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Lecture 17

Mammalian viruses and some

i
important
t t viral
i l di
diseases

Objectives
• Understand the taxonomic and Baltimore classifications of viruses
• Be familiar with the names of the major viral families and some common human viruses
• Describe the 7 types of virus replication in the Baltimore scheme
• D
Describe
ib th
the steps
t iin viral
i l replication
li ti iin animal
i l cellsll ((cff bacteriophage
b t i h replication)\
li ti )\
• Describe the two approaches used by enveloped viruses in infecting cells
• Describe how enveloped viruses acquire their envelope and leave infected cells
• Describe the 4 different effects animal viruses can have on infected cells
• Discuss influenza virus as an example of a lytic virus, Baltimore class V
• Describe the steps involved in the replication of influenza virus
• Understand the important of haemagglutinin and neuraminidase proteins of influenza viruses in
typing viral strains
• Understand the concepts of antigenic shift and antigenic drift in influenza viruses
• Understand the concern about influenza pandemics and current concerns about “bird flu”
• Discuss poliovirus as an example of a lytic virus, Baltimore class IV virus
• Di
Discuss h
herpes simplex
i l virus i as an examplel off a virus
i capable
bl off llatent
t t iinfections
f ti and
daB
Baltimore
lti
class 1 virus
• Give examples of oncogenic viruses
• Discuss hepatitis B virus as an example of a Baltimore class VII virus and an oncogenic virus
• Discuss retroviruses as an example of Baltimore class VI viruses
• Describe the replication of retroviruses (eg HIV)
• Understand the routes of transmission of HIV and the prevalence of AIDS globally
• Understand the routes of transmission of viral infections
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Classification of animal viruses

1. Traditional taxonomic approach
• System of Order
Order, Family
Family, Subfamily,
Subfamily Genus,
Genus
Species
– Order -virales
– Family – viridae
– Genera - virus
2. Strategy of viral replication approach
• Baltimore viral replication scheme
– Classification based on relationship of viral genome
to its mRNA

Taxonomic approach
1. Poxviridae – eg small pox virus
2. Herpesviridae – eg herpes simplex virus
3. Hepadnaviridae – eg Hepatitis B virus
4. Retroviridae – eg lentivirus – HIV 1
5. Paramyxoviridae – eg parainfluenza virus III, measles
virus, mumps virus
6. Coronaviridae – eg SARS virus
7
7. Picornaviridae – eg poliovirus
poliovirus, rhinovirus
rhinovirus, hepatitis A
virus,
8. Togaviridae – eg rubella virus
9. Flaviviridae – eg yellow fever virus, Hepatitis C virus

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Baltimore classification of viruses

7 classes:
• dsDNA viruses
• ssDNA viruses
• dsRNA viruses
• (+)-sense ssRNA
viruses
• (-)-sense ssRNA
viruses
• RNA reverse
transcribing viruses
• DNA reverse
transcribing viruses
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Viral replication - nomenclature

• mRNA is complementary to the strand of DNA used as
its template
p – that mRNA can be translated into p protein
ie mRNA in the plus (+) configuration; its complement is
said to be in the minus (-) configuration
• Virus with ss-RNA with the same orientation as its
mRNA – positive-strand RNA virus
• Virus with ss-RNA genome complementary to its mRNA
– negative-strand RNA virus
• Note
N t also
l – RNA polymerases
l d
do nott generally
ll catalyse
t l
the formation of RNA from an RNA template but instead
require a DNA template – so RNA viruses require a
specific RNA-dependent RNA polymerase

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Viral replication – RNA viruses

• Class IV – ss RNA (+) – RNA serves directly as mRNA;
mRNA encodes a virus-specific RNA polymerase –
makes
k complementary
l t negative
ti strands
t d and d th
then uses
them as templates to make additional plus strands
• Class V (ss RNA (-)) or Class III (ds RNA) – incoming
mRNA cannot be used as mRNA; as cells do not have
an RNA polymerase capable of handling synthesis of
mRNA from negative strands , these viruses contain
their own polymerase enzyme injected into the cell with
the genomic RNA; the complementary strand is
synthesised by this viral RNA-dependent RNA
polymerase and used as a message.
• Retroviruses (class VI) replicate through a DNA
intermediate – process of copying from RNA to DNA –
requires viral reverse transcriptase (carried in the virion
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Formation of mRNA and new

genomes – RNA viruses

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Viral replication – DNA viruses

• Class I – dsDNA viruses – production of mRNA and
genome replication occurs as it would from the host
genome – different
diff t viruses
i use different
diff t strategies
t t i to t
ensure viral mRNA is expressed in preference to host
cell mRNA
• Class II – ssDNA – must synthesise complementary
DNA strand before mRNA can be produced – so viruses
form a dsDNA intermediate (using host cell enzymes)
during replication – intermediate used for transcription.
ds-intermediate
ds intermediate also used to replicate genome – one
strand becomes the genome and the other is discarded.
• Class VII – partially dsDNA but replicate through a RNA
intermediate – involves use of reverse transcriptase. Eg
Hepatitis B virus – hepadnavirus (see later)

Formation of mRNA and new

genomes – DNA viruses

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Examples of DNA Viruses

Family Pox Herpes Adeno Papova Parvo Hepadna

Genome <---------------------------------------dsDNA--------------------------------------> ssDNA Partial dsDNA

Capsid Complex <---------------------------------------------Icosahedral-------------------------------------------------->

symmetry
Envelope Y
<-----------------Yes------------------> <-----------------------------No------------------------------>
N Y
Yes

Herpes simplex Human Papilloma Adeno- Hepatitis B

e.g. Vaccinia virus
virus 2 adenovirus Associated

Molluscum
Contagiosum

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Positive Sense RNA Viruses

Family Corona Toga/Flavi Picorna Calici Retro

Genome <-------------------------------------------ss (+) RNA---------------------------------------------> Diploid (+) RNA

Capsid symmetry Helical <--------------------------------------Icosahedral------------------------------------------------->

Envelope <----------------------Yes--------------------> <---------------------No----------------------> Yes

eg
e.g. Human corona Rubella virus Polio Norwalk agent HIV-1
virus Hepatitis C virus Hepatitis A virus Hepatitis E virus

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Negative Sense RNA Viruses

Family Paramyxo Rhabdo Filo Orthomyxo Arena Bunya Reo

Genome <-----------------ss(-) RNA------------------------> ss(-) RNA ss(+) or (+/-) ss(+) or (+/-) ds RNA
segments segments segments segments
Capsid
p <---------------------------------------------------Helical-------------------------------------------------------> Icosahedral
symmetry
Envelope <----------------------------------------------------Yes-----------------------------------------------------------> No

e.g. Measles Rabies virus Ebola virus Influenza Lassa virus Hanta virus Rotavirus
Mumps virus
Para-
influenza

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Viral replication in eukaryotic cells

• No compartments in prokaryotes – transcription of mRNA can lead
directly to translation
• In eukaryotic cells – DNA replication & transcription occurs in the
nucleus, translation in the cytoplasm
• So
– DNA viruses using host polymerases must replicate in the nucleus
– Other DNA viruses (pox, herpes viruses) replicate in the cytoplasm
• Transcripts from eukaryotic genes must be processed and
transported to the cytoplasm before they can be used as mRNA –
some intermediate processing steps are required – to allow binding
of mRNA to the ribosome
• So –
– Genomes of positive stranded RNA viruses must be in a processed
state in the virion if the RNA is to serve directly as mRNA

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Multiplication of Animal viruses

• Attachment Viruses attaches to cell
membrane
• Penetration
P t ti B endocytosis
By d t i or ffusion
i
• Uncoating By viral or host enzymes
• Biosynthesis Production of nucleic acid and
proteins
• Maturation
M t ti N l i acid
Nucleic id and
d capsidid
proteins assembly
• Release By budding (enveloped viruses)
or rupture 15

Fig. 14.8

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Fig. 14.11 Release of enveloped

virion

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Effect of animal viruses on cells

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Lytic infections
Example
Influenza
• Orthomyxoviridae
• ssRNA (-) – Baltimore Class V
• Linear genome, RNA in 7 or 8 strands
• Helical nucleocapsid
• Enveloped virus

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Structure of influenza virus. The diagram illustrates the main structural features of the
virion. The surface of the particle contains three kinds of spike proteins: the
hemagglutinin (HA), neuraminidase (NA), and matrix (M2) protein embedded in a lipid
bilayer derived from the host cell and covers the matrix (M1) protein that surrounds the
viral core.. (From Fields Virology, 4th ed, Knipe & Howley, eds, Lippincott Williams
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& Wilkins, 2001, Fig. 47-2)

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Replication of Influenza A virus

1. A virion attaches to the host cell membrane
via HA and enters the cytoplasm by
receptor-mediated endocytosis
• HA2 promotes fusion of the virus envelope
and the endosome membranes..
2.The major envelope protein M1 dissociates
from the nucleocapsid and viral RNA
segments are translocated into the nucleus
3. In the nucleus, the viral polymerase
complexes transcribe (STEP 3a) and
replicate (STEP 3b) the viral RNA segments
4. Newly synthesized mRNAs migrate to
cytoplasm where they are translated into
viral proteins
5a. Newly synthesised M1 viral proteins move to
the nucleus - bind freshlyy synthesized
y
copies of viral RNA segments.
5 b. Posttranslational processing of HA, NA, and
M2 includes transportation via Golgi
apparatus to the cell membrane
6. The newly formed nucleocapsids migrate into
the cytoplasm - interact via M1 with a region
of the cell membrane where HA, NA and M2
have been inserted
7. Then the newly synthesized virions bud from
infected cell. NA destroys the sialic acid 21
moiety of cellular receptors, thereby
releasing the progeny virions.

Influenza A hemagglutinin and neuraminidase subtypes

Fields Virology, 4th ed, Knipe & Howley, eds, Lippincott Williams & Wilkins, 2001, Table 47-1
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Influenza A reservoir

The reservoir of influenza A viruses. The working hypothesis is that wild aquatic birds are the primordial reservoir of all influenza viruses
for avian and mammalian species. Transmission of influenza has been demonstrated between pigs and humans (solid lines). There is
extensive evidence for transmission between wild ducks and other species, and the five different host groups are based on phylogenetic
analysis of the nucleoproteins of a large number of different influenza viruses. (From Fields Virology, 4th ed, Knipe & Howley, eds,
Lippincott Williams & Wilkins, 2001, Fig. 47-3.)
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Pandemics
1918 Spanish flu Possible emergence from swine or an Pandemic with >20 million deaths
(1) (H1N1 avian host of a mutated H1N1 virus globally
viruses like
swine flu)
1957 Asian flu Possible mixed infection of an animal Pandemic, H1N1virus disappeared
(2) (H2N2) with human H1N1and avian H2N2 virus
strains in Asia
1968 Hong Kong High probability of mixed infection of Pandemic, H2N2 virus disappeared
(2) flu (H3N2) an animal with human H2N2 and avian
H3Nx virus strains in Asia
1977 Russian flu Source unknown but virus is almost Benign pandemic, primarily
(3) (H1N1) identical to human epidemic strains involving persons born after the
from 1950. Reappearance detected at 1950s. H1N1 virus has cocirculated
almost the same time in China and with H3N2 virus in humans since
Siberia 1977

Incidents with limited spread

1976 Swine flu United States/New Jersey. Virus Localized outbreak in military training
(4) (H1N1) enzootic in U.S. swine herds since at camp, with one death
least 1930
1986 (H1N1) The Netherlands. Swine virus One adult with severe pneumonia
(5) derived from avian source
1988 Swine flu United States/Wisconsin. Swine Pregnant woman died after exposure to
(6) (H1N1) virus sick pig
1993 (H3N2) The Netherlands. Swine reassortant Two children with mild disease. Fathers
(7) between old human H3N2 (1973/75- suspected to have transmitted the virus to
like) and avian H1N1 the children after having been infected by
pigs.
1995 (H7N7) United Kingdom Duck virus One adult with conjunctivitis
(8)
1997 Chicken Hong Kong Poultry virus 18 confirmed human case, 6 deaths
(9) flu (H5N1) 25

Cumulative number of confirmed human cases of avian

Influenza A/(H5N1) reported to WHO
18 June 2008

2003 2004 2005 2006 2007 2008 Total

Country
case
cases deaths cases deaths cases deaths cases deaths deaths cases deaths cases deaths
s

Azerbaijan 0 0 0 0 0 0 8 5 0 0 0 0 8 5
Bangladesh 0 0 0 0 0 0 0 0 0 0 1 0 1 0
Cambodia 0 0 0 0 4 4 2 2 1 1 0 0 7 7
China 1 1 0 0 8 5 13 8 5 3 3 3 30 20
Djibouti 0 0 0 0 0 0 1 0 0 0 0 0 1 0
Egypt 0 0 0 0 0 0 18 10 25 9 7 3 50 22
Indonesia 0 0 0 0 20 13 55 45 42 37 18 15 135 110
Iraq 0 0 0 0 0 0 3 2 0 0 0 0 3 2
Lao People's
Democratic 0 0 0 0 0 0 0 0 2 2 0 0 2 2
Republic
Myanmar 0 0 0 0 0 0 0 0 1 0 0 0 1 0
Nigeria 0 0 0 0 0 0 0 0 1 1 0 0 1 1
Pakistan 0 0 0 0 0 0 0 0 3 1 0 0 3 1
Thailand 0 0 17 12 5 2 3 3 0 0 0 0 25 17
Turkey 0 0 0 0 0 0 12 4 0 0 0 0 12 4
Viet Nam 3 3 29 20 61 19 0 0 8 5 5 5 106 52
Total 4 4 46 32 98 43 115 79 88 59 34 26 385 243
http://www.who.int/csr/disease/avian_influenza/country/cases_table_2008_06_19/en/index.html
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Transmission of influenza
•Direct contact
•Aerosol

Flu could hitch a ride on banknotes

16:02 22 June 2007
NewScientist.com news service
Debora MacKenzie,
MacKenzie Toronto
The flu virus persists so well on banknotes that money could help
spread the next pandemic, researchers say.
Yves Thomas and colleagues at the University Hospitals of Geneva
in Switzerland dripped various strains of flu virus – including some
that were circulating during winter 2007 – onto Swiss banknotes
and left them at room temperature for varying amounts of time
before testing for live virus.
Some strains of flu lasted onlyy two hours,, but the most common flu,,
H3N2, lasted up to 72 hours. However, all the strains lasted longer
when they were dripped onto the notes along with human nasal mucus.
Some lasted as long as 17 days. One strain that lasted only two
hours on its own lasted 24 hours in mucus.

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Lytic infection
Poliovirus
• Picornaviridae
• ssRNA virus (+) – Baltimore
Class IV
• Simple icosahedral
nucleocapsid
• Very small virus
• Polio
• Almost eradicated from the
world by effective vaccination
program
• http://www.polioeradication.or
Transmission
• Common vehicle (water)
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29

Latent infections
Herpes simplex virus and varicella-zoster virus
• Herpesviridae
• dsDNA
d DNA virus
i – Baltimore
B lti Cl
Class I
• Icosahedral nucleocapsid
• Enveloped
• cold sores (herpes simplex virus) and chicken pox and shingles
(varicella-zoster virus)
• Virus remains latent in the neurones of the sensory ganglia from
which they emerge to cause infections of the skin

Transmission
• Direct contact (chicken pox scabs)
• aerosol

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Oncogenic viruses
• Cancer the result of the loss of the cell’s normal control
of its growth
• Growth & division of cells regulated by at least 2 types of
genes
– Proto-oncogenes – promote growth
– Tumour repressor genes – restrain growth
• Changes in either can lead to uncontrolled growth and
so cancer …
• Initiation event of cancer process can be the activation of
a proto-oncogene
t i t an oncogene or inactivation
into i ti ti off the
th
tumour repressor gene
• Not always possible to prove direct link with oncogenic
virus

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normal transformed by virus

contact-inhibited pile up, rounded

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Viruses associated with cancers

Cancer virus family Genome in
virion
Adult T-cell Human T-cell Retroviridae ss RNA (+)
leukaemia leukaemia virus Baltimore VI
type 1
Burkitt’s Epstein-Barr virus Herpesviridae ds DNA
lymphoma Baltimore 1
Nasopharyngeal Epstein-Barr virus Herpesviridae DNA
carcinoma
Hepatocellular Hepatitis B virus Hepadnaviridae ds DNA
carcinoma Baltimore
VII
Skin & cervical Papilloma virus Papillomaviridae ds DNA
cancers Baltimore I34

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Hepadnavirus
• Hepatitis B
• Very small genome – 3.4 kb
• G
Genome partially
ti ll dds-DNA
DNA – 1 strand
t d iincomplete,
l t bboth
th h
have gaps
• Once inside host cell viral DNA polymerase (carried in the virion)
completes the replication
• Polymerase is a versatile protein – contains DNA polymerase as
well as reverse transcriptase and acts as a protein primer for
synthesis of one of the DNA strands
• Replication of the genome involves transcription by host RNA
polymerase – viral reverse transcriptase then copies this into a DNA
molecule

Transmission
• Direct contact – body fluids of infected person

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•Chronic HBV infection can lead to cirrhosis and then to liver cancer

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Retroviruses
• Retroviridae
• ssRNA (positive strand) – Baltimore Class
VI
• Enveloped viruses
• Replicate via DNA intermediate – reverse
transcriptase
• First viruses to be associated with cancer
• HIV
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Retrovirus
• Cartoon of a
retrovirus
• Genetic map of a
typical retroviral
genome
• Genetic map of Rous
sarcoma virus –
retrovirus
t i th
thatt causes
malignant tumours in
birds

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Replication of a retrovirus

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Transmission of HIV
• Sexual transmission.
• Transfusion of infected
blood and blood
products.
• Vertical transmission.
• Needle sharing among
injecting drug users.
• Occupational exposure.

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41

Transmission of viral diseases

1. Airborne transmission – examples – viruses shed from the
upper respiratory tract (common cold, influenza); viruses shed
from skin lesions (eg chicken pox
pox, herpes viruses)
viruses).
2. Faecal-oral transmission – viruses shed in the faeces –
transmitted by contaminated water or food – eg Hepatitis A,
rotavirus, enteroviruses (eg polio), norovirus.
3. Body fluids transmission – viruses transmitted in blood or
other body fluids – eg Hepatitis B and C; HIV;
4. Vector transmission – viruses carried by insects and
arthropods – arboviruses (arthropod borne viruses). Most
arboviruses are normally carried by birds and animals
(subclinical infections) and spread to people by insects or
arthropods.

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Transmission of viral infections

5. Foetal and neonatal transmission – virus infections in the
mother that can cause serious problems for the foetus or
neonate.
neonate
– Teratogenic effects
• Rubella (German measles) in the first trimester of pregnancy –
congenital defects such as heart defects, blindness, mental
retardation;
• Cytomegalovirus (CMV) – depending on the stage of gestation
and the status of the mother – can result in death or premature
birth or a range of congenital defects;
• other virus infections have also been linked to congenital defects
defects.
– Vertical transmission – Hepatitis B, HIV can be transmitted
from the mother to the neonate.
– Viral disease acquired at birth – genital herpes in the mother
can lead to herpes encephalitis in the neonate.

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