CSB351Y1 Study Guide - Midterm Guide: Polio Vaccine, Helicase, Immunoglobulin A

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CSB TERM TEST 2 NOTES
POSITIVE-SENSE, NON-ENVELOPED RNA VIRUSES
These viruses can be directly translated by the host ribosomes. They include Polioviruses,
Calciviruses, Astroviruses, large # of plant viruses (non enveloped); Flaviviridae,
Togaviridae (enveloped).
Positive sense non enveloped RNA viruses all have genomic RNA that acts directly as mRNA for
protein synthesis and all contain RNA, protein and no lipid envelopes. Plant and bacterial viruses
contain a single type of coat protein whereas animal picornaviruses contain 4 types of coat protein.
+VE SENSE SINGLE STRANDED RNA VIRUSES (picornaviruses, poliovirus, rhinoviruses,Hep A,
coxsackievirus)
After entry into the host cell and uncoating, protein synthesis start directly from viral RNA and is
followed by replication and packaging. These viruses use two dierent translational strategies:
a) synthesis of subgenomic RNA (first gene is a polymerase)
b) formation of a polyprotein, followed by post translational processing to generate functional
proteins.
!PICORNAVIRUSES are T=1 icosahedral with 4 structural proteins. VP1-3 form the binding site for
the cellular receptor and VP4 is in direct contact with the genomic RNA. It contains a polyA tail and
VPg (virion protein genomic) covalently linked to the 5’ end in place of the cap. VPg is attached to
the 5’ end via a phospodiester linkage with a tyrosine-OH group. It functions in streaming viral RNA
towards the ribosomes for translation. The 5’ noncoding region of picornaviruses is unusually long
and contains a high degree of secondary structure. The translation is cap-independent.
Picornaviruses will specifically target cellular mRNAs to inhibit their translation through a cap-
binding protein which inactivates cellular mRNA translation by cleaving e1F-4G (this is cap
dependent translation) therefore viral translation is followed by a strong decrease in host mRNA.
Polioviruses has an internal ribosomal entry site (IRES) whereby they internally initiate translation.
The two cellular proteins P52 and P57 bind to the IRES and allow the ribosomes to bind.
Picornavairses possess a monocistronic genome meaning there is only one ORF which encodes a
large polyprotein. This polyprotein is proteolytically cleaved to yield structural and non structural
proteins. The polyprotein is first cleaved into P1, P2 and P3 precursors were P1 is a capsid
precursor and P2 and P3 are precursors for polymerase and proteases. These precursors contain
the QG glutamine-glycine motifs which are targets fro proteolytic cleave with protease 3C.
Most picornaviruses use existing functional molecules of the cell as receptors which results
in receptor mediated endocytosis (poliovirus attaches to the cellular receptor CD55). Picornaviruses
inject RNA directly across plasma membrane after conformation change in the capsid although this
is not the primary mechanism of entry that’s supported.
Antiviral therapy: the “canyons” formed by the viral proteins for cellular receptor binding can be
blocked by therapeutical agents. The drug Win fits into the pocket formed by VP1 the bottom of
which is highly conserved which prevents receptor binding. This region is also not likely to mutate
like the top of the receptor molecule so development of resistance is unlikely.
After virus entry and uncoating, poliovirus RNA is directly translated to produce the proteins
necessary for replication. Replication is entirely cytoplasmic where 3 virus specific RNA structures
are associated with membranous vesicles: sRNA lacking VPg, replicating intermediates (-ve strand
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template + some +ve strands) and replicative form which is a possible end product of RNA
replication. All nascent RNAs are found with VPg attached at their 5’ ends (both positive and
negative) which suggests that VPg acts as a primer for initiation of RNA synthesis. There are two
models for the role of VPg in replication:
(1) VPg becomes uridinylated and acts as a primer for (-) strand RNA synthesis
(2) Host factor adds polyU to polyA tail forming a hairpin and primes elongation of the (-) strand;
hairpin is later cleaved.
Model of circular RNP complex that is used to initiate (-)strand RNA synthesis: viral proteins 3CD
and VPg, polyA binding protein PABP and polyrC binding protein PCBP interact with each other and
the ends of the vocal RNA to form a circular RNP complex. The inhibition of translation initiation
allows for the clearance of the viral RNA over time by the elongation of translating ribosomes to the
3’ end of the coding sequence. Once the template RNA is cleared of translating ribosomes, VPg-
pUpU associates with the 3’ end of the viral RNA template and completes the formation of the
circular pre initiation RNA replication complex. (-)strand synthesis initiates by the elongation of the
VPg-primer by the viral polymerase 3D. Additional viral and cellular proteins, proteolytic processing
events and cellular membranes are also required for viral RNA replication. Polio virus is the only one
that replicates the polyA tail.
Viral assembly: the four dierent capsid proteins self-assemble to form a pentamer after which the
capsid precursor is cleaved into two subunits, producing a mature virion.
All picornaviruses are spread through oral-fecal route. This means they must be acid resistant. They
produce lots of their own copies in the stomach which is released into the environment in the
feces. While the virus is in the body it can climb through the terminal nerves in the intestine into the
brain. Most people that are infected will have diarrhea and will shed the virus. 99% of cases are
benign and only 1% end up in paralysis. The target tissue infected by the virus determines the
predominant disease caused. Primary viremia is within the blood stream where the virus replicates in
the oropharynx and infects the nasal and oral passages (rhino, echo, coxsackie, polio) after which is
it passed in stool. Secondary viremia occurs at the target tissue if the virus was able to bypass
clearance by antibodies. Skin: echo and coxsackie —> hand-foot-and-mouth disease; rash,
herpangina. Muscle: each and coxsackie A and B —> myocarditis and pericarditis of the heart and
pleurodynia of the thorax. Brain: polio and coxsackie —> encephalitis and paralytic disease.
Meninges: echo, polio and coxsackie —> meningitis. Liver: hepatitis A.
Poliovirus is a model picornavirus for vaccine development and studies of replication. Poliomyelitis
is virtually absent from the developed world because of the Salk and Sabin vaccines. Polio is found
worldwide, especially in places with poor hygiene. It is restricted to humans and chimps. They exist
in 3 dierent serotypes. Polioviruses rapidly mutate upon replication within the human gut but the
same vaccine strain of polio used since 1955 is still capable of inducing immunity against the wild
type. A single vaccination may be protective for the entire life of the individual. Polio is spread
through oral-fecal and nasopharyngeal routes. Infection can cause transient viremia but the virus
may persist in the gut for 5 weeks within the gut associated lymph tissue GALT. The virus also
replicates in the intestine, the CNS and lymphoid tissues. Polio can strike at any age
but mainly aects children under 5 yrs. Young children who are not yet toilet trained are a ready
source of transmission, regardless of their environment. Most people infected with polio have no
signs of illness and are never aware. They can carry the virus in their intestine and silently spread the
infection to thousands of people before the first case of polio paralysis emerges. Polio vaccine uses
attenuated but live virus which poses a risk of the virus mutating and causing harm especially in
immune compromised. There have been cases of mild vaccine related outbreaks in Panama and
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Document Summary

These viruses can be directly translated by the host ribosomes. Calciviruses, astroviruses, large # of plant viruses (non enveloped); flaviviridae, Positive sense non enveloped rna viruses all have genomic rna that acts directly as mrna for protein synthesis and all contain rna, protein and no lipid envelopes. Plant and bacterial viruses contain a single type of coat protein whereas animal picornaviruses contain 4 types of coat protein. +ve sense single stranded rna viruses (picornaviruses, poliovirus, rhinoviruses,hep a, coxsackievirus) After entry into the host cell and uncoating, protein synthesis start directly from viral rna and is followed by replication and packaging. These viruses use two di erent translational strategies: synthesis of subgenomic rna ( rst gene is a polymerase, formation of a polyprotein, followed by post translational processing to generate functional proteins. Picornaviruses are t=1 icosahedral with 4 structural proteins. Vp1-3 form the binding site for the cellular receptor and vp4 is in direct contact with the genomic rna.

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