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Final

CSB351Y1 Study Guide - Final Guide: Hepatitis B Virus, Hepatitis C Virus, Dengue Virus


Department
Cell and Systems Biology
Course Code
CSB351Y1
Professor
Mounir Abou Haidar
Study Guide
Final

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Positive Sense RNA Viruses Virology – CSB351
1
Virology (CSB351)
Positive Sense ssRNA Viruses
Lecture 20, 21, 22 and 23 – Picornaviridea (Non-Enveloped)
Positive Sense RNA Viruses
These can be both NonEnveloped (Picornaviruses, Caliciviruses, and Astroviruses) and Enveloped (Flaviviruses,
Togaviruses, and Coronaviruses)
What do these non-enveloped viruses have in common? All have positive sense genomic RNA which acts directly
as mRNA for protein synthesis – plant and bacterial viruses contain only 1 type of coat protein whereas animal
Picornaviruses contain 4 types of coat protein, where the 4th is hidden on the interior – following entry into the
cell and uncoating, protein synthesis starts directly from viral RNA followed by replication and packaging – there
exists two different translational strategies: (1) synthesis of sgRNA (2) formation of a polyprotein which require
a protease to cleave off functional proteins
Types of Picornavirus
Enterovirus which includes PolioRhinovirus which targets the nose causing a benign cold – Hepatovirus which
includes Hep A infecting the liver – Cardiovirus that infects the heart
Structure
T=1 icosahedral formed from 4 structural proteins – VP1 VP2 and VP3 form a canyon where the cellular
receptor binds – VP4 is contained within the virion making contacts with the genomic RNA
Genome
It is a (+) sense ssRNA virus with a 5’ VPg (Virion Protein Genomic) cap and 3’ poly A tail – The VPg is
attached to 5’ terminal pUpU via a phosphodiester linkage with a Tyrosine –OH group – there also
contains a 5’ untranslated region is long containing the IRES to which the ribosome attaches via cellular
proteins P52 and P57 (therefore translation is cap independent) – they have a strategy in which they
disable cap-dependent translation via cleaving eIF-4G allowing favorability toward translating their own
proteins
Proteolytic Cleavage
First cleavage into P1, P2 and P3 where P1 is precursor to capsid proteins, P2 and P3 are precursors for
polymerases and proteases – proteases cleaves between glutamine and glycine residues
Replication
Relatively wasteful as it needs to make a poly protein every time it needs a capsid protein … so you will
have equivalent number of capsid proteins and polymerasesPoliovirus replication contains 3
membranous vesicles: (1) ssRNA lacking VPg (2) replicating intermediates (RI) (3) replicative form (RF) - it
was found that all nascent RNA contain VPg on their 5’ end, including (-) sense suggesting that it acts as a
primer for initiation of RNA synthesis – virus is released through cell lysis
Essentially they circularize the RNA via protein interactions forming a circular RNP complex – once
RNA is clear of ribosomes, VPg associates with 3’ end causing the initiation of elongation for the
VPg primer by viral polymerase 3D
Entry into Cells
Only need to know that poliovirus attaches to cellular receptor CD155 (Pvr) – virus does NOT fuse with
cellular membrane – viral attachment onto Pvr via VP1 – VPg interacts with VP1 N-termini causing a
conformational change to inject genomic RNA into the cell – the drug Win blocks the canyon where
poliovirus binds (this region is too narrow for Ab to bind so no adaptive immune response)
Pathogenesis of Picornaviruses
All Picornaviruses enter the body through oral-fecal route which can be ingested and replicate in the
oropharynx of an individual – enter viremic state and continuation of replication – virus end up at target
tissue
Hepatitis A targets the liver
Echovirus targets the meninges, muscles and skin
Coxsackie targets the meninges, muscles, skin and brain
Polio targets the brain and meninges
Polio Found mainly in regions with poor hygiene – restricted to humans and chimps – there exist 3 distinct
serotypes, 1, 2, and 3 – transmission via oral-fecal route and nasopharyngeal causing transient viremia
and replication in the GALT as well as in the intestine, CNS and lymphoid tissues

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Virology – CSB351 Positive Sense RNA Viruses
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Pathology
Asymptomatic (90%) limited to the oropharynx and GI tractAbortive Poliomyelitis is influenza
like symptomsInvasion of the CNS leads to meningitis, back pain and muscle spasm… nom-
paralytic – Paralytic Poliomyelitis (0.1-2%) where 10% are fatal and the remaining have residual
flaccid paralysis without loss of sensation – can lead to acute flaccid paralysis (AFP) – Bulbar
Paralysis more severe as polio targets the brainstem causing reduced breathing and may result in
death (~10%)… back in the day, people would be placed into an iron lung which would regulate
their breathing - Postpolio Syndrome has been diagnosed in individuals who previously has
contracted polio which symptoms include fatigue, weakness and muscle atrophy
Vaccines
Include Formalin-killed Salk vaccine (IPV) as well as Live, attenuated strains by Sabin (OPV) which
produces Ab in different mucosal areas like the intestines and nasal cavities
Countries in which polio is endemic include Afghanistan, India, Nigeria and Pakistan
Vaccine Associated Paralytic Poliomyelitis (VAPP) arose in areas where OPV was distributed
and unvaccinated individuals contracted the virus through stool from OPV vaccinated people.
The attenuated polio must have reverted back to acquire increased virulence similar to wild
type – policy change from OPV to IPV strictly eliminated VAPP in the US
Return of Type 2 Polio was brought by the change in vaccination from a trivalent vaccine
(types 1, 2 and 3) to two monovalent vaccines (one for type 1 and another for type 3) – the
type 2 polio came from the vaccine as they have mutated to become virulent again to make
the vaccine-derived poliovirus (VDPV) – this highlights the risks of using live attenuated
vaccines to eradicate disease
Rhinovirus
Major agent of the common cold and acute respiratory disease caused by over 100 known serotypes
restricted to humans – 90% of HRV attaches to ICAM-1 (an adhesion receptor) – transmission is airborne
and via contact
Entry
Attachment to ICAM-1 through small canyon by VP1 – Endocytosis into endosome – acidification of
endosome causes uncoating into cytoplasm releasing genomic RNA – same replication as
Picornavirus (see Lecture 20)
Treatment
Zinc nasal sprays can bind into the canyon responsible for attachment onto ICAM-1 – RhinoRx
contains ICAM-1 receptors attached to soluble IgA acting as a decoy
Hepatovirus
Prototype is Hepatitis A virus (HAV) – targets the liver – contains only 3 known capsid proteins (VP1, VP2,
VP3) – the genome is similar to that of other Picornaviruses (see Lecture 20) – in developing countries,
most people acquire HAV – major source of transmission involves the oral-fecal route as it is shed in feces
but also can be transmitted via blood and via sexual contact but only during the viremic stage – no need
for medication as the body will rid it on its own… 99% of people recover, however in rare cases, fulminant
hepatitis occurs requiring transplant
Pathology
Up to 2/3 of people produce jaundice – common symptoms include fever, nausea, tenderness on
liver and dark urine – shown via elevated levels of ALT
Vaccines
Immunization against HAV through the development of formalin-inactivated HAV vaccines
(TWINRIX) which protects against HAV and HBV
Non-Polio Enterovirus
Coxsackievirus
Coxsackievirus A (CA) and B (CB) are antigenically unrelated – Coxsackie A is a hand, foot and
mouth virus where as Coxsackie B causes pericarditis and myocarditis – similar transmission to
other Picornaviruses
Pathology
Replication in the throat and small intestine and in lymphatic tissue before reaching the
target organs via viremia – causes flulike symptoms as well as rash – can infect a wide pleura
of organs
Skin and Mucosa – vesicles present on skin surface on palms of hand and feet and
mouth (CA)
Striated Muscles – pleurodynia is sudden pain in chest caused by diaphragm (CB)

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Positive Sense RNA Viruses Virology – CSB351
3
Heart – myocarditis, pericarditis and myopericarditis – is fatal neonatal (CB)
Liver and Alimentary Tract – gastroenteritis
Pancreas – destruction of islets secreting insulin causing diabetes (CB)
Respiratory – pneumonia and common cold, upper and lower respiratory tract
infections
Eye – conjunctivitis
Aphtovirus
Causes foot and mouth disease (FMDV) in cattle and pigs as it is very sensitive to acidic environments –
genome appears to encode 3 separate VPg proteins which appear to be used with equal efficiency
Cardiovirus
The mengovirus can infect many different species including humans – natural infection occurs by
ingesting contaminated material causing sudden symptoms including acute myocarditis possibly resulting
in death
This virus expresses a unique 67aa Leader protein (L) that suppresses IFN production – this L protein is
also encoded by the theiler’s virus which contains a zinc-binding motif also inhibiting production of IFN
Theiler’s Murine Encephalomyelitis Virus (TMEV)
Immune system activity to rid this virus can cause multiple sclerosis (MS) like symptoms – can also
induce autoimmune diseases since they contain similar epitopes to that of the body causing MS,
Crohn’s disease, type 1 diabetes, RA, schizophrenia, etc.
Lecture 23 – Calicivirus (Norovirus)
Caliciviridae
They share common properties with picornaviruses however are different
Norovirus / Norwalk virus
Causes the stomach flu and is very common cause of food borne disease – infects the GI tract – symptoms
include stomach cramping, diarrhea, low fever, vomiting, etc.
Structure
Produces empty T=1 capsids and T=3 capsids filled with the genomic RNA
Genome
Contains 3 ORFs – one encodes a polyprotein containing the 3D RdRp, the second encodes a sgRNA
which translates to the capsid protein VP1, the third ORF is unknown
Replication
Virus attaches to host via histo-blood group antigens (HBGAs) and is internalized, uncoated and
releases viral genomic RNA – ORF is translated to produce RdRp – (-) sense ssRNA is transcribed and
replicates genomic RNAsgRNA encodes structural proteins
Lecture 24 and 25 – Togaviridae (Enveloped)
Togaviridae
Transition from non-enveloped to enveloped (+) sense ssRNA viruses Includes genus Alphavirus and Rubivirus
Alphaviruses
They are generally not highly pathogenic to humans – includes Sindbis virus (SIN) and Semliki Forest Virus
(SFV) as well as many other encephalopathic viruses
Structure
Icosahedral in structure with T=4 that contains 3 different proteins – 2 envelope proteins (E1 and
E2) capable of adhesion to humans and mosquitoes and a capsid protein (CP)
Genome
Linear with a 5’ methylated cap and 3’ poly A tail – ns proteins are encoded with a single ORF
creating a poly protein which is then autocleaved to yield 3 or 4 proteins – structural proteins are
translated from sgRNA which is transcribed from the (-) sense complementary replicative form of
the genomic RNA… sgRNA promoter is stronger then that of the genomic RNA allowing for higher
expression of structural proteins then ns proteins – then virion concentration is high, the virus
encodes defective-interfering particles (DI) that helps regulate protein production
Translation of ns proteins results in two polyproteins, a long P1234 produced through read-
through of a stop codon 10-20% of the time or a truncated P123
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