recombination allows for rapid evolution:
- Exchanging large sections produces new genomes
- Hybrid viruses may have new features (antigens, virulence, etc.)
- High frequency event: up to 20% of Poliovirus genomes are recombinant after 1 growth cycle
Reassortment of Genome Segments occurs:
- Segmented RNA viruses: Reo, Retro, Bunya, Arena, and Orthomyxo, etc. (Influenza virus)
- Segments can mix if the cell is infected with multiple strains
- New variants may be highly virulent
19
Q
Describe Poliovirus
A
Picornaviridae, enterovirus
(+) ssRNA genome, linear mRNA molecule
Infects GI epithelial cells, may spread to muscles and neurons
Vaccination with live or killed virus induces protective antibodies
20
Q
Describe Polio disease and its clinical features
A
- Transmission: fecal-oral Persists in water supply Infects only humans - Pathogenesis: 95% asymptomatic acute GI infection 5% mild disseminated disease 1% paralytic infection of motor neurons - Diagnosis Motor neuron involvement Serology and culture - Treatment Control symptoms, if any Breathing support if needed - Prevention Vaccine Sanitation Peace….
21
Q
Describe Poliovirus entry, replication & translation
A
Entry:
- Poliovirus changes shape after binding to receptor, capsid proteins become hydrophobic
- Capsid proteins form pore through membrane.
- RNA genome enters cell at plasma or endosome membrane
Replication:
- The same enzyme (RDRP) copies (+) and (-) strands
- When capsid proteins accumulate, new mRNA is packaged instead of translated
- With (+) RNA (such as Poliovirus), collisions occur between RDRP and ribosomes, but they are not a big problem
- Translation happens first when RDRP is scarce
- (-) RNA synthesis occurs later when RDRP is abundant
22
Q
Describe Rotavirus
A
Reovirus
dsRNA
segmented
naked icosahedron
23
Q
Describe Rotavirus disease and its clinical features
A
- Causes severe gastroenteritis Profuse watery diarrhea Dehydration Maladsorption - Affects infants and children (adults are usually asymptomatic) - >600,000 deaths annually, mostly in developing world - Peak incidence during winter - Diagnosis Not required in most cases - Treatment Oral Rehydration Solutions - Prevention Live-attenuated Vaccines (Rotarix and Rotateq)
24
Q
Describe Rotavirus life cycle
A
- Genome is segmented, one gene each
- RDRP in the virion first transcribes mRNA
- After viral proteins are translated, new virions and genome segments are synthesized in the cytoplasm
- Virions assemble and then bud into the rough ER
- Egress is via exocytosis (membrane vesicles carry virions out) or by cell lysis
- Virions mature in gut lumen, then infect more enterocytes or are shed in profuse diarrhea
25
Describe Influenza Virus
Orthomyxovirus
(-) ssRNA
segmented
enveloped
26
Describe Influenza Virus disease and its clinical features
- Acute respiratory illness, mainly during the winter
- “Uncomplicated”
upper and/or lower respiratory tract involvement
fever, headache, myalgia, and weakness
- “Complicated”
1° pneumonia caused by influenza
2° bacterial pneumonia
Mixed viral and bacterial pneumonia
Muscle involvement: myositis (pain) and rhabdomyelitis (breakdown)
- Antiviral drugs
Tamiflu® (oseltamivir), Influenza A and B
Relenza® (zanamivir), Influenza A and B
Amantadine & Rimantadine, Influenza A only
- Vaccines
Fluzone® and many others, trivalent inactivated vaccine
FluMist® live attenuated vaccine
- 2013-14 trivalent vaccines
A/California/7/2009 (H1N1)
A/Texas/50/2012 (H3N2)
B/Yamagata lineage
27
Describe Influenza Virus life cycle
* Genome is segmented, (-) ssRNA
* Genome segments traffic to the nucleus for transcription and replication by RDRP
* Viral proteins and genome segments accumulate at the plasma membrane
* Virions assemble and egress by budding
* Neuraminidase (N antigen) releases virions from sialic acid on cell surface
* Virions are shed in respiratory droplets (coughs and sneezes)
28
Describe HIV
Retrovirus
(+) ssRNA
2 copies
enveloped
29
Describe HIV & AIDS and their clinical features
Stages of HIV disease:
1. Exposure to virus (transmission)
2. Primary HIV infection (acute phase)
3. Seroconversion
4. Latent period
5. Early symptomatic HIV infection
6. AIDS (CD4 cell count below 200/mm3)
7. Advanced HIV infection (CD4 cell count below 50/mm3)
HIV Cell Tropism:
- Only humans can be infected
- Virus binds to CD4 and chemokine receptors on T cells and macrophages
- Depletion of these cells and chronic immune activation cause immunodeficiency
- Diagnosis:
Serologic assays for antibodies
Nucleic acid assays for viral load
CD4 T cell count
```
- Prevention:
Risk avoidance
Community awareness
Public health measures
Antiviral drugs (chemoprophylaxis)
```
- HIV Treatment
ART = Antiretroviral Therapy
Drugs must be combined to avoid resistance
New formulations reduce pills and doses, increase compliance
- Types of HIV Drugs
Nucleoside reverse transcriptase inhibitors (NRTIs)
Non-nucleoside reverse transcriptase inhibitors (NNRTIs)
Protease inhibitors (PIs)
Integrase strand transfer inhibitors (INSTIs)
CCR5 antagonists
30
Describe HIV life cycle
• After the virion fuses with the plasma membrane, the Reverse Transcriptase enzyme (RT, included in the virion) converts the (+) ssRNA genomes into dsDNA
• The dsDNA genomes integrate into the host chromosome for life
• Host RNA Pol II transcribes mRNA from the integrated genome, which also serves as the
genome that is packaged into new virions
• Viral proteins and 2 genomes bud from the plasma membrane
• Virion maturation occurs outside the cell when the viral protease cleaves the capsid
proteins, forming the final trapezoidal shape
31
What are some common features of DNA viruses?
- Transcription and replication in nucleus (not poxvirus)
- Host RNA polymerase transcribes mRNA (not poxvirus)
RNA Pol II and transcription factors (proteins that enhance viral transcription) recognize viral promoters
Both cellular and viral factors regulate transcription by host RNA Pol (viral TF’s are important virulence factors and may even be essential proteins)
- Viral or host DNA polymerase replicates genome
Some virus genomes are recognized by the host DNA Pol complex [these viruses do not encode their own polymerase (small genomes), ex: Parvovirus: Adeno-associated virus 2]
Large DNA viruses encode their own polymerase and accessory proteins; ex Herpesviruses & Adenovirus
32
What are the steps in DNA virus replication?
1. Recognition of the target cell
2. Attachment
3. Entry: Penetration or Fusion
4. Uncoating
5. Transcription of mRNA → Host RNA Polymerase
6. Protein synthesis
7. Replication of the genome → Host or viral DNA Polymerase
8. Assembly of virions
9. Egress: lysis, budding, exocytosis
33
What are the origins of diversity in DNA viruses?
- Recombination between and within genomes
- DNA polymerases have higher fidelity than RDRP
- Mutations occur ~1 in 105-6 nucleotides
- DNA viruses are genetically more stable than RNA viruses
34
Describe Adenovirus and its clinical features
```
- Respiratory
A bad cold with a fever
Pharyngoconjunctival fever
Laryngitis and cough
Pneumonia
- Other sites: Acute hemorrhagic cystitis, Epidemic keratoconjunctivitis, Gastroenteritis
- Transmission
Aerosol, fecal-oral, objects
Poorly chlorinated swimming pools
- Susceptible populations
Children
Military recruits
- Sites of outbreaks
Daycare centers
Swimming clubs
“Boot camp”
```
```
Diagnosis & Treatment:
- Match the diagnostic test to the patient sample
Culture
Antigen detection
PCR
Serology
- Treat immunocompromised patients with cidofovir
Reserved for the most dire cases
Cidofovir is nephrotoxic
```
35
Describe Adenovirus life cycle
1. Adenovirus fiber protein binds to cell receptor
2. Entry is by endocytosis
3. Endosome acidification causes fibers to lyse the vesicle
4. Capsid traffics to nucleus and DNA genome uncoats through the nuclear pore
- Genome replicates in nucleus
- Host RNA Pol II makes mRNA
- Gene expression phases
Immediate Early
Early
Late
- Genome replication by viral DNA Pol
- Capsid assembly in nucleus
- Virions egress by lysis
36
Describe HPV and its clinical features
- Most commonly diagnosed sexually transmitted infection in the United States
```
- Epithelial Diseases:
Verruca vulgaris (common warts)
Verruca planaris (plantar warts)
Condyloma acuminata (genital warts)
```
- Malignancies:
Head and neck cancer
Cervical cancer
Penile cancer
Diagnosis & Treatment:
- Diagnosis for genital HPV is recommended
DNA tests for HPV types
Important to screen for 13 high-risk types linked to cancer
- Treat warts by excision
Cryotherapy (freezing)
Chemical ablation (salicylic acid, etc.)
Colposcopy (minor surgery of the cervix)
- Treat malignancies with oncotherapy
- Vaccines
Gardasil
Quadrivalent for types 6, 11, 16, 18
Cervarix
*Bivalent for types 16 and 18
Both are VLPs: Virus-like Particles composed of empty capsids
37
Describe HPV replication
Host RNA Pol transcribes viral mRNA
Host DNA Pol synthesizes viral genomes
Viral factors E6 and E7 are oncogenes
38
Describe Herpesvirus life cycle
- HVs are highly restricted to humans (not HSV)
- Each HV prefers different cell types
DNA genome enters nucleus for mRNA transcription
- Viral gene expression occurs in Immediate Early, Early, and Late phases
- Genome replication is by viral polymerase and accessory factors
- Egress is by exocytosis
39
What is Herpesvirus latency?
- Definition of HV latency: the genome is present in a cell but infectious virions are absent
- HVs establish latency in a variety of cell types before symptoms or virus replication are apparent
- The genomes are maintained for the life of the infected person
- Major barrier to vaccines
40
Describe HSV-1 disease: primary
Spread by close contact with active lesions or asymptomatic shedding
Gingivostomatitis usually occurs in childhood
Lesions on mouth, face, nose, eyes usually above the waist, can be genital
Latency established in neurons
41
Describe HSV-1 disease: recurrent
Tingling and itching (prodrome) may precede outbreak
Lesions on lips or inside mouth
Other sites: eyes, genitals, fingers
Triggers are fever, sunlight, hormones, stress, physical trauma, etc.
Lesions are contagious
42
Describe HSV-2 disease: primary
Spread by close contact between mucous membranes (genital and/or oral)
Acquired in adulthood
Symptoms: many lesions, pain, itching, fever, malaise, headache usually but not always below the waist
Latency established in neurons
Double infections with HSV-1 and HSV- 2 are common
43
Describe HSV-2 disease: recurrent
Prodrome: itching, tingling at lesion site a day before outbreak
Vesicular lesions appear on labia, penis, anus, mouth, eyes, etc.
Lesions are contagious, but shedding and transmission can occur without symptoms
Frequency of recurrences is highly individual; ranges from never to monthly
44
What does HSV do to the brain?
HSV-1 (and HSV-2) primary infections often cause meningitis
Stiff neck
Headache
Recurrent HSV infections occasionally cause encephalitis
Fever
Neurologic symptoms
HSV targets the temporal lobe
45
Describe HSV prevention, diagnosis and treatment
```
Prevention:
Safe sex
Avoid contact with cold sores
Don’t kiss a baby when you have an outbreak
Chemoprophylaxis
Valtrex and Famvir approved for daily use to prevent outbreaks
Vaccines
None approved
Trials of subunit vaccine failed
```
Diagnosis & treatment:
Serology or PCR can distinguish between HSV-1 and -2
Antiviral therapy can shorten infections and reduce transmission
Antiviral prophylaxis is advised for people with frequent outbreaks
Acyclovir is the parent drug
Acyclovir = Zovirax
Valaciclovir = Valtrex
Penciclovir = Famvir
46
Describe primary VZV disease: Varicella (chicken pox)
```
- Aerosol transmission
Highly contagious
- Latency in dorsal root ganglia neurons
Latency established before rash appears
- Distinctive rash
“Dew drops on rose petals”
Few to hundreds on face and trunk
- Complications
Hepatitis
Encephalitis
Pneumonitis
Bacterial infection of lesions (MRSA, strep)
```
47
Describe recurrent VZV disease: Herpes Zoster (Shingles)
- More common in the elderly and immunocompromised
- Prodrome: burning, itching, tingling
- Outbreak occurs along a single dermatome
- Lesions are extremely painful and itchy
- Lesions are contagious and spread varicella to children
- Complications
Bell’s palsy
Postherpetic neuralgia
Retinitis
48
Describe HZO disease (Herpes Zoster Ophthalmicus)
Approximately 30% of zoster outbreaks affect the face
All tissues of the eye can be infected and damaged during HZO
Zoster in the eye can destroy the retina, rapidly leading to blindness
Long-lasting pain is common
49
Describe VZV prevention, diagnosis and treatment
Prevention:
Vaccines with live, attenuated virus (Oka/Merck strain)
Varivax to prevent varicella, ages 1-50
80-90% effective after 2 doses
Zostavax to prevent zoster, ages 50+
~50% effective for zoster
~90% effective for post herpetic neuralgia
Diagnosis:
Clinical signs are distinctive
PCR, antigen, serology kits
Treatment:
Not required for uncomplicated VZV
Zoster treatment only effective during first 3 days of outbreak
Antiviral drugs:
Acyclovir and its derivatives are marginally effective
Foscarnet is second-line therapy
50
Describe Epstein Barr Virus disease
Transmission by saliva
EBV infects oral epithelial cells and B cells in tonsils
Latency in B cells
EBV infects >90% of people by adulthood
Childhood infections are often asymptomatic
Older teens often have “Mono”
170,000 cases of infectious mononucleosis (IM) per year, 15% hospitalized
51
Describe EBV recurrences
EBV is latent in a small fraction of B cells
Immune surveillance suppresses EBV in healthy people
Recurrences are linked to immunosuppression
Malignancies
Hodgkin lymphoma
AIDS-associated non-Hodgkin lymphoma
Post-transplant lymphoproliferative disease
Burkitt lymphoma
Nasopharyngeal carcinoma
Oral hairy leukoplakia
52
Describe EBV diagnosis and treatment
```
- Infectious mononucleosis
Clinical signs
Serology for heterophile antibodies
Blood smear for elevated WBCs and atypical lymphocytosis
- Malignancies
Treat symptoms (supportive care)
Alleviate immunosuppression
Oncotherapy
- Antivirals: None
- Prevention: None
```
53
Describe cytomegalovirus disease (CMV)
“The spectrum of human illness caused by CMV is diverse and mostly dependent on the host.”
Primary CMV infections are usually asymptomatic
50-95% of people are infected by adulthood
Syndrome like Infectious Mononucleosis may occur
Fever, lassitude, diffuse lymphadenopathy
Absence of sore throat and presence of rash distinguishes from EBV IM
Becomes a major problem for immunosuppressed patients (AIDS, transplant recipient)
54
Describe congenital CMV disease
Risk is highest when a pregnant woman has a primary infection
~2% of pregnant women seroconvert to CMV+
Many transient and permanent outcomes for neonate with most important as hearing loss
55
Describe CMV prevention, diagnosis and treatment
```
- Serology, culture, PCR
Some pregnant women are screened, not routine
- Antiviral drugs
Ganciclovir
Foscarnet
Cidofovir
- Prevention: None
Live, attenuated vaccine was ineffective
Vaccine is highest priority in Institute of Medicine
```
56
Describe Roseola infantum = exanthem subitum: HHV6b & HHV7
HHV6b and HHV7 infect CD4+ T cells, site of latency
Transmitted in saliva
3-day illness of high fever, followed by a faint rash on the trunk
Peak incidence at age 7-13 months
Occurs throughout the year (no seasonality)
57
Describe Roseola prevention, diagnosis and treatment
```
- Diagnosis based on clinical manifestations
Rule out drug allergy
- Treatment: none
Supportive care for fever
Avoid giving antibiotics (parents may want them)
- Prevention: none
Normal hygiene
Child may attend daycare
```
58
What are the mechanisms of viral transmission?
```
Respiratory: aerosols
Fecal-oral: food, water, dirty hands
Contact: lesions, saliva, fomites
Zoonoses: animals, insects
Blood: direct contact, blood products, organ transplants
Sexual: mucous membranes, blood
Maternal-neonatal: birth, breastmilk
Genetic: prions, retroviruses
```
59
Explain susceptibility and severity in viral diseases
```
Susceptibility and severity of viral disease depend on:
- The nature of exposure
route, i.e. aerosol v. scratch, etc.
- The viral dose
More virus increases risk of disease
- The status of the person
Age, general health, immune status
- The virus-host interactions
Unique genetic features of each
```
60
What are the main features of virus entry, dissemination and transmission?
Virus can enter our body through many ways, among them: our eyes, respiratory track, genitalia, skin (via a scratch), etc
Viruses can infect M cells and easily reach the blood stream; M cells sample the gut contents and present it to underlying immune cells
Viruses may spread from the surface of the body to lymph nodes and the blood stream
1° viremia leads to replication in internal organs -may occur without symptoms (incubation stage)
2° viremia disseminates the virus to organs where it is shed
Transmission may be by direct contact or through the environment (air, water, objects)
Exposure to infected blood is now a common route of transmission
For example, smallpox is acquired through the respiratory tract, disseminates in the blood, and sheds from pustules on the skin
61
What are the general patterns of infection?
- Acute
- Chronic
Persistent
Latent
Slow
- Transforming
62
Describe virus-host interactions
Virus infection may be unnoticed, cause illness, induce autoimmunity, be persistent, or be lethal
A successful virus will avoid destruction by the immune system and avoid destroying the host before replication is finished
Symptoms of viral disease (fever, tissue damage, rash, aches, pains, nausea) are mainly caused by the host response to infection
Virus replication → cell injury ← host response
Cell injury is caused directly by viruses and indirectly by the host
Virus infection may halt essential cell functions
Infected cells are susceptible to apoptosis
Loss of cell functions can lead to organ damage or failure
The host immune response to a virus may be the sole cause of disease
Immune pathology usually caused by T cells and antibody complexes
Caution: vaccination can make some viral infections worse!
63
What are the different types of antivirals?
Nucleoside analogs (“Nucs”)
Non-nucleosides (“Non nucs”)
Protease inhibitors
Entry inhibitors
64
How do antiviral drugs work?
```
-Target essential virus functions
Entry
Genome replication
Assembly
Release from cell
-Target host cell defenses (intrinsic immunity)
Interferon pathway
-Activate immune response
```
65
What are some of the issues with antivirals?
*Specificity
Most drugs target functions of only one virus
Broad spectrum drugs are rare
*Cytotoxicity
“Off target” effects can harm cells
“On target” drugs directed at viral enzymes can be defeated by resistance mutations
*Duration of antiviral effects
Most drugs are reversible (competitive inhibitors)
Virus replication can resume when drug is cleared (Rebound)
Treatment might need to be life-long….
66
Points related to antiviral resistance
- Resistance mutations often exist in a patient before drug treatment
- Drug treatment selects for resistant virus strains
- Factors favoring the emergence of resistant variants:
High rate of virus replication
High mutation rate (RNA viruses >> DNA viruses)
High selective drug pressure (long term or multiple treatments)
Immunosuppressed host that cannot clear virus-infected cells
67
How do we counter resistance to antivirals?
- Alleviate immunosuppression in the treated person
Reduce doses of anti-T cell drugs (steroids, cyclosporin, etc.)
- Combine drugs with different targets
Standard of care for HIV and HCV infections
Drugs with different mechanisms of action synergize
Lower probability that multiple resistance mutations will be present
- Target host functions
Infected cells may have unique profile that can be a drug target
Virus mutations do not impact cellular genes
Some cancer drugs target dividing cells and also inhibit viruses
Beware of toxicity!
68
Acyclovir
-Nucleoside analog of guanosine
```
-Effective against:
HSV-1 = HSV-2 >> VZV
*Who should be treated?
Neonates infected with HSV at birth
People with frequent recurrences (Type 1 or 2)
Complicated HSV infections:
Encephalitis
Dissemination throughout body
Eye infections
People with zoster (within 3 days of appearance of rash)
```
-Derivatives:
Valaciclovir
Penciclovir
Famciclovir
69
Ganciclovir
-Nucleoside analog of guanosine
-Similar mechanism of action to acyclovir
*Who should be treated?
Bone marrow and organ transplant patients
Immunosuppressed people with active CMV
CMV retinitis
-Highly toxic
Suppresses bone marrow
Mutagenic and teratogenic
Severe side effects
-Derivative: Valganciclovir
70
“Broad Spectrum” Treatments
for DNA viruses
```
Foscarnet
Trisodium phosphonoformate
Inhibits viral DNA polymerase
Effective against all herpesviruses
I.V. route only, toxic to kidneys
```
Cidofovir
Nucleoside analog of cytosine
Effective against DNA viruses: herpesvirus, adenovirus, papillomavirus, poxvirus
I.V. route only, toxic to kidneys
71
Hep B treatment
-HBV is treated with drugs designed for HCV and HIV
-Current drug options:
Pegylated interferon alpha (PEG-IFN-α) = Pegasys™
Entecavir = Baraclude™
Tenofovir disoproxil fumarate = Viread™
-Who should be treated?
People with chronic active HBV disease
People co-infected with HCV and/or HIV
People who are progressing to cirrhosis, liver failure, or hepatocellular carcinoma
72
Influenza treatment
*Zanamivir & Oseltamivir
Both are sialic acid analogs that inhibit viral neuraminidase (sialidase),
Virions remain attached to cell
```
*Who should be treated?
The severely ill (hospitalized)
Children younger than 2
Adults over 65
Pregnant women
Immunosuppressed people
Anyone suspected of having influenza
```
73
Ribavirin
- "Broad spectrum" treatment for RNA viruses
- Nucleoside analog of guanosine
- Oral, i.v., and aerosol formulations
- Approved for use against HCV and RSV
```
-Off-label use:
HSV
Influenza
SARS
La Crosse encephalitis
Nipah encephalitis
Lassa fever
Hemorrhagic fever with renal syndrome
Crimean-Congo hemorrhagic fever
Bolivian hemorrhagic fever
Hantavirus pulmonary syndrome
```
74
Hep C treatment
```
Combination therapy
Peg-interferon-α with ribavirin
Not all HCV genotypes respond to drugs
Difficult and complicated treatment regimen
Flu-like symptoms
Anemia
Neutropenia and thrombocytopenia
Rashes
Hair loss
Thyroid dysfunction
Depression and fatigue
Irritability and mania
More...
```
75
Sofosbuvir
- Treats Hep C
- Nucleoside analog of uridine
- Inhibits RDRP
- Causes chain termination
```
-Must be combined with standard therapy or new drugs:
Peg-IFN-α + Ribavirin
NS5A inhibitors
Daclatasvir (Bristol-Myers Squibb)
Ledipasvir (Gilead)
Telaprevir (Vertex)
```
76
Telaprevir
- Treats Hep C (genotype 1)
- Inhibits NS3.4A protein
- Non-structural protein in the replication complex
- Complex molecule
77
HIV treatment
AZT = Zidovudine™ was the first drug for HIV, now an “antique”
Nucleoside analog of thymidine
“NRTI” class (Nucleoside Reverse Transcriptase Inhibitor)
Current Treatment Strategy for HIV:
drug combinations
```
Clases of anti-HIV drugs:
-Entry inhibitor
Maraviroc
-NRTI (Nucleoside/tide RT inhibitor)
Tenofovir
-NNRTI (Non-nucleoside RT inhibitor)
Efavirenz
-IN (Integrase inhibitor)
Raltegravir
-PI (Protease inhibitor)
Darunavir = Prezista™
```
78
Stribild
*4 Drug Combination for HIV treatment
Elvitegravir → Integrase
Cobicistat → Liver enzyme
Emtricitabine → Reverse transcriptase
Tenofovir disoproxil fumarate → Reverse transcriptase
*Cobicistat is a drug enhancer
inhibits CYP3A4 that breaks down drugs in the liver
Cobicistat treatment boosts the potency of elvitegravir
This allows fewer pills or doses
Stribild dose: one pill daily
