Download - 26 Virology
-
7/26/2019 26 Virology
1/105
MICROBIOLOGY LECTURE SERIESLUZ GREGORIA LAZO-VELASCO, MD
-
7/26/2019 26 Virology
2/105
GENERAL PROPERTIES OF
VIRUSES
Smallest infectious agents (20nm-300nmin diameter)
Contain only one kind of nucleic acid(RNA or DNA) as their genome
Nucleic acid is encased in a protein shellwhich may be surrounded by a lipd-containing membrane
VIRION entire infectious unit
Inert in the extracellular environment;replicate only in living cells
-
7/26/2019 26 Virology
3/105
GENERAL PROPERTIES OF
VIRUSES
Viral nucleic acid contains informationnecessary for programming the
infected host cell to synthesize virus-specific macromolecules required forthe production of viral progeny
During the replicative cycle, numerous
copies of viral nucleic acid and coatproteins are produced
-
7/26/2019 26 Virology
4/105
GENERAL PROPERTIES OF
VIRUSES
Coat proteins assemble together toform the capsid (encases and
stabilizes the viral nucleic acid againstthe extracellular environment;facilitates the attachment andpenetration by the virus upon contact
with new susceptible cells)
-
7/26/2019 26 Virology
5/105
-
7/26/2019 26 Virology
6/105
GENERAL PROPERTIES OF
VIRUSES
Rich in diversity viruses vary greatlyin structure, genome organizationand expression, strategies of
replication and transmission Host range maybe broad or extremely
limited
Known to infect unicellular organismssuch as mycoplasmas, bacteria andalgae and all higher plants andanimals
-
7/26/2019 26 Virology
7/105
TERMS AND DEFINITIONS IN
VIROLOGY
CAPSID protein shell, or coat, thatencloses the nucleic acid genome
CAPSOMERES morphologic unitsseen in the electron microscope onthe surface of icosahedral virusparticles
DEFECTIVE VIRUS virus particlethat is functionally deficient in someaspect of replication
-
7/26/2019 26 Virology
8/105
TERMS AND DEFINITIONS IN
VIROLOGY
ENVELOPE lipid-containingmembrane that surrounds some virusparticles
NUCLEOCAPSID protein-nucleicacid complex representing thepackaged form of the viral genome
STRUCTURAL UNITS basic proteinbuilding blocks of the coat; usually acollection of >1 non-identical proteinsubunit
-
7/26/2019 26 Virology
9/105
TERMS AND DEFINITIONS IN
VIROLOGY
SUBUNIT a single folded viralpolypeptide chain
VIRION complete virus particle;serves to transfer the viral nucleic acidfrom one cell to another
-
7/26/2019 26 Virology
10/105
EVOLUTIONARY ORIGIN OF
VIRUSES
Origin of viruses not known
2 theories:
1. Viruses may be derived fromDNA or RNA nucleic acid components ofhost cells that became able to replicateautonomously and evolve
independently
2. Viruses may be degenerateforms of intracellular parasites
-
7/26/2019 26 Virology
11/105
CLASSIFICATION OF VIRUSES
BASIS OF CLASSIFICATION1. Virion morphology, size, shape, type of
symmetry, presence or absence of peplomers,and presence or absence of membranes
2. Virus genome properties, including type of
nucleic acid (DNA or RNA), size of genome (kbor kbp), strandedness (single or double),whether linear or circular, sense (positive,negative, ambisense), segments (number,size), nucleotide sequence, G + C content, andpresence of special features [repetitiveelements, isomerization, 5'-terminal cap, 5'-terminal covalently linked protein, 3'-terminalpoly(A) tract]
-
7/26/2019 26 Virology
12/105
CLASSIFICATION OF VIRUSES
BASIS OF CLASSIFICATION3. Genome organization and replication,
including gene order, number and position ofof open reading frames, strategy of replication(patterns of transcription, translation), and
cellular sites (accumulation of proteins, virionassembly, virion release)
4. Virus protein properties, number, size, andfunctional activities of structural andnonstructural proteins, AA sequence,modifications (glycosylation, phosphorylation,myristylation), and special functional activities(transcriptase, reverse transcriptase,neuraminidase, fusion activities)
-
7/26/2019 26 Virology
13/105
CLASSIFICATION OF VIRUSES
BASIS OF CLASSIFICATION5. Antigenic properties
6. Physicochemical properties of the virion,including molecular mass, buoyant
density, pH stability, thermal stability, andsusceptibility to physical and chemicalagents, especially ether and detergents
7. Biologic properties, including natural hostrange, mode of transmission, vectorrelationships, pathogenicity, tissuetropisms, and pathology
-
7/26/2019 26 Virology
14/105
UNIVERSAL SYSTEM OF VIRUS
TAXONOMY
Viruses are separated into FAMILIES on thebasis of virion morphology, genomestructure and strategies of replication
Virus family names have the suffix viridae Genera subdivisions based on biological,
genomic, physicochemical or serologicdifferences; genus names carry the suffix virus
Subfamilies have been defined in severalfamilies
Order
-
7/26/2019 26 Virology
15/105
DNA VIRUSES
A. Parvoviruses
Human parvovirus B19 aplasticcrisis, fifth disease, fetal death
B. AnellovirusesC. Polyomaviruses
JC virus progressive multifocalleukoencephalopathy
BK virus nephropathy in transplantrecipients
Merkel cell virus - Merkel cell skin CA
-
7/26/2019 26 Virology
16/105
DNA VIRUSES
D. Papillomaviruses
wart viruses
E. Adenoviruses- acute respiratorydiseases, conjuctivitis ,gastroenteritis
F. Hepadnaviruses acute and
chronic hepatitis
-
7/26/2019 26 Virology
17/105
DNA VIRUSES
G. Herpesviruses
Herpes simplex type 1 & 2 (oral &genital lesions)
Varicella-zoster virus (chickenpox &shingles)
Cytomegalovirus
Epstein-Barr virus (infectious
mononucleosis, assoc. with human neoplasms)Human herpesvirus 6 & 7 (T
lymphocytic)
Human herpesvirus 8 (Kaposi sarcoma)
-
7/26/2019 26 Virology
18/105
DNA VIRUSES
H. Poxviruses
smallpox
vaccinia
molluscum contangiosumcowpox
monkeypox
-
7/26/2019 26 Virology
19/105
RNA VIRUSES
A. Picornaviruses
Enteroviruses (polioviruses,coxsackieviruses, and echoviruses,
rhinoviruses (common colds) andhepatoviruses (Hepatitis A)
B. Astroviruses- gastroenteritis
C. Caliciviruses
Noroviruses (Norwalk virus) epidemic acute gastroenteritis
-
7/26/2019 26 Virology
20/105
RNA VIRUSES
D. Hepeviruses
Human Hepatitis E virus
E. Picobirnaviruses
F. ReovirusesRotaviruses (wheel-shaped appearance;
gastroenteritis)
G. Arboviruses and Rodent-Borne Viruses
Dengue Virus
Yellow fever virus
West Nile fever virus
Encephalitis virus
-
7/26/2019 26 Virology
21/105
RNA VIRUSES
H. Togaviruses
Rubella virus
I. Flaviviruses
Hepatitis C virusJ. Arenaviruses
K. Coronaviruses
colds
SARS (severe acute respiratorysyndrome)
-
7/26/2019 26 Virology
22/105
RNA VIRUSES
L. Retroviruses
AIDS
M. Orthomyxoviruses
Influenza virusesN. Bunyaviruses
O. Bornaviruses
P. Rhabdoviruses
Rabies virus
Q. Paramyxoviruses
Mumps, measles, parainfluenza,metapneumo & respiratory syncytial viruses
-
7/26/2019 26 Virology
23/105
RNA VIRUSES
R. Filoviruses
Marburg virus severe hemorrhagic
Ebola virus fever in Africa
-
7/26/2019 26 Virology
24/105
PRINCIPLES OF VIRUS STRUCTURE
Cubic Symmetry All cubic symmetry observed with
animal viruses is of the icosahedralpattern, the most efficient
arrangement for subunits in a closedshell
Helical Symmetry
protein subunits are bound in a periodic
way to the viral nucleic acid, winding itinto a helix; the filamentous viralnucleic acid-protein complex(nucleocapsid) is then coiled inside alipid-containing envelope
-
7/26/2019 26 Virology
25/105
PRINCIPLES OF VIRUS STRUCTURE
Complex Structures Some virus particles do not exhibit
simple cubic or helical symmetrybut are more complicated in
structure.
-
7/26/2019 26 Virology
26/105
CHEMICAL COMPOSITION OF
VIRUSES VIRAL PROTEIN
Facilitate transfer of the viral nucleicacid from one host to another
Serve to protect the viral genome
against inactivation by nucleases Participate in the attachment of the
virus particle to a susceptible cell
Provide structural symmetry of the
virus particle Determines the antigenic
characteristics of the virus
Some viruses carry enzymes (which
are proteins) inside the virions
-
7/26/2019 26 Virology
27/105
CHEMICAL COMPOSITION OF
VIRUSES VIRAL NUCLEIC ACID
Viruses contain a SINGLE kind ofnucleic acid either DNA or RNAthat encodes the genetic information
necessary for replication of the virus. The genome may be single-stranded
or double-stranded, circular orlinear, and segmented or
nonsegmented. The type of nucleic acid, its
strandedness, and its size are majorcharacteristics used for classifyingviruses into families
-
7/26/2019 26 Virology
28/105
CHEMICAL COMPOSITION OF
VIRUSES VIRAL NUCLEIC ACID
Viral RNAs exist in several forms
may be a single linear molecule(picornaviruses)
several segments of RNA that maybe loosely associated within thevirion (orthomyxoviruses)
The isolated RNA of viruses with
positive-sense genomes (ie,picornaviruses, togaviruses) isinfectious, and the moleculefunctions as an mRNA within the
infected cell
-
7/26/2019 26 Virology
29/105
CHEMICAL COMPOSITION OF
VIRUSES VIRAL NUCLEIC ACID
The isolated RNA of the negative-sense RNA viruses, such asrhabdoviruses and orthomyxoviruses,
is not infectious The sequence and composition of
nucleotides of each viral nucleic acidare distinctive. Many viral genomes
have been sequenced. The sequencescan reveal genetic relationshipsamong isolates
-
7/26/2019 26 Virology
30/105
CHEMICAL COMPOSITION OF
VIRUSES VIRAL NUCLEIC ACID
Viral nucleic acid may becharacterized by its G + C content.
DNA viral genomes can be analyzed
and compared using restrictionendonucleases, enzymes that cleaveDNA at specific nucleotidesequences; each genome will yield a
characteristic pattern of DNAfragments after cleavage with aparticular enzyme
-
7/26/2019 26 Virology
31/105
CHEMICAL COMPOSITION OF
VIRUSES
VIRAL LIPID ENVELOPES
A number of different viruses contain
lipid envelopes as part of theirstructure
The lipid is acquired when the viralnucleocapsid buds through a cellular
membrane in the course of maturation
-
7/26/2019 26 Virology
32/105
CHEMICAL COMPOSITION OF
VIRUSES
VIRAL GLYCOPROTEINS
Viral envelopes contain glycoproteins
In contrast to the lipids in viralmembranes, which are derived fromthe host cell, the envelopeglycoproteins are virus-encoded.
the sugars added to viral glycoproteinsoften reflect the host cell in which thevirus is grown
-
7/26/2019 26 Virology
33/105
CHEMICAL COMPOSITION OF
VIRUSES
VIRAL GLYCOPROTEINS
It is the surface glycoproteins of anenveloped virus that attach the virus
particle to a target cell by interactingwith a cellular receptor
often involved in the membrane fusionstep of infection
important viral antigens
-
7/26/2019 26 Virology
34/105
CULTIVATION OF VIRUSES
Many viruses can be grown in cell culturesor in fertile eggs under strictly controlledconditions
Growth of virus in animals is still used for
the primary isolation of certain viruses andfor studies of the pathogenesis of viraldiseases and of viral oncogenesis.
-
7/26/2019 26 Virology
35/105
-
7/26/2019 26 Virology
36/105
The fundamental process ofviral infection is the viralreplicative cycle.
-
7/26/2019 26 Virology
37/105
The cellular response tothat infection may
range
No apparenteffect
Cytopathologywithaccompanyingcell death
Hyperplasiaor cancer
-
7/26/2019 26 Virology
38/105
Viral disease Some harmful abnormality that results from viral
infection of the host organism.
Clinical disease consists of overt signs and symptoms.
Syndrome a specific group of signs and symptoms.
Inapparent (subclinical) Viral infections that fail to produce any symptoms in
the host.
-
7/26/2019 26 Virology
39/105
Important Features
of Acute Viral DiseasesLocal Infections Systemic Infections
Specific disease example Respiratory (rhinovirus) Measles
Site of pathology Portal of entry Distant site
Incubation period Relatively short Relatively long
Viremia Absent PresentDuration of immunity Variablemay be short Usually lifelong
Role of secretory antibody(IgA) in resistance
Usually important Usually not important
-
7/26/2019 26 Virology
40/105
Most viral infections do not result inthe production of disease.
-
7/26/2019 26 Virology
41/105
Important principles that pertain to
viral disease include the following:
Many viral infections are subclinical.
The same disease may be produced by a variety of viruses.
The same virus may produce a variety of diseases.
The disease produced bears no relationship to viral morphology.
The outcome in any particular case is determined by both viral andhost factors and is influenced by the genetics of each.
-
7/26/2019 26 Virology
42/105
Viral pathogenesis
The interaction of viral and host factors that leads
to disease production. Disease pathogenesis subset of events
during an infection that results in diseasemanifestation in the host
A virus is pathogenic for a particular host if itcan infect and cause signs of disease in thathost.
A strain of a certain virus is more virulentthan another strain if it commonly producesmore severe disease in a susceptible host.
-
7/26/2019 26 Virology
43/105
Steps in viral pathogenesis
1. Entry into the host2. Primary viral replication
3. Viral spread4. Cellular injury5. Host immune response6. Viral clearance or establishment
of persistent infection7. Viral shedding
Common Routes
-
7/26/2019 26 Virology
44/105
Common Routes
of Viral Infection in Humans
Route of Entry Virus Group Produce LocalSymptoms at Portal ofEntry
Produce GeneralizedInfection Plus SpecificOrgan Disease
Respiratory tract Parvovirus B19
Adenovirus Most types
Herpesvirus Epstein-Barr virus,herpes simplex virus
Varicella virus
Poxvirus Smallpox virus
Picornavirus Rhinoviruses Some enteroviruses
Togavirus Rubella virus
Coronavirus Most types
Orthomyxovirus Influenza virus
Paramyxovirus Parainfluenza viruses,respiratory syncytialvirus
Mumps virus, measlesvirus
-
7/26/2019 26 Virology
45/105
Common Routes
of Viral Infection in HumansRoute of Entry Virus Group Produce Local
Symptoms at Portal ofEntry
Produce GeneralizedInfection Plus SpecificOrgan Disease
Mouth, intestinal tract Adenovirus Some types
Herpesvirus Epstein-Barr virus,herpes simplex virus
Cytomegalovirus
Picornavirus Some enteroviruses,including poliovirus andhepatitis A virus
Reovirus Rotaviruses
C
-
7/26/2019 26 Virology
46/105
Common Routes
of Viral Infection in HumansRoute of Entry Virus Group Produce LocalSymptoms at Portal
of Entry
Produce Generalized Infection PlusSpecific Organ Disease
Skin
Mild trauma Papillomavirus Most types
Herpesvirus Herpes simplex virus
Poxvirus Molluscumcontagiosum virus, orfvirus
Injection Hepadnavirus Hepatitis B
Herpesvirus Epstein-Barr virus, cytomegalovirus
Retrovirus Human immunodeficiency virus
Bites Togavirus Many species, including easternequine encephalitis virus
Flavivirus Many species, including yellow fevervirus
Rhabdovirus
-
7/26/2019 26 Virology
47/105
Entry & Primary Replication
Viruses usually replicate at the primary site ofentry.
Someproduce disease at the portal of entry
and have no necessity for further systemicspread.
-
7/26/2019 26 Virology
48/105
Many viruses produce disease at sites distantfrom their point of entry
The most common route is via the
bloodstream or lymphatics. Presence of virus in the blood -viremia
Virions may be free in the plasma or
associated with particular cell types The viremic phase is short in many viral
infections.
-
7/26/2019 26 Virology
49/105
Viruses tend to exhibit organ and cell
specificities tropism determines thepattern of systemic illness produced during a
viral infection Tissue & cell tropism by a given virus usually
reflect the presence of specific cell surface
receptors for that virus
-
7/26/2019 26 Virology
50/105
Destruction of virus-infected cells in the target tissuesand physiologic alterations produced in the host bythe tissue injury are partly responsible for thedevelopment of disease.
Some tissues Can rapidly regenerate, such as intestinal epithelium.
Can withstand extensive damage better than others, suchas the brain.
Some physiologic effects may result from nonlethalimpairment of specialized functions of cells, such asloss of hormone production.
-
7/26/2019 26 Virology
51/105
General symptoms associated with many viralinfections, such as malaise and anorexia, mayresult from host response functions such as
cytokine production. Clinical illness is an insensitive indicator of
viral infection.
Inapparent infections by viruses are verycommon.
-
7/26/2019 26 Virology
52/105
The host either succumbs orrecovers from viral infection.
OR
-
7/26/2019 26 Virology
53/105
Recovery mechanisms
Innate immune response
Adaptive immune responses
Interferon and other cytokines, humoral andcell-mediated immunity, and possibly otherhost defense factors are involved.
The relative importance of each componentdiffers with the virus and the disease.
-
7/26/2019 26 Virology
54/105
In acute infections, recovery is associatedwith viral clearance.
However, there are times when the host
remains persistently infected with the virus(chronic or latent).
-
7/26/2019 26 Virology
55/105
This is a necessary step to maintain a viralinfection in populations of hosts.
Shedding usually occurs from the body surfacesinvolved in viral entry.
Shedding occurs at different stages of diseasedepending on the particular agent involved.
It represents the time at which an infected
individual is infectious to contacts. In some viral infections, such as rabies, humans
represent dead-end infections, shedding doesnot occur.
-
7/26/2019 26 Virology
56/105
Nonspecific host defense mechanisms areusually elicited very soon after viral infection.
The most prominent among the innate
immune responses is the induction ofinterferons.
These responses help inhibit viral growth during
the time it takes to induce specific humoral andcell-mediated immunity.
-
7/26/2019 26 Virology
57/105
Both humoral and cellular components of theimmune response are involved in control of viralinfections.
Viruses elicit a tissue response different from the
response to pathogenic bacteria. Polymorphonuclear leukocytes form the principal
cellular response to the acute inflammation causedby pyogenic bacteria.
Infiltration with mononuclear cells and lymphocytescharacterizes the inflammatory reaction ofuncomplicated viral lesions.
-
7/26/2019 26 Virology
58/105
Virus-encoded proteins serve as targets for the immuneresponse. Virus-infected cells may be lysed by cytotoxic T lymphocytes as
a result of recognition of viral polypeptides on the cell surface.
Humoral immunity protects the host against reinfection by
the same virus. Neutralizing antibody directed against capsid proteins
blocks the initiation of viral infection, presumably at thestage of attachment, entry, or uncoating.
Secretory IgA antibody important in protecting against infection by viruses through the
respiratory or gastrointestinal tracts.
Viruses have evolved a variety of ways that serve to
-
7/26/2019 26 Virology
59/105
Viruses have evolved a variety of ways that serve tosuppress or evade the host immune response andthus avoid being eradicated.
Infect cells of the immune system and abrogating theirfunction (HIV).
Infect neurons that express little or no class I MHC(herpesvirus).
Encode immunomodulatory proteins that inhibit MHCfunction (adenovirus, herpesvirus).
Inhibit cytokine activity (poxvirus, measles virus). Mutate and change antigenic sites on virion proteins
(influenza virus, HIV). Downregulate the level of expression of viral cell
surface proteins (herpesvirus).
-
7/26/2019 26 Virology
60/105
-
7/26/2019 26 Virology
61/105
-
7/26/2019 26 Virology
62/105
-
7/26/2019 26 Virology
63/105
Antiviral Chemotherapy
Interferons
Viral Vaccines
-
7/26/2019 26 Virology
64/105
Limitations:
Antiviral agents must be capable of selectivelyinhibiting viral functions without damaging the
host. Many rounds of virus replication occur during the
incubation period and the virus has spread beforesymptoms appear
making a drug relatively ineffective.
-
7/26/2019 26 Virology
65/105
Can be used to treat established infectionswhen vaccines would not be effective.
Antivirals are needed to reduce morbidity and
economic loss due to viral infections and totreat increasing numbers ofimmunosuppressed patients who are at
increased risk of infection.
Examples of Antiviral Compounds
-
7/26/2019 26 Virology
66/105
Examples of Antiviral Compounds
Used for Treatment of Viral Infections:Drug Nucleoside Analog Mechanism of Action Viral Spectrum1
Acyclovir Yes Viral polymerase inhibitor Herpes simplex, varicella-zoster
Amantadine No Blocks viral uncoating Influenza A
Cidofovir No Viral polymerase inhibitor Cytomegalovirus, herpessimplex, polyomavirus
Didanosine (ddI) Yes Reverse transcriptaseinhibitor
HIV-1, HIV-2
Foscarnet No Viral polymerase inhibitor Herpesviruses, HIV-1, HBV
Fuzeon No HIV fusion inhibitor (blocksviral entry)
HIV-1
Ganciclovir Yes Viral polymerase inhibitor Cytomegalovirus
Indinavir No HIV protease inhibitor HIV-1, HIV-2
Lamivudine (3TC) Yes Reverse transcriptaseinhibitor
HIV-1, HIV-2, HBV
Nevirapine No Reverse transcriptaseinhibitor
HIV-1
Examples of Antiviral Compounds
-
7/26/2019 26 Virology
67/105
Examples of Antiviral Compounds
Used for Treatment of Viral Infections:Drug Nucleoside Analog Mechanism of Action Viral Spectrum1
Ribavirin Yes Perhaps blocks capping ofviral mRNA
Respiratory syncytial virus,influenza A and B, Lassafever, hepatitis C, others
Ritonavir No HIV protease inhibitor HIV-1, HIV-2
Saquinavir No HIV protease inhibitor HIV-1, HIV-2
Stavudine (d4T) Yes Reverse transcriptaseinhibitor
HIV-1, HIV-2
Trifluridine Yes Viral polymerase inhibitor Herpes simplex,cytomegalovirus, vaccinia
Valacyclovir Yes Viral polymerase inhibitor Herpesviruses
Vidarabine Yes Viral polymerase inhibitor Herpesviruses, vaccinia,HBV
Zalcitabine (ddC) Yes Reverse transcriptaseinhibitor
HIV-1, HIV-2, HBV
Zidovudine (AZT) Yes Reverse transcriptaseinhibitor
HIV-1, HIV-2, HTLV-1
-
7/26/2019 26 Virology
68/105
Comprise the majority of available antiviralagents.
MOA:
They inhibit nucleic acid replication by inhibitionof polymerases for nucleic acid replication.
Some analogs can be incorporated into thenucleic acid and block further synthesis or alter its
function. Analogs can inhibit cellular enzymes as well as
virus-encoded enzymes.
-
7/26/2019 26 Virology
69/105
The most effective analogs are those able tospecifically inhibit virus-encoded enzymes, withminimal inhibition of analogous host cellenzymes.
Resistance: Virus variants resistant to the drug usually arise over
time, sometimes quite rapidly.
The use of combinations of antiviral drugs can delaythe emergence of resistant variants (eg, "triple drug"therapy used to treat HIV infections).
-
7/26/2019 26 Virology
70/105
Examples of nucleoside analogs include
acyclovir (Acycloguanosine),
lamivudine (3TC),
ribavirin,
vidarabine (Adenine Arabinoside),
and zidovudine (azidothymidine; AZT).
-
7/26/2019 26 Virology
71/105
Nucleotide analogs differ from nucleosideanalogs in having an attached phosphategroup.
Their ability to persist in cells for long periodsof time increases their potency.
Example:
Cidofovir (HPMPC)
-
7/26/2019 26 Virology
72/105
Nevirapine was the first member of the class ofnonnucleoside reverse transcriptase inhibitors.
It does not require phosphorylation for activity
and does not compete with nucleosidetriphosphates.
MOA:
Bind directly to reverse transcriptase and disruptingthe enzyme's catalytic site.
Resistant mutants emerge rapidly.
-
7/26/2019 26 Virology
73/105
Saquinavir
The first protease inhibitor to be approved fortreatment of HIV infection.
A peptidomimetic agent designed bycomputer modeling as a molecule that fitsinto the active site of the HIV protease
enzyme.
-
7/26/2019 26 Virology
74/105
MOA
Inhibit the viral proteasethat is required at the
late stage of thereplicative cycle
cleave the viralgag andgag-polpolypeptide
precursors
form the mature virioncore
activate the reversetranscriptase that will be
used in the next round ofinfection.
yields noninfectious virus
particles
-
7/26/2019 26 Virology
75/105
Protease inhibitors include
Indinavir
Ritonavir
etc
-
7/26/2019 26 Virology
76/105
Fuzeon
a large peptide
MOA:
Blocks the virus and cellular membrane fusionstep involved in entry of HIV-1 into cells.
-
7/26/2019 26 Virology
77/105
These synthetic amines specifically inhibit influenza A viruses by blockingviral uncoating.
They must be administered prophylactically to have a significantprotective effect.
Amantadine andRimantadine
An organic analog of inorganic pyrophosphate
Selectively inhibits viral DNA polymerases and reverse transcriptases atthe pyrophosphate-binding site.
Foscarnet(Phosphonoformic
Acid, PFA)
An inhibitor of poxviruses. It was the first antiviral agent to be described and contributed to the
campaign to eradicate smallpox.
It blocked a late stage in viral replication, resulting in the formation ofimmature, noninfectious virus particles.
Methisazone
-
7/26/2019 26 Virology
78/105
Host-coded proteins that are members of thelarge cytokine family and which inhibit viralreplication.
They are produced very quickly (within hours)in response to viral infection or otherinducers.
Are one of the body's first responders in thedefense against viral infection.
-
7/26/2019 26 Virology
79/105
Interferons are central to the innate antiviralimmune response.
Also modulate humoral and cellular
immunity.
Have broad cell growth regulatory activities.
-
7/26/2019 26 Virology
80/105
Three general groups
IFN- type I (viral IFN)
The IFN- family is large, being coded by at least 20
genes in the human genome IFN- type I (viral IFN)
IFN- type II (immune IFN)
** the IFN- and IFN- families are coded byone gene each.
P i f H I f
-
7/26/2019 26 Virology
81/105
Properties of Human Interferons
Type
Property Alpha Beta Gamma
Current nomenclature IFN- IFN- IFN-
Former designation Leukocyte Fibroblast Immune interferon
Type designation Type I Type I Type II
Number of genes thatcode for family
20 1 1
Principal cell source Most cell types Most cell types Lymphocytes
Inducing agent Viruses; dsRNA Viruses; dsRNA Mitogens
Stability at pH 2.0 Stable Stable LabileGlycosylated No Yes Yes
Introns in genes No No Yes
Homology with IFN- 8095% 30% < 10%
P i f H I f
-
7/26/2019 26 Virology
82/105
Properties of Human Interferons
Type
Chromosomal locationof genes
9 9 12
Size of secreted protein(number of aminoacids)
165 166 143
IFN receptor IFNAR IFNAR IFNGR
Chromosomal locationof IFN receptor genes
21 21 6
-
7/26/2019 26 Virology
83/105
The different interferons are similar in size,but the three classes are antigenically distinct.
IFN- and IFN- are resistant to low pH.
IFN- and IFN- are glycosylated, but thesugars are not necessary for biologic activity,so cloned interferons produced in bacteria are
biologically active.
-
7/26/2019 26 Virology
84/105
Dendritic cells are potent interferon producers;
under the same virus challenge conditions,
dendritic cells can secrete up to 1000x moreinterferon than fibroblasts.
-
7/26/2019 26 Virology
85/105
Interferons are produced by all vertebrate species. Normal cells do not generally synthesize interferon
until they are induced to do so. Infection with viruses is a potent insult leading to
induction; RNA viruses are stronger inducers of interferon than DNA
viruses. Interferons also can be induced by double-stranded RNA,
bacterial endotoxin, and small molecules such as tilorone.
IFN- not produced in response to most viruses but is induced
by mitogen stimulation.
-
7/26/2019 26 Virology
86/105
IFN- and IFN- synthesized by many cell types.
IFN-
produced mainly by lymphocytes, especially T cellsand natural killer (NK) cells.
Dendritic cells are potent interferon producers;
under the same virus challenge conditions, dendriticcells can secrete up to 1000x more interferon thanfibroblasts.
-
7/26/2019 26 Virology
87/105
Interferon does not protect the virus-infectedcell that produces it, and interferon itself isnot the antiviral agent.
Rather, interferon moves to other cells whereit induces an antiviral state by prompting thesynthesis of other proteins that actuallyinhibit viral replication. Interferon molecules
bind to specific cell surface receptors ontarget cells.
-
7/26/2019 26 Virology
88/105
Receptor binding triggerstyrosine phosphorylation
and activation oftranscription factors (STATproteins) in the cytoplasm
Translocate into the nucleusand mediate transcriptionof interferon-inducible
genes (which occurs withinminutes after interferon
binding).
Synthesis of severalenzymes believed to be
instrumental in thedevelopment of the
antiviral state.
Several pathways appear to be
-
7/26/2019 26 Virology
89/105
p y pp
involved:
A dsRNA-dependent protein kinase, PKR, whichphosphorylates and inactivates cellular initiation factoreIF-2 and thus prevents formation of the initiation complexneeded for viral protein synthesis;
An oligonucleotide synthetase, 2-5A synthetase, which
activates a cellular endonuclease, RNase L, which in turndegrades mRNA;
A phosphodiesterase, which inhibits peptide chainelongation;
Nitric oxide synthetase, which is induced by IFN- inmacrophages. These explanations, however, fail to revealwhy the antiviral state acts selectively against viral mRNAsand not cellular mRNAs.
-
7/26/2019 26 Virology
90/105
Other steps in viral replication may also beinhibited by interferon.
-
7/26/2019 26 Virology
91/105
Interferons are almost always host species-specific in function but are not specific for agiven virus.
When interferon is added to cells prior toinfection, there is marked inhibition of viralreplication but nearly normal cell function.
Interferons are extremely potent, so that very
small amounts are required for function.
-
7/26/2019 26 Virology
92/105
May block induction of expression of interferon (herpesvirus,papillomavirus, filovirus, hepatitis C virus, rotavirus);
May block the activation of the key PKR protein kinase(adenovirus, herpesviruses);
May activate a cellular inhibitor of PKR (influenza,poliovirus);
May block interferon-induced signal transduction
(adenovirus, herpesviruses, hepatitis B virus); May neutralize IFN- by acting as a soluble interferon receptor
(myxoma virus).
Specific viral proteins
-
7/26/2019 26 Virology
93/105
The purpose of viral vaccines is to utilize theimmune response of the host to prevent viraldisease.
Vaccination is the most cost-effective methodof prevention of serious viral infections.
-
7/26/2019 26 Virology
94/105
Immunity to viral infection is based on thedevelopment of an immune response to specificantigens located on the surface of virus particles orvirus-infected cells.
For enveloped viruses, the important antigens are thesurface glycoproteins.
Although infected animals may develop antibodiesagainst virion core proteins or nonstructural proteins
involved in viral replication, that immune response isbelieved to play little or no role in the development ofresistance to infection.
-
7/26/2019 26 Virology
95/105
The pathogenesis of a particular viral infectioninfluences the objectives of immunoprophylaxis.
Mucosal immunity (local IgA)
is important in resistance to infection by viruses that
replicate exclusively in mucosal membranes (rhinoviruses,influenza viruses, rotaviruses).
Viruses that have a viremic mode of spread (polio,hepatitis, measles)
are controlled by serum antibodies. Cell-mediated immunity also is involved in protection
against systemic infections (measles, herpes).
-
7/26/2019 26 Virology
96/105
Killed-Virus Vaccines
Attenuated Live-VirusVaccines
-
7/26/2019 26 Virology
97/105
Made by purifying viral preparations to acertain extent and then inactivating viralinfectivity in a way that does minimal damage
to the viral structural proteins Mild formalin treatment is frequently used.
-
7/26/2019 26 Virology
98/105
Advantages
There is no reversion tovirulence by the vaccine virusand that vaccines can be
made when no acceptableattenuated virus is available.
-
7/26/2019 26 Virology
99/105
Disadvantages
Extreme care is required in their manufacture tomake certain that no residual live virulent virus is
present in the vaccine. The immunity conferred is often brief and must beboosted, which not only involves the logisticproblem of repeatedly reaching the persons in needof immunization but also has caused concern aboutthe possible effects (hypersensitivity reactions) ofrepeated administration of foreign proteins.
-
7/26/2019 26 Virology
100/105
Disadvantages
Parenteral administration of killed-virusvaccine, even when it stimulates circulating
antibody (IgM, IgG) to satisfactory levels, hassometimes given limited protection becauselocal resistance (IgA) is not induced adequatelyat the natural portal of entry or primary site of
multiplication of the wild virus infectioneg,nasopharynx for respiratory viruses, alimentarytract for poliovirus
-
7/26/2019 26 Virology
101/105
Disadvantages
The cell-mediated response to
inactivated vaccines is generally poor. Some killed-virus vaccines have inducedhypersensitivity to subsequent infection,perhaps owing to an unbalanced immune
response to viral surface antigens thatfails to mimic infection with natural virus.
-
7/26/2019 26 Virology
102/105
Utilize virus mutants that antigenicallyoverlap with wild-type virus but are restrictedin some step in the pathogenesis of disease.
-
7/26/2019 26 Virology
103/105
Advantage
Act like the natural infection with regard totheir effect on immunity.
They multiply in the host and tend tostimulate longer-lasting antibodyproduction, to induce a good cell-mediated
response, and to induce antibodyproduction and resistance at the portal ofentry.
-
7/26/2019 26 Virology
104/105
Disadvantages The risk of reversion to greater virulence during multiplication
within the vaccinee. Although reversion has not proved to be aproblem in practice, its potential exists.
Unrecognized adventitious agents latently infecting the culturesubstrate (eggs, primary cell cultures) may enter the vaccinestocks. Viruses found in vaccines have included avian leukosisvirus, simian polyomavirus SV40, and simian cytomegalovirus.The problem of adventitious contaminants may be circumventedthrough the use of normal cells serially propagated in culture
(eg, human diploid cell lines) as substrates for cultivation ofvaccine viruses.
-
7/26/2019 26 Virology
105/105
Disadvantages
The storage and limited shelf life of attenuatedvaccines present problems, but this can be overcomein some cases by the use of viral stabilizers (eg, MgCl
2for poliovaccine).
Interference by coinfection with a naturally occurring,wild-type virus may inhibit replication of the vaccinevirus and decrease its effectiveness. This has been
noted with the vaccine strains of poliovirus, which canbe inhibited by concurrent infections by variousenteroviruses.