Human Viral Human Viral Disease; Disease; Virus Replication Virus Replication Cycle Cycle
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Human Viral Disease; Virus Replication Cycle. Human-Virus Interaction Virus extinction Clear virus, immunity Large number of deaths Small Population –Favors.
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Slide 1
Human Viral Disease; Virus Replication Cycle
Slide 2
Human-Virus Interaction Virus extinction Clear virus, immunity
Large number of deaths Small Population Favors persistent virus
infection Virus infection with an immunological nave person i.e.
herpes simplex virus, parent to newborn Large Population Many
susceptible to infection Virus infected individuals available all
the time Sporadic spread of virus i.e. common cold virus, school
class room
Slide 3
Asymptomatic infection no disease symptoms Acute infection
disease symptoms Persistent infection long term Chronic: infectious
virus Latent: no virus replication, virus reactivation
Transformation alter cell regulation, tumor production, cancer No
infectious virus Viral DNA, complete or partial Patterns of Virus
Disease
Slide 4
DNA Virus Infections
Slide 5
RNA Virus Infections
Slide 6
Acute Infection: Varicella- zooster virus (VZV) Herpesvirus one
virus, two diseases Varicella virus Chickenpox; common childhood
disease Primary acute mucosal/skin infection Resolves in 1-2 weeks
Virus infect and latent in nerve cells
Slide 7
Persistent Chronic Infection: VZV Zooster virus Shingles Latent
in nerve tissue Presence of viral DNA, no infectious virus Virus
held in check by host immune defense Later in life, reactivation of
virus, replicates, descends down nerve tissue, replicates in skin
cells
Slide 8
One-Step Virus Replication In Cell Culture High level of virus
infection (1-10 virus/cell) Synchronous virus replication in cells
All events required for cell infection
Virus Attachment (Adsorption) Contact and interaction of virus
to host cell Recognition of virus to host cell Virus molecule that
binds to host cell called ligand (viral protein or
glycoprotein)
Slide 11
Attachment: Host Cell Virus binds to host cell molecule -
receptor (i.e. cell protein, glycoprotein, lipid) Receptors are
molecules that have a role in normal functioning of the cell
Slide 12
Attachment: Cell Receptor Virus may bind up to three different
cell receptors in succession: Low affinity receptor - in high
abundance, virus contacts cell surface Primary receptor - in lower
concentration Co-receptor follows binding of primary receptor
Slide 13
Attachment: Specificity Host Range - the organism(s) that the
virus is able to infect (narrow or wide) i.e. plant, animal, human
Tissue Tropism- the cell type(s) a virus is able to infect i.e.
skin, oral, GI, CNS
Slide 14
Attachment: Binding 3-D fit between viral ligand and cell
receptor Mainly weak electrostatic charges. Evidence for this is
interaction may require: specific pH specific ionic strength
presence of specific ions i.e. Ca ++, Mg ++
Slide 15
Attachment: Nonenveloped Picornavirus Virus ligand - a deep
cleft (canyon) in triangular face of capsid (viral proteins VP1,
VP2, VP3) Binds to cell receptor ICAM 1 (intracellular adhesion
molecule 1), normal function is to bind cells i.e. WBC
Slide 16
Attachment: Nonenveloped Virus to Host Cell Membrane
Slide 17
Attachment: Enveloped HIV Virus Host cell protein in virus
envelope (cyclophilin A) initially binds HIV to low affinity
receptor (heparin sulfate) of the cell Followed by binding of viral
ligand (gp120) to primary receptor (CD4) on T helper cells,
macrophages, and glial cells Binding of gp120 to CD4 results in
conformational change of gp120, which then binds to chemokine co-
receptor CXCR4 on T lymphocytes or CCR5 on macrophages
Slide 18
Attachment: Enveloped Virus to the Host Cell Membrane
Slide 19
Entry / Uncoating Entry is the mechanism used by the virus to
penetrate into the host cell Uncoating is the separation of the
nucleic acid from the capsid, and refers to changes that occur to
make the viral nucleic acid ready for expression
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Entry: Nonenveloped Virus Receptor-mediated endocytosis
Clathrin coated pits (seen by EM) Invagination, pinch off membrane
Forms intracellular endosome, contains the virus Endosome becomes
acidified
Slide 21
Uncoating: Nonenveloped Virus Acid pH causes conformational
changes in capsid protein Hydrophobic region interacts with
membrane, forms a pore Viral nucleic acid released
Slide 22
Entry / Uncoating: Nonenvelpoed Poliovirus
Slide 23
Nonenveloped Virus: Endocytosis
Slide 24
Entry / Uncoating: Enveloped Virus Receptor mediated fusion of
virus envelope with cell plasma membrane Two modes of entry: Direct
entry (pH independent) Receptor-mediated endocytosis (pH dependent;
for uncoating)
Slide 25
Direct Entry / Uncoating: Enveloped Sendai Virus At cell
surface by a viral fusion protein (active upon cleavage) Viral
capsid released into cytoplasm
Slide 26
Fusion at the Cell Membrane: Enveloped Virus
Slide 27
Entry By Receptor- Mediated Endocytosis: Enveloped Influenza
Virus Lower pH in endosome Conformational change in HA of influenza
exposes a fusion peptide Fusion of viral envelope with endosomal
envelope Release capsid into cytoplasm
Slide 28
Influenza Virus Envelope : Cell Membrane
Slide 29
Endocytosis: Enveloped Virus
Slide 30
Receptor-Mediated Endocytosis: Enveloped Virus
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Synthesis: Early Gene Expression Release of viral genome into
cell (cytoplasm or nucleus) Virus regulates host cell metabolic
machinery Only some viral genes expressed (early transcription
& translation) Viral regulatory proteins and enzymes for
initial synthetic events
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Synthesis: Genome Replication Replication of viral nucleic acid
Cellular or viral polymerase New genome synthesis signals for
additional viral synthetic events
Slide 33
Synthesis: Late Gene Expression Further expression of viral
genome late transcription and translation Some regulatory proteins
Mainly structural (capsid, envelope) proteins for progeny
virus
Slide 34
Assembly (Maturation) This phase of viral replication is
FUNDAMENTALLY DIFFERENT from organisms Viruses assembled from
component parts, not from division of a pre-existing virus i.e. not
exponential growth kinetics, but burst of new virions
Slide 35
Self Assembly Concentration of viral structural proteins and
genomes (reactants) adequate Self forming process (recognition
between viral components) Assembly follows basic laws of
thermodynamics
Slide 36
Virion Assembly Assembly requires protein-protein interactions
and protein-nucleic acid interactions The order of assembly occurs
two ways: The genome serves as a focus for assembly of the capsid
surrounding it (helical viruses) A hollow capsid formed and then
filled with the genome (icosahedral virus)
Slide 37
Assembly Helical Virus: TMV Rigid helical virus Composed of RNA
plus identical capsomers arranged in a helix TMV capsid proteins
only recognize TMV RNA This means that the protein-nucleic acid
interactions are very specific
Slide 38
TMV Assembly: Proteins First, 34 capsid proteins assemble into
a pair of disks The outer portions interact to hold the two disks
together, while the inner portion has a gap where RNA binds When
the RNA enters, the gap is closed to hold the RNA in place
Slide 39
TMV Assembly: Genome RNA interacts with the disks beginning at
the pac (packaging signal) site, which is about 1000 bases from the
3 end of the genome The pac site consists of ~ 500 bases that can
form a series of hairpin loops
Slide 40
Summary: TMV Assembly Capsomers Disc Multiple helical disc RNA
binds to disc Helix elongation of RNA through central hole
Slide 41
Assembly: Icosahedral Virus Has 20 triangular faces and each
face is composed of 3 subunits (or multiples of 3). The subunits
may be identical or different
Slide 42
Assembly: Poliovirus Protomer is made with Vp0, VP1, and VP3
Five protomers combine to form a pentamer Twelve pentamers combine
to form an empty procapsid (60 protomers) RNA enters the procapsid
A maturation cleavage converts VP0 into VP2 and VP4 to form intact
virion
Slide 43
Cell Lysis Virus lytic infections cause distinct changes of
infected cell Changes called cytopathic effect (CPE) and include:
Inclusion body Nuclear pyknosis (shrinking) Vacuole Apoptosis
Syncytia (multinucleated cells)
Slide 44
Inclusion (Negri) Body - Rabies Virus
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Syncytia (giant cell) Formation - Herpesvirus
Slide 46
Virus Release: Cell Lysis CPE usually secondary result of
changes in host cell metabolism by viral replication Virus may halt
or alter host cell DNA synthesis, transcription, and/or protein
synthesis (translation) Results in disintegration of infected cell
and release of progeny virus
Slide 47
Virus Release: Budding (Exocytosis) Synthesis and insertion of
viral glycoproteins in host cell membrane (nuclear, ER, Golgi,
plasma membrane) Assembly of viral nucleocapsid Nucleocapsid and
virus modified membrane brought together (capsid protein may
interact directly with viral glycoprotein or via a viral matrix
protein) Exocytosis, or budding - may or may not kill the cell
Slide 48
Virus Budding Through Cell Plasma Membrane
Slide 49
Polarized Cell Plasma Membrane Exit Viral envelope proteins
contain apical or basolateral plasma membrane transport signals
Virus that bud apically tend to cause localized infections (release
via surface) Virus that bud basolaterally tend to cause systemic
infections (release via interior)
Slide 50
Reading & Questions Chapter 4: Patterns of Some Viral
Diseases of Humans Chapter 6: The Beginning and End of the Virus
Replication Cycle (omit Questions 3, 4)
Slide 51
QUESTIONS???
Slide 52
Class Discussion Lecture 3 1. How does an acute virus infection
differ from a persistent (chronic, latent) infection? 2. Is virus
attachment/entry similar to a normal cell process? 3. How is the
capsid of a helical virus (TMV) assembled? 4. How is the capsid of
a spherical virus (poliovirus) assembled? 5. Non-enveloped virus
are able to self- assemble in vitro, but not enveloped viruses.
Why?