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Chapter 25
The RNA Viruses That
Infect Humans
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Neuraminidase
spike
Hemagglutinin spike
Envelope
forming
Nucleocapsids
1
2
3
4
5
6
Virus (structure shown
in a cutaway view)
adsorbs to a
respiratory epithelial
cell by hemagglutinin
spikes and fuses with
the membrane.
The virus is endocytosed into
a vacuole and uncoated to
release its 8 nucleocapsid
segments into the cytoplasm.
(+) Sense RNA is used to
synthesize glycoprotein spikes
inserted into the host
membrane.
Release of mature virus
occurs when viral parts
gather at the cell
membrane and are
budded off with an
envelope containing
spikes.
The (+) sense RNA strands are
used to synthesize new (−)
sense RNA strands. These are
assembled into nucleocapsids
and transported out of the
nucleus to the cell membrane.
The nucleocapsids are transported into the
nucleus. There the (−) sense RNA strand
(black) is transcribed into a (+) sense strand
(red) that will be translated into viral proteins
that make up the capsid and spikes.
*
RNA Viruses
• Diverse group of microbes
• Assigned to one of 12 families based on
envelope, capsid, and nature of RNA genome
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*
Enveloped Segmented Single-
Stranded RNA Viruses
• Orthomyxoviruses
• Bunyaviruses
• Arenaviruses
*
The Biology of
Orthomyxoviruses: Influenza
• 3 distinct influenza virus types: A, B, C; Type A
causes most infections
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
*
Influenza Infection
• Virus attaches to, and multiplies in, the cells of the
respiratory tract
• Segments of RNA genome enter the nucleus
• Finished viruses are assembled and bud off the cell
Neuraminidase
spike
Hemagglutinin
spike
Envelope
forming
Nucleocapsid
s
1
2
3
4
5
6
Virus (structure shown
in a cutaway view)
adsorbs to a
respiratory epithelial
cell by hemagglutinin
spikes and fuses with
the membrane.
The virus is endocytosed into
a vacuole and uncoated to
release its 8 nucleocapsid
segments into the
cytoplasm.
(+) Sense RNA is used to
synthesize glycoprotein spikes
inserted into the host membrane.
Release of mature virus
occurs when viral parts
gather at the cell
membrane and are
budded off with an
envelope containing
spikes.
The (+) sense RNA strands are
used to synthesize new (−)
sense RNA strands. These are
assembled into nucleocapsids
and transported out of the
nucleus to the cell membrane.
The nucleocapsids are transported into the
nucleus. There the (−) sense RNA strand
(black) is transcribed into a (+) sense strand
(red) that will be translated into viral proteins
that make up the capsid and spikes.
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
*
• Key to influenza are
glycoprotein spikes –
– Hemagglutinin (H) –
15 different subtypes;
most important virulence
factor; binds to host cells
– Neuraminidase (N) –
9 subtypes – hydrolyzes
mucus and assists viral
budding and release
• Both glycoproteins
frequently undergo genetic
changes decreasing the
effectiveness of the host
immune response
Influenza Glycoproteins
Binding sites used to anchor virus to host cell
receptors (low rate of mutation)
Site for antibody binding
(high rate of mutation)
Viral envelope
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*
• Constant mutation is called
antigenic drift – gradually
change their amino acid
composition
• Antigenic shift – one of
the genes or RNA strands
is substituted with a gene
or strand from another
influenza virus from a
different animal host
– Genome of virus consists of
10 genes encoded on 8
separate RNA strands
Influenza Mutation
Human influenza virus
With duck HA spike
HA RNA
NA RNA NA RNA
HA RNA
HA
NA
Human influenza virus
Duck influenza virus
Immune system has
no recall for duck
antigens
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*
Influenza B
• Only undergo antigenic drift
• Not known to undergo antigenic shift
Influenza C
• Known to cause only minor respiratory
disease; probably not involved in epidemics
Influenza Strains
*
Influenza A
• Acute, highly contagious respiratory illness
• Seasonal, pandemics; among top 10 causes of
death in U.S. – most commonly among elderly
and small children
• Binds to ciliated cells of respiratory mucosa
• Causes rapid shedding of cells, stripping the
respiratory epithelium; severe inflammation
• Fever, headache, myalgia, pharyngeal pain,
shortness of breath, coughing
• Weakened host defenses predispose patients to
secondary bacterial infections, especially
pneumonia
*
Diagnosis, Treatment,
Prevention
• Rapid immunofluorescence tests to detect antigens
in a pharyngeal specimen; serological testing to
screen for antibody titer
• Treatment: control symptoms; amantadine,
rimantadine, zanamivir (Relenza), and oseltamivir
(Tamiflu)
• Flu virus has developed high rate of resistance to
amantadine and rimantadine
• Annual trivalent vaccine recommended – especially
for health workers
*
Bunyaviruses and Arenaviruses
• Transmitted zoonotically; cause periodic epidemics;
extremely dangerous; biosafety level 4 viruses
Bunyaviruses – transmitted by insects and ticks
– California encephalitis, Rift Valley fever, Korean
hemorrhagic fever
– American bunyavirus is a hantavirus, Sin Nombre –
emerging disease; high fever, lung, edema, and
pulmonary failure; 33% mortality rate
• Carried by deer and harvest mice; transmitted via
airborne dried animal waste
Arenaviruses
• Lassa fever, Argentine hemorrhagic fever, Bolivian
hemorrhagic fever, and Lymphocytic choriomeningitis
• Closely associated with rodent host
• Transmission through aerosols and contact
Concept Check:
Which of these happen(s) in the case of
antigenic shift in influenza A?
A. Single mutations in hemagglutinin
B. Recombination of RNA segments between
bird and human strains
C. Change from influenza A to influenza B
D. Both A and B
*
Enveloped Nonsegmented
ssRNA Viruses
• Paramyxoviruses
• Rhabdoviruses
• Filoviruses
• Togaviruses
• Flaviviruses
• Coronaviruses
*
Paramyxoviruses
Paramyxoviruses
(parainfluenza, mumps
virus)
Morbillivirus (measles virus)
Pneumovirus (respiratory
syncytia virus)
• Respiratory transmission
• Envelope has glycoprotein
and F spikes that initiate
cell-to-cell fusion
• Fusion with neighboring
cells – syncytium or
multinucleate giant cells
form
Uncoatin
g
Point of cell
fusion
Host
cell2
Host
cell1
Host
cell3
Paramyxovirus
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*
Parainfluenza
• Widespread as influenza but more benign
• Respiratory transmission
• Seen mostly in children
• Minor cold, bronchitis, bronchopneumonia,
croup
• No specific treatment available; supportive
therapy
*
Mumps
• Epidemic parotitis; self-limited, associated with
painful swelling of parotid salivary glands
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© Biophoto Associates/Photo Researchers, Inc.
*
Mumps
• Humans are the only reservoir
• 40% of infections are subclinical; long-term
immunity
• 300 cases in U.S./year
• Incubation 2-3 weeks fever, muscle pain and
malaise, classic swelling of one or both cheeks
• Usually uncomplicated invasion of other organs;
in 20-30% of infected adult males, epididymis
and testes become infected; sterility is rare
• Symptomatic treatment
• Live attenuated vaccine MMR
*
Measles
• Caused by Morbillivirus
• Also known as red measles and rubeola
• Different from German measles
• Very contagious; transmitted by respiratory aerosols
• Humans are the only reservoir
• Less than 100 cases/yr in U.S.; frequent cause of death
worldwide
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*
Measles
• Virus invades
respiratory tract
• Sore throat, dry cough,
headache, conjunctivitis,
lymphadenitis, fever,
Koplik spots – oral
lesions
• Exanthem
Koplik’s
spots
CDC
CDC
(a)
(b)
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*
Measles
• Most serious complication is subacute
sclerosing panencephalitis (SSPE), a
progressive neurological degeneration of the
cerebral cortex, white matter, and brain stem
– 1 case in a million infections – very rare
– Involves a defective virus spreading through the
brain by cell fusion and destroys cells
– Leads to coma and death in months or years
• Attenuated viral vaccine MMR
*
Respiratory Syncytial Virus (RSV)
• Also called Pneumovirus
• Infects upper respiratory tract and produces giant
multinucleate cells
• Most prevalent cause of respiratory infection in
children 6 months or younger; most susceptible
to serious disease
• Epithelia of nose and eye portal of entry;
replicates in nasopharynx
• Fever, rhinitis, pharyngitis, otitis, croup
• Treatment: synagis, a monoclonal antibody that
blocks attachment, ribavirin
*
Rabies
• Rhabdovirus family; genus
Lyssavirus
• Enveloped, bullet-shaped
virions
• Slow, progressive zoonotic
disease
• Primary reservoirs are wild
mammals; it can be spread
by both wild and domestic
mammals by bites,
scratches, and inhalation of
droplets
Glycoprotein spikes
Matrix protein
Nucleocapsid
(a) (b)
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CDC
Rabies Distribution in the United
States
*
Fo
x
Skunk
Raccoo
n
Fo
x
Coyot
e
Coyot
e
Skun
k
Skunk
Skunk
Fo
x
Fo
x
Raccoo
n
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*
Rabies
• Virus enters through bite, grows at trauma site for a
week and multiplies, then enters nerve endings and
advances toward the ganglia, spinal cord and brain
• Infection cycle completed when virus replicates in the
salivary glands
Clinical phases of rabies:
• Prodromal phase – fever, nausea, vomiting,
headache, fatigue; some experience pain, burning,
tingling sensations at site of wound
• Furious phase – agitation, disorientation, seizures,
twitching, hydrophobia
• Dumb phase – paralyzed, disoriented, stuporous
• Progress to coma phase, resulting in death
*
• Often diagnosed at autopsy – intracellular inclusions
(Negri bodies) in nervous tissue
• Bite from wild or stray animals demands assessment of
the animal, meticulous wound care, and specific
treatment
• Preventive therapy initiated if signs of rabies appear
• Treatment – passive and active postexposure
immunization
– Infuse the wound with human rabies immune globulin
(HRIG) and globulin; vaccination with human diploid cell
vaccine (HDCV), an inactivated vaccine given in 6 doses
with 2 boosters
• Control – vaccination of domestic animals, elimination of
strays, and strict quarantine practices
– Live oral vaccine incorporated into bait for wild animals
Rabies
Concept Check:
For which disease are active and passive
immunization given simultaneously?
A. Influenza
B. Yellow Fever
C. Measles
D. Rabies
*
Coronaviruses
• Relatively large RNA viruses with distinctively
spaced spikes on their envelopes
• Common in domesticated animals
• 3 types of human coronaviruses have been
characterized:
– HCV causes a cold
– An enteric virus
– Severe Acute Respiratory Syndrome (SARS)
• Airborne transmission
• 9% of cases fatal
*
Severe Acute Respiratory Syndrome-
Associated Coronavirus (SARS)
• Newly emerging disease – 2002
• Transmitted through droplet or direct contact
• Fever, body aches, and malaise
• May or may not experience respiratory symptoms
with breathing problems; severe cases can result in
respiratory distress and death
• Diagnosis relies on exclusion of other likely agents
• Treatment is supportive
*
Rubella
• Caused by Rubivirus, a Togavirus
• ssRNA with a loose envelope
• German measles
• Endemic disease
• Most cases reported are adolescents and young
adults
• Transmitted through contact with respiratory
secretions
• Diagnosis based on serological testing
• No specific treatment available
• Attenuated viral vaccine MMR
*
Rubella
Two clinical forms:
• Postnatal rubella –
malaise, fever, sore throat,
lymphadenopathy, rash,
generally mild, lasting about
3 days
• Congenital rubella –
infection during 1st trimester
most likely to induce
miscarriage or multiple
defects such as cardiac
abnormalities, ocular
lesions, deafness, mental
and physical retardation
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© James Stevenson/Photo Researchers, Inc.
*
Hepatitis C Virus (HCV)
• Flavivirus
• Acquired through blood contact – blood
transfusions, needle sharing by drug abusers
• Infections with varying characteristics – 75-85% will
remain infected indefinitely; possible to have severe
symptoms without permanent liver damage; more
common to have chronic liver disease, without overt
symptoms
• Cancer may also result from chronic HCV infection
• Treatment with interferon and ribavirin to lessen liver
damage; no cure
• No vaccine
*
Arboviruses: Viruses Spread by
Arthropod Vectors
• Mosquitoes, ticks, flies, and gnats
• 400 viruses
• Togaviruses, flaviviruses, some bunyaviruses and
reoviruses
• Most illnesses caused by these viruses are mild
fevers; some may cause severe encephalitis, and
life-threatening hemorrhagic fever
*
The Influence of the Vector
• Vectors and viruses tend to be clustered in the
tropics and subtropics; many temperate zones
have periodic epidemics
• Arbovirus life cycles are closely tied to the
ecology of the vectors
• Infections show a peak incidence when the
arthropod is actively feeding and reproducing
• Humans can serve as dead-end, accidental hosts
or they can be a maintenance reservoir
• Controlling the vector controls the disease
Worldwide Distribution of Major
Arboviral Diseases
*
West Nile fever
(outlined areas)
Yellow fever
Dengue fever
St. Louis
encephalitis
Japanese encephalitis
WEE Western equine encephalitis
EEE Eastern equine encephalitis
VEE Venezuelan equine encephalitis
Shows relatively restricted
distribution
Ross
River
fever
Murray
Valley
encephaliti
s
Omsk fever
LaCrosse
encephaliti
s
EEE
VEE
Congolian
hemorrhagi
c
fever Rift
Valley
fever
Kyasanur
fever
Roci
o
fever
Mayar
o
fever
Colorad
o
tick
fever WEE
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
*
General Characteristics of
Arbovirus Infections
• Acute arbovirus infection may result in
undifferentiated mild fever with rash; no long-
term effects; prominent symptoms are fever,
headache, myalgia, joint stiffness, rash
• Viral encephalitis – brain, meninges, and spinal
cord are involved; convulsions, tremor, paralysis,
loss of coordination, memory deficits, changes in
speech and personality, coma; survivors may
experience permanent brain damage
*
• Colorado tick fever (CTF) – most common tick-borne
viral fever in U.S.; Rocky Mountain states
• Western equine encephalitis (WEE) – western U.S.
and Canada; extremely dangerous to infants and small
children
• Eastern equine encephalitis (EEE) – eastern U.S. and
Canada
• California encephalitis – 2 different strains:
– California strain – western states; little human impact
– LaCrosse strain – eastern U.S. and Canada;
prevalent cause of viral encephalitis
• St. Louis encephalitis (SLE) – most common of all in
America; epidemics in midwestern and southern states;
inapparent infections are very common
• West Nile encephalitis
Arbovirus Infections in the USA
*
Hemorrhagic Fevers
Yellow fever – eliminated in U.S.
• Two patterns of transmission:
– Urban cycle – humans and mosquitoes, Aedes aegypti
– Sylvan cycle – forest monkeys and mosquitoes; South
America
• Acute fever, headache, muscle pain; may progress to
oral hemorrhage, nosebleed, vomiting, jaundice, and
liver and kidney damage; significant mortality rate
Dengue fever – flavivirus carried by Aedes mosquito;
not in U.S.; usually mild infection
– Dengue hemorrhagic shock syndrome, breakbone fever
– extreme muscle and joint pain; can be fatal
Concept Check:
Rubella is a serious infection for both children
and adults.
A. True
B. False
*
HIV Infections and AIDS
• Human immunodeficiency virus
• Acquired immunodeficiency syndrome
• First emerged in early 1980s
• HIV-1 may have originated from a
chimpanzee virus – or maybe…..
• 1959 first documented case of AIDS
GP-120
GP-41
Capsid
Protease
molecule
(b)
(a)
HIV
GP-41
GP-120
RNAstrands
Integrase
molecules
Reverse
transcriptase
molecules
Antireceptor spikes
CD4 receptor
on white
blood cell
Co-receptor on
white blood
cell
*
Human Immunodeficiency Virus (HIV)
• Retrovirus, genus
Lentivirus
• Encode reverse
transcriptase enzyme
which makes a double
stranded DNA from the
single-stranded RNA
genome
• Viral genes permanently
integrated into host DNA
• The cause of Acquired
Immunodeficiency
Syndrome (AIDS)
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*
Causative Agent
• HIV-1 and HIV-2
• T-cell lymphotropic viruses I and II – leukemia
and lymphoma
• HIV can only infect host cells that have the
required CD4 marker plus a coreceptor
HIV
GP-41
GP-120
Antireceptor
spikes
CD4
receptor
on white
blood cell
Co-receptor on
white blood
cell
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Blood exposure
through needles
Lacerations
Direct blood
exposure,
during sexual
intercourse or
other intimate
contact
Semen, vaginal
fluid exposure
during sexual
intercourse
Infected
macrophage
Microscopic
view
of
process
Dendritic cells
underlying skin
shelter and
amplify virus
Spread of virus to
lymphatic organs,
bone marrow,
circulation
Membrane
or
skin
portal
of
entry
*
Epidemiology of HIV Infections
• Transmission occurs by
direct and specific
routes: mainly through
sexual intercourse and
transfer of blood or
blood products; babies
can be infected before
or during birth, and
from breast feeding
• HIV does not survive
long outside of the
body – good!
Epithelial
cell
Infected blood
Infected sexual secretions
HIV
Infected white blood
cells
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
(b)
*Numbers are rounded.
26% White
54% Black
19% Hispanic
1% Other
75% Men
42% MSM
25% IDU
Children < 13 are 0.4%
(a) Total HIV infections and AIDS diagnoses,
by age group as of 2009*
43% Age 35−49
38% Age 20−34
16% Age 50−64
0.5% Age 13−19
2% Age >65
25% Women
Estimates of 2009
new infections by
race (N > 56,000)
Estimates of 2009
new infections by
race (N > 56,000)
MSM: Male to male sexual contact.
IDU: Intravenous drug users.
Estimates of 2009
new infections by
risk (N > 56,000)
33%
Heterosexual
*
• First nationally notifiable in
1984
• 6th most common cause of
death among people aged
25-44 years in the U.S.
• Men account for 75% of new
infections
• IV drug abusers can be HIV
carriers; significant factor in
spread to heterosexual
population
• In 2009, the number of
infected individuals worldwide
is estimated to be 35 million
with ~1.2 million in the U.S.
Epidemiology of HIV Infection
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
*
Pathogenesis and Virulence Factors
• HIV enters through mucous
membrane or skin and travels to
dendritic phagocytes beneath the
epithelium, multiplies, and is shed
• Virus is taken up and amplified by
macrophages in the skin, lymph
organs, bone marrow, and blood
• HIV attaches to CD4 and
coreceptor; HIV fuses with cell
membrane
• Reverse transcriptase makes a
DNA copy of RNA
• Viral DNA is integrated into host
chromosome
• Can produce a lytic infection or
remain latent
Nucleus
Host DNA
l
(a)
Complete dsDNA
Early dsDNA
Complete ssDNA
Early ssDNA
Translation of
viral genes
ssRNA molecules
Reverse
transcriptas
e
Steps show
activity of
one strand
of
viral DNA
Docking
and
fusion
Provirus integrated
into site on host
chromosome
The virus is adsorbed and fuses with the cell.
The twin RNAs are uncoated. Reverse transcriptase
catalyzes the synthesis of a single complementary
strand of DNA (ssDNA). This single strand serves as
a template for synthesis of a double strand (ds) of
DNA. In latency, dsDNA is inserted into the host
chromosome as a provirus.
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Multiplication Cycle of HIV
*
Nucleus
Host DNA
l
mRNA
(a) (b) (c)
Immune stimulus
Capsid
assembly
Complete dsDNA
Early dsDNA
Complete ssDNA
Early ssDNA
Translation of
viral genes
ssRNA molecules
Reverse
transcriptase
Steps show
activity of
one strand of
viral DNA
Docking and
fusion
Latent
period
Provirus integrated
into site on host
chromosome
The virus is adsorbed and fuses with the
cell. The twin RNAs are uncoated. Reverse
transcriptase catalyzes the synthesis of a
single complementary strand of DNA
(ssDNA). This single strand serves as a
template for synthesis of a double strand
(ds) of DNA. In latency, dsDNA is inserted
into the host chromosome as a provirus.
After a latent period, various immune
activators stimulate the infected cell,
causing reactivation of the provirus
genes and production of viral mRNA.
HIV mRNA is translated by the cell’s synthetic machinery
into virus components (capsid, reverse transcriptase,
spikes), and the viruses are assembled. Budding of mature
viruses lyses the infected cell.
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*
Primary effects of HIV infection:
– Extreme leukopenia – lymphocytes in particular
– Formation of giant T cells and other syncytia allowing
the virus to spread directly from cell to cell
– Infected macrophages release the virus in central
nervous system, with toxic effect, inflammation
Secondary effects of HIV:
– Destruction on CD4 lymphocytes allows for
opportunistic infections and malignancies
Effects of HIV
*
Signs and Symptoms of
HIV Infections and AIDS
• Symptoms of HIV are directly
related to viral blood level and
level of T cells
• Initial infection –
mononucleosis-like symptoms
that soon disappear
• Asymptomatic phase 2-15
years (avg. 10) – what problem
does this cause?
• HIV destroys the immune
system
• When T4 cell levels fall below
200/μL, AIDS symptoms appear
including fever, swollen lymph
nodes, diarrhea, weight loss,
neurological symptoms,
opportunistic infections, and
cancers
2 weeks
Period of infectiousness (virus present)
Exposure
Incubation
period
Symptoms
occur
II
I
I I
I
I
V
1
month
Antibody (−) Antibody (+)
Antibody
appears
in
serum
Acute
symptoms
of
HIV
infection
2−15 years Months−years
(I) Infection with virus.
(II) Appearance of antibodies in standard HIV tests.
(III) Asymptomatic HIV disease, which can encompass an
extensive time period.
(IV) Overt symptoms of AIDS include some combination of
opportunistic infections, cancers, and general loss of
immune function.
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Stages of HIV Infection
*
2
months
Level of viruses/HIV antigen
Level of antibodies to one or more
antigens
Level of CD4 T cells
>500
cells/μl
<200
cells/μl
Variable
number
Variable number of years – AIDS
2 Weeks
Infectio
n
Concentration
of
Blood
Component
• Virus levels are high during the initial acute infection and
decrease until the later phases of HIV disease and AIDS.
• Antibody levels gradually rise and remain relatively high
throughout phases III and IV.
• T-cell numbers remain relatively normal until the later
phases of HIV disease and full-blown AIDS.
I I
I
II
I
I
V
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
*
Diagnosis of HIV Infection
• Testing based on detection of antibodies specific to
the virus in serum or other fluids; done at 2 levels
• Initial screening
– ELISA, latex agglutination, and rapid antibody tests
– Rapid results but may result in false positives
• Follow up with Western blot analysis to rule out false
positives
• False negatives can also occur; persons who may
have been exposed should be tested a second time
3-6 months later
*
Diagnosis of AIDS is made when a person
meets the criteria:
1. Positive for the virus, and
2. They fulfill one of the additional criteria:
• They have a CD4 count of fewer than 200
cells/ml of blood
• Their CD4 cells account for fewer than 14% of
all lymphocytes
• They experience one or more of a CDC-provided
list of AIDS-defining illnesses
Diagnosis of AIDS
*
AIDS -Defining Illnesses
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*
Preventing and Treating HIV
• No vaccine available
– Monogamous sexual
relationships
– Condoms
– Universal precautions
• No cure; therapies slow down
the progress of the disease or
diminish the symptoms
– Inhibit viral enzymes: reverse
transcriptase, protease,
integrase
– Inhibit fusion
– Inhibit viral integration
– Highly active anti-retroviral
therapy
HIV protease
Protease inhibitor
AZT
ssRNA molecule
Cytoplasm
Location of reaction
External to cell
Reverse
transcriptase
Viral DNA
Reverse
transcriptase
No complete viral DNA
(a) Reverse transcriptase blockers.
A prominent group of drugs (AZT, ddI, 3TC) act
as nucleoside analogs to inhibit reverse
transcriptase. They are inserted in place of the
natural nucleotide by reverse transcriptase but
block further action of the enzyme and synthesis
of viral DNA.
Virus cannot produce
new infections
Defective
virus
Uncut viral proteins
(b) Protease inhibitors that cause abnormal
viruses to be released.
Protease inhibitors plug into the active sites on
HIV protease.This enzyme is necessary to cut
long HIV protein strands and produce smaller
protein units. During budding viruses incorporate
this uncut nonfunctioning protein. The resultant
viruses are unable to mount an infection.
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
*
Adult T-Cell Leukemia and
Hairy-Cell Leukemia
Leukemia is a malignant disease of the white blood
cell forming elements in bone marrow
• 2 leukemias are thought to be viral:
• Adult T-Cell leukemia – HTLV-I; signs include
cutaneous T-cell lymphoma with lymphadenopathy
and dissemination of the tumors to other organs
• HTLV II – may be a factor in certain
neurodegenerative conditions
Concept Check:
Which of the following cells is a target of HIV
infection?
A. Dendritic cells
B. Monocytes
C. Helper T cells
D. All of these can support infection
*
Nonenveloped Nonsegmented ssRNA Viruses:
Picornaviruses and Caliciviruses
• Picornaviruses
– Enterovirus –
poliovirus, HAV
– Rhinovirus –
rhinovirus
– Cardiovirus –
infects heart and
brain
Capsi
d
RNA core
(a)
(b)
© Science VU/CDC/Visuals
Unlimited
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Picornaviruses
*
*
Poliovirus and Poliomyelitis
Poliomyelitis (polio) – acute enteroviral infection
of the spinal cord that can cause neuromuscular
paralysis
• Poliovirus – naked capsid; resistant to acid,
bile, and detergents; can survive stomach acids
when ingested
• Worldwide vaccination programs have reduced
the number of cases; eradication is expected
*
• Transmitted by fecal-
oral route
• Polioviruses adhere to
receptors of mucosal
cells in oropharynx
and intestine, multiply
in number and shed in
throat and feces, some
leak into blood
• Most infections are
short-term, mild
viremia
Pathogenesis of Poliomyelitis
(a)
(c)
(d)
(b)
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
*
• Some develop mild
nonspecific symptoms of
fever, headache, nausea,
sore throat, and myalgia
• If viremia persists, virus
spreads to spinal cord and
brain
• If nervous tissue is
infected but not destroyed
– muscle pain and spasm,
meningeal inflammation,
and vague hypersensitivity
Pathogenesis of Poliomyelitis
(a)
(c)
(d)
(b)
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
*
• Invasion of motor neurons
causes flaccid paralysis
• Decades later post-polio
syndrome (PPS) –
progressive muscle
deterioration; occurs in
25-50% of patients
infected with polioviruses
in childhood
Pathogenesis of Poliomyelitis
(a)
Anterior horn
of spinal
cord
Asymptomati
c
Aseptic
meningitis
Minor non-CNS
illness
Paralyti
c
0 20
Percen
t
40 60 80 100
Anterior horn cells,
normal
© Cabisco/Visuals Unlimited
(b1)
Anterior horn cells,
damaged
© Science VU/Charles W. Stratton/Visuals
Unlimited
(b2)
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
*
Treatment and Prevention
• Treatment is largely supportive for pain and
suffering; respiratory failure may require
artificial ventilation; physical therapy may be
needed
• Prevention is vaccination:
– Inactivated polio vaccine (IPV) Salk vaccine
– Oral polio vaccine (OPV) Sabin vaccine, attenuated
virus – no longer recommended in the U.S.
• Worldwide eradication is being attempted
*
Nonpolio Enteroviruses
• Most common
– Coxsackieviruses A and B
– Echoviruses
– Nonpolioenteroviruses
• Similar to poliovirus in epidemiological and
infectious characteristics but less virulent
• Responsible for respiratory infections,
conjunctivitis, and hand-foot-mouth disease
• Rare cases of coxsackievirus and echovirus
paralysis, aseptic meningitis, and encephalitis
*
Hepatitis A Virus and Infectious
Hepatitis
• Cubical picornavirus relatively resistant to heat and acid
• Not carried chronically, principal reservoirs are
asymptomatic, short-term carriers or people with clinical
disease
• Fecal-oral transmission; multiplies in small intestine and
enters the blood and is carried to the liver
• Most infections subclinical or vague, flu-like symptoms
occur; jaundice is seldom present
*
• No specific treatment once the symptoms begin
• Inactivated viral vaccine
• Attenuated viral vaccine
• Pooled immune serum globulin for those
entering into endemic areas
Hepatitis A Virus and Infectious
Hepatitis
Concept Check:
Poliomyelitis is generally acquired via
A. Sexual Contact
B. Insect Vector
C. Ingestion
D. Inhalation
*
Human Rhinovirus (HRV)
• More than 110 serotypes
associated with the
common cold
• Unique molecular surface
makes development of a
vaccine unlikely
• Many strains circulating in
the population at one time;
acquired from
contaminated hands and
fomites
Rhinovirus
particle
Antibod
y
(b)
(a)
Knob
antigen
Pocket
antigen
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
*
• Sensitive to acidic environments; optimum
temperature is 33oC
• Headache, chills, fatigue, sore throat, cough,
nasal drainage
• Treat the symptoms
• Handwashing and care in handling nasal
secretions
Human Rhinovirus (HRV)
*
Caliciviruses
• Norwalk agent best known; believed to cause
1/3rd of all viral gastroenteritis cases
• Transmitted by fecal-oral route
• Infection in all ages at any time of year
• Acute onset, nausea, vomiting, cramps,
diarrhea, chills
• Rapid and complete recovery
*
Nonenveloped Segmented
dsRNA Viruses: Reoviruses
Unusual double-stranded RNA genome
Two best known:
• Reovirus – cold-like upper respiratory infection, enteritis
• Rotavirus – oral-fecal transmission; primary viral cause of
mortality and morbidity resulting from diarrhea in infants
and children Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
(a) (b)
Bryon Skinner/CDC From Farrar and Lambert, Pocket Guide for
Nurses: Infectious Diseases, 1984. Williams
and Wilkins, Baltimore, MD. Reprinted by
permission of Dr. William Edmund Farrar, Jr.
*
Prions and Spongiform
Encephalopathies
Prions – proteinaceous infectious particles; highly
resistant to chemicals, radiation, and heat
• Cause transmissible spongiform
encephalopathies (TSEs) in humans and
animals
– Neurodegenerative diseases with long incubation
periods
*
Prion Characteristics
*
• Creutzfeldt-Jakob Disease
(CJD) – alteration in the
structure of normal PrP protein
found in the brain
– Abnormal PrP converts normal
PrP into abnormal form
• Abnormal PrP results in nerve
cell death, spongiform
damage, and severe loss of
brain function
• Transmission is through direct
or indirect contact with infected
brain tissue or CSF
Human TSE
Neurons Glial cells
© M. Abbey/Photo Researchers, Inc.
Neuron
Spongifor
m
lesions
© Pr. J.J. Hauwl/ISM/Phototake
(a)
(b)
Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
*
• Variant CJD became apparent in the late 1990s
after eating meat from cattle afflicted with
bovine spongiform encephalopathy
• Difficult to diagnose; requires examination of
biopsied brain or nervous tissue
• Prevention relies on avoidance of contaminated
tissue
• Treatment focuses on easing symptoms
Human TSE
Concept Check:
Which of the following enzymes would degrade
the causative agent for Cruetzfeldt-Jakob?
A. Nucleases that degrade nucleic acids
B. Proteases that degrade proteins
C. Both Nucleases and Proteases
D. Neither will affect it

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Microbiology and Parasitology Lecture.pptx

  • 1. Chapter 25 The RNA Viruses That Infect Humans Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 2. Neuraminidase spike Hemagglutinin spike Envelope forming Nucleocapsids 1 2 3 4 5 6 Virus (structure shown in a cutaway view) adsorbs to a respiratory epithelial cell by hemagglutinin spikes and fuses with the membrane. The virus is endocytosed into a vacuole and uncoated to release its 8 nucleocapsid segments into the cytoplasm. (+) Sense RNA is used to synthesize glycoprotein spikes inserted into the host membrane. Release of mature virus occurs when viral parts gather at the cell membrane and are budded off with an envelope containing spikes. The (+) sense RNA strands are used to synthesize new (−) sense RNA strands. These are assembled into nucleocapsids and transported out of the nucleus to the cell membrane. The nucleocapsids are transported into the nucleus. There the (−) sense RNA strand (black) is transcribed into a (+) sense strand (red) that will be translated into viral proteins that make up the capsid and spikes. * RNA Viruses • Diverse group of microbes • Assigned to one of 12 families based on envelope, capsid, and nature of RNA genome Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 3. * Enveloped Segmented Single- Stranded RNA Viruses • Orthomyxoviruses • Bunyaviruses • Arenaviruses
  • 4. * The Biology of Orthomyxoviruses: Influenza • 3 distinct influenza virus types: A, B, C; Type A causes most infections Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 5. * Influenza Infection • Virus attaches to, and multiplies in, the cells of the respiratory tract • Segments of RNA genome enter the nucleus • Finished viruses are assembled and bud off the cell Neuraminidase spike Hemagglutinin spike Envelope forming Nucleocapsid s 1 2 3 4 5 6 Virus (structure shown in a cutaway view) adsorbs to a respiratory epithelial cell by hemagglutinin spikes and fuses with the membrane. The virus is endocytosed into a vacuole and uncoated to release its 8 nucleocapsid segments into the cytoplasm. (+) Sense RNA is used to synthesize glycoprotein spikes inserted into the host membrane. Release of mature virus occurs when viral parts gather at the cell membrane and are budded off with an envelope containing spikes. The (+) sense RNA strands are used to synthesize new (−) sense RNA strands. These are assembled into nucleocapsids and transported out of the nucleus to the cell membrane. The nucleocapsids are transported into the nucleus. There the (−) sense RNA strand (black) is transcribed into a (+) sense strand (red) that will be translated into viral proteins that make up the capsid and spikes. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 6. * • Key to influenza are glycoprotein spikes – – Hemagglutinin (H) – 15 different subtypes; most important virulence factor; binds to host cells – Neuraminidase (N) – 9 subtypes – hydrolyzes mucus and assists viral budding and release • Both glycoproteins frequently undergo genetic changes decreasing the effectiveness of the host immune response Influenza Glycoproteins Binding sites used to anchor virus to host cell receptors (low rate of mutation) Site for antibody binding (high rate of mutation) Viral envelope Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 7. * • Constant mutation is called antigenic drift – gradually change their amino acid composition • Antigenic shift – one of the genes or RNA strands is substituted with a gene or strand from another influenza virus from a different animal host – Genome of virus consists of 10 genes encoded on 8 separate RNA strands Influenza Mutation Human influenza virus With duck HA spike HA RNA NA RNA NA RNA HA RNA HA NA Human influenza virus Duck influenza virus Immune system has no recall for duck antigens Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 8. * Influenza B • Only undergo antigenic drift • Not known to undergo antigenic shift Influenza C • Known to cause only minor respiratory disease; probably not involved in epidemics Influenza Strains
  • 9. * Influenza A • Acute, highly contagious respiratory illness • Seasonal, pandemics; among top 10 causes of death in U.S. – most commonly among elderly and small children • Binds to ciliated cells of respiratory mucosa • Causes rapid shedding of cells, stripping the respiratory epithelium; severe inflammation • Fever, headache, myalgia, pharyngeal pain, shortness of breath, coughing • Weakened host defenses predispose patients to secondary bacterial infections, especially pneumonia
  • 10. * Diagnosis, Treatment, Prevention • Rapid immunofluorescence tests to detect antigens in a pharyngeal specimen; serological testing to screen for antibody titer • Treatment: control symptoms; amantadine, rimantadine, zanamivir (Relenza), and oseltamivir (Tamiflu) • Flu virus has developed high rate of resistance to amantadine and rimantadine • Annual trivalent vaccine recommended – especially for health workers
  • 11. * Bunyaviruses and Arenaviruses • Transmitted zoonotically; cause periodic epidemics; extremely dangerous; biosafety level 4 viruses Bunyaviruses – transmitted by insects and ticks – California encephalitis, Rift Valley fever, Korean hemorrhagic fever – American bunyavirus is a hantavirus, Sin Nombre – emerging disease; high fever, lung, edema, and pulmonary failure; 33% mortality rate • Carried by deer and harvest mice; transmitted via airborne dried animal waste Arenaviruses • Lassa fever, Argentine hemorrhagic fever, Bolivian hemorrhagic fever, and Lymphocytic choriomeningitis • Closely associated with rodent host • Transmission through aerosols and contact
  • 12. Concept Check: Which of these happen(s) in the case of antigenic shift in influenza A? A. Single mutations in hemagglutinin B. Recombination of RNA segments between bird and human strains C. Change from influenza A to influenza B D. Both A and B
  • 13. * Enveloped Nonsegmented ssRNA Viruses • Paramyxoviruses • Rhabdoviruses • Filoviruses • Togaviruses • Flaviviruses • Coronaviruses
  • 14. * Paramyxoviruses Paramyxoviruses (parainfluenza, mumps virus) Morbillivirus (measles virus) Pneumovirus (respiratory syncytia virus) • Respiratory transmission • Envelope has glycoprotein and F spikes that initiate cell-to-cell fusion • Fusion with neighboring cells – syncytium or multinucleate giant cells form Uncoatin g Point of cell fusion Host cell2 Host cell1 Host cell3 Paramyxovirus Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 15. * Parainfluenza • Widespread as influenza but more benign • Respiratory transmission • Seen mostly in children • Minor cold, bronchitis, bronchopneumonia, croup • No specific treatment available; supportive therapy
  • 16. * Mumps • Epidemic parotitis; self-limited, associated with painful swelling of parotid salivary glands Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. © Biophoto Associates/Photo Researchers, Inc.
  • 17. * Mumps • Humans are the only reservoir • 40% of infections are subclinical; long-term immunity • 300 cases in U.S./year • Incubation 2-3 weeks fever, muscle pain and malaise, classic swelling of one or both cheeks • Usually uncomplicated invasion of other organs; in 20-30% of infected adult males, epididymis and testes become infected; sterility is rare • Symptomatic treatment • Live attenuated vaccine MMR
  • 18. * Measles • Caused by Morbillivirus • Also known as red measles and rubeola • Different from German measles • Very contagious; transmitted by respiratory aerosols • Humans are the only reservoir • Less than 100 cases/yr in U.S.; frequent cause of death worldwide Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 19. * Measles • Virus invades respiratory tract • Sore throat, dry cough, headache, conjunctivitis, lymphadenitis, fever, Koplik spots – oral lesions • Exanthem Koplik’s spots CDC CDC (a) (b) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 20. * Measles • Most serious complication is subacute sclerosing panencephalitis (SSPE), a progressive neurological degeneration of the cerebral cortex, white matter, and brain stem – 1 case in a million infections – very rare – Involves a defective virus spreading through the brain by cell fusion and destroys cells – Leads to coma and death in months or years • Attenuated viral vaccine MMR
  • 21. * Respiratory Syncytial Virus (RSV) • Also called Pneumovirus • Infects upper respiratory tract and produces giant multinucleate cells • Most prevalent cause of respiratory infection in children 6 months or younger; most susceptible to serious disease • Epithelia of nose and eye portal of entry; replicates in nasopharynx • Fever, rhinitis, pharyngitis, otitis, croup • Treatment: synagis, a monoclonal antibody that blocks attachment, ribavirin
  • 22. * Rabies • Rhabdovirus family; genus Lyssavirus • Enveloped, bullet-shaped virions • Slow, progressive zoonotic disease • Primary reservoirs are wild mammals; it can be spread by both wild and domestic mammals by bites, scratches, and inhalation of droplets Glycoprotein spikes Matrix protein Nucleocapsid (a) (b) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. CDC
  • 23. Rabies Distribution in the United States * Fo x Skunk Raccoo n Fo x Coyot e Coyot e Skun k Skunk Skunk Fo x Fo x Raccoo n Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 24. * Rabies • Virus enters through bite, grows at trauma site for a week and multiplies, then enters nerve endings and advances toward the ganglia, spinal cord and brain • Infection cycle completed when virus replicates in the salivary glands Clinical phases of rabies: • Prodromal phase – fever, nausea, vomiting, headache, fatigue; some experience pain, burning, tingling sensations at site of wound • Furious phase – agitation, disorientation, seizures, twitching, hydrophobia • Dumb phase – paralyzed, disoriented, stuporous • Progress to coma phase, resulting in death
  • 25. * • Often diagnosed at autopsy – intracellular inclusions (Negri bodies) in nervous tissue • Bite from wild or stray animals demands assessment of the animal, meticulous wound care, and specific treatment • Preventive therapy initiated if signs of rabies appear • Treatment – passive and active postexposure immunization – Infuse the wound with human rabies immune globulin (HRIG) and globulin; vaccination with human diploid cell vaccine (HDCV), an inactivated vaccine given in 6 doses with 2 boosters • Control – vaccination of domestic animals, elimination of strays, and strict quarantine practices – Live oral vaccine incorporated into bait for wild animals Rabies
  • 26. Concept Check: For which disease are active and passive immunization given simultaneously? A. Influenza B. Yellow Fever C. Measles D. Rabies
  • 27. * Coronaviruses • Relatively large RNA viruses with distinctively spaced spikes on their envelopes • Common in domesticated animals • 3 types of human coronaviruses have been characterized: – HCV causes a cold – An enteric virus – Severe Acute Respiratory Syndrome (SARS) • Airborne transmission • 9% of cases fatal
  • 28. * Severe Acute Respiratory Syndrome- Associated Coronavirus (SARS) • Newly emerging disease – 2002 • Transmitted through droplet or direct contact • Fever, body aches, and malaise • May or may not experience respiratory symptoms with breathing problems; severe cases can result in respiratory distress and death • Diagnosis relies on exclusion of other likely agents • Treatment is supportive
  • 29. * Rubella • Caused by Rubivirus, a Togavirus • ssRNA with a loose envelope • German measles • Endemic disease • Most cases reported are adolescents and young adults • Transmitted through contact with respiratory secretions • Diagnosis based on serological testing • No specific treatment available • Attenuated viral vaccine MMR
  • 30. * Rubella Two clinical forms: • Postnatal rubella – malaise, fever, sore throat, lymphadenopathy, rash, generally mild, lasting about 3 days • Congenital rubella – infection during 1st trimester most likely to induce miscarriage or multiple defects such as cardiac abnormalities, ocular lesions, deafness, mental and physical retardation Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. © James Stevenson/Photo Researchers, Inc.
  • 31. * Hepatitis C Virus (HCV) • Flavivirus • Acquired through blood contact – blood transfusions, needle sharing by drug abusers • Infections with varying characteristics – 75-85% will remain infected indefinitely; possible to have severe symptoms without permanent liver damage; more common to have chronic liver disease, without overt symptoms • Cancer may also result from chronic HCV infection • Treatment with interferon and ribavirin to lessen liver damage; no cure • No vaccine
  • 32. * Arboviruses: Viruses Spread by Arthropod Vectors • Mosquitoes, ticks, flies, and gnats • 400 viruses • Togaviruses, flaviviruses, some bunyaviruses and reoviruses • Most illnesses caused by these viruses are mild fevers; some may cause severe encephalitis, and life-threatening hemorrhagic fever
  • 33. * The Influence of the Vector • Vectors and viruses tend to be clustered in the tropics and subtropics; many temperate zones have periodic epidemics • Arbovirus life cycles are closely tied to the ecology of the vectors • Infections show a peak incidence when the arthropod is actively feeding and reproducing • Humans can serve as dead-end, accidental hosts or they can be a maintenance reservoir • Controlling the vector controls the disease
  • 34. Worldwide Distribution of Major Arboviral Diseases * West Nile fever (outlined areas) Yellow fever Dengue fever St. Louis encephalitis Japanese encephalitis WEE Western equine encephalitis EEE Eastern equine encephalitis VEE Venezuelan equine encephalitis Shows relatively restricted distribution Ross River fever Murray Valley encephaliti s Omsk fever LaCrosse encephaliti s EEE VEE Congolian hemorrhagi c fever Rift Valley fever Kyasanur fever Roci o fever Mayar o fever Colorad o tick fever WEE Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 35. * General Characteristics of Arbovirus Infections • Acute arbovirus infection may result in undifferentiated mild fever with rash; no long- term effects; prominent symptoms are fever, headache, myalgia, joint stiffness, rash • Viral encephalitis – brain, meninges, and spinal cord are involved; convulsions, tremor, paralysis, loss of coordination, memory deficits, changes in speech and personality, coma; survivors may experience permanent brain damage
  • 36. * • Colorado tick fever (CTF) – most common tick-borne viral fever in U.S.; Rocky Mountain states • Western equine encephalitis (WEE) – western U.S. and Canada; extremely dangerous to infants and small children • Eastern equine encephalitis (EEE) – eastern U.S. and Canada • California encephalitis – 2 different strains: – California strain – western states; little human impact – LaCrosse strain – eastern U.S. and Canada; prevalent cause of viral encephalitis • St. Louis encephalitis (SLE) – most common of all in America; epidemics in midwestern and southern states; inapparent infections are very common • West Nile encephalitis Arbovirus Infections in the USA
  • 37. * Hemorrhagic Fevers Yellow fever – eliminated in U.S. • Two patterns of transmission: – Urban cycle – humans and mosquitoes, Aedes aegypti – Sylvan cycle – forest monkeys and mosquitoes; South America • Acute fever, headache, muscle pain; may progress to oral hemorrhage, nosebleed, vomiting, jaundice, and liver and kidney damage; significant mortality rate Dengue fever – flavivirus carried by Aedes mosquito; not in U.S.; usually mild infection – Dengue hemorrhagic shock syndrome, breakbone fever – extreme muscle and joint pain; can be fatal
  • 38. Concept Check: Rubella is a serious infection for both children and adults. A. True B. False
  • 39. * HIV Infections and AIDS • Human immunodeficiency virus • Acquired immunodeficiency syndrome • First emerged in early 1980s • HIV-1 may have originated from a chimpanzee virus – or maybe….. • 1959 first documented case of AIDS
  • 40. GP-120 GP-41 Capsid Protease molecule (b) (a) HIV GP-41 GP-120 RNAstrands Integrase molecules Reverse transcriptase molecules Antireceptor spikes CD4 receptor on white blood cell Co-receptor on white blood cell * Human Immunodeficiency Virus (HIV) • Retrovirus, genus Lentivirus • Encode reverse transcriptase enzyme which makes a double stranded DNA from the single-stranded RNA genome • Viral genes permanently integrated into host DNA • The cause of Acquired Immunodeficiency Syndrome (AIDS) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 41. * Causative Agent • HIV-1 and HIV-2 • T-cell lymphotropic viruses I and II – leukemia and lymphoma • HIV can only infect host cells that have the required CD4 marker plus a coreceptor HIV GP-41 GP-120 Antireceptor spikes CD4 receptor on white blood cell Co-receptor on white blood cell Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 42. Blood exposure through needles Lacerations Direct blood exposure, during sexual intercourse or other intimate contact Semen, vaginal fluid exposure during sexual intercourse Infected macrophage Microscopic view of process Dendritic cells underlying skin shelter and amplify virus Spread of virus to lymphatic organs, bone marrow, circulation Membrane or skin portal of entry * Epidemiology of HIV Infections • Transmission occurs by direct and specific routes: mainly through sexual intercourse and transfer of blood or blood products; babies can be infected before or during birth, and from breast feeding • HIV does not survive long outside of the body – good! Epithelial cell Infected blood Infected sexual secretions HIV Infected white blood cells Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 43. (b) *Numbers are rounded. 26% White 54% Black 19% Hispanic 1% Other 75% Men 42% MSM 25% IDU Children < 13 are 0.4% (a) Total HIV infections and AIDS diagnoses, by age group as of 2009* 43% Age 35−49 38% Age 20−34 16% Age 50−64 0.5% Age 13−19 2% Age >65 25% Women Estimates of 2009 new infections by race (N > 56,000) Estimates of 2009 new infections by race (N > 56,000) MSM: Male to male sexual contact. IDU: Intravenous drug users. Estimates of 2009 new infections by risk (N > 56,000) 33% Heterosexual * • First nationally notifiable in 1984 • 6th most common cause of death among people aged 25-44 years in the U.S. • Men account for 75% of new infections • IV drug abusers can be HIV carriers; significant factor in spread to heterosexual population • In 2009, the number of infected individuals worldwide is estimated to be 35 million with ~1.2 million in the U.S. Epidemiology of HIV Infection Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 44. * Pathogenesis and Virulence Factors • HIV enters through mucous membrane or skin and travels to dendritic phagocytes beneath the epithelium, multiplies, and is shed • Virus is taken up and amplified by macrophages in the skin, lymph organs, bone marrow, and blood • HIV attaches to CD4 and coreceptor; HIV fuses with cell membrane • Reverse transcriptase makes a DNA copy of RNA • Viral DNA is integrated into host chromosome • Can produce a lytic infection or remain latent Nucleus Host DNA l (a) Complete dsDNA Early dsDNA Complete ssDNA Early ssDNA Translation of viral genes ssRNA molecules Reverse transcriptas e Steps show activity of one strand of viral DNA Docking and fusion Provirus integrated into site on host chromosome The virus is adsorbed and fuses with the cell. The twin RNAs are uncoated. Reverse transcriptase catalyzes the synthesis of a single complementary strand of DNA (ssDNA). This single strand serves as a template for synthesis of a double strand (ds) of DNA. In latency, dsDNA is inserted into the host chromosome as a provirus. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 45. Multiplication Cycle of HIV * Nucleus Host DNA l mRNA (a) (b) (c) Immune stimulus Capsid assembly Complete dsDNA Early dsDNA Complete ssDNA Early ssDNA Translation of viral genes ssRNA molecules Reverse transcriptase Steps show activity of one strand of viral DNA Docking and fusion Latent period Provirus integrated into site on host chromosome The virus is adsorbed and fuses with the cell. The twin RNAs are uncoated. Reverse transcriptase catalyzes the synthesis of a single complementary strand of DNA (ssDNA). This single strand serves as a template for synthesis of a double strand (ds) of DNA. In latency, dsDNA is inserted into the host chromosome as a provirus. After a latent period, various immune activators stimulate the infected cell, causing reactivation of the provirus genes and production of viral mRNA. HIV mRNA is translated by the cell’s synthetic machinery into virus components (capsid, reverse transcriptase, spikes), and the viruses are assembled. Budding of mature viruses lyses the infected cell. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 46. * Primary effects of HIV infection: – Extreme leukopenia – lymphocytes in particular – Formation of giant T cells and other syncytia allowing the virus to spread directly from cell to cell – Infected macrophages release the virus in central nervous system, with toxic effect, inflammation Secondary effects of HIV: – Destruction on CD4 lymphocytes allows for opportunistic infections and malignancies Effects of HIV
  • 47. * Signs and Symptoms of HIV Infections and AIDS • Symptoms of HIV are directly related to viral blood level and level of T cells • Initial infection – mononucleosis-like symptoms that soon disappear • Asymptomatic phase 2-15 years (avg. 10) – what problem does this cause? • HIV destroys the immune system • When T4 cell levels fall below 200/μL, AIDS symptoms appear including fever, swollen lymph nodes, diarrhea, weight loss, neurological symptoms, opportunistic infections, and cancers 2 weeks Period of infectiousness (virus present) Exposure Incubation period Symptoms occur II I I I I I V 1 month Antibody (−) Antibody (+) Antibody appears in serum Acute symptoms of HIV infection 2−15 years Months−years (I) Infection with virus. (II) Appearance of antibodies in standard HIV tests. (III) Asymptomatic HIV disease, which can encompass an extensive time period. (IV) Overt symptoms of AIDS include some combination of opportunistic infections, cancers, and general loss of immune function. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 48. Stages of HIV Infection * 2 months Level of viruses/HIV antigen Level of antibodies to one or more antigens Level of CD4 T cells >500 cells/μl <200 cells/μl Variable number Variable number of years – AIDS 2 Weeks Infectio n Concentration of Blood Component • Virus levels are high during the initial acute infection and decrease until the later phases of HIV disease and AIDS. • Antibody levels gradually rise and remain relatively high throughout phases III and IV. • T-cell numbers remain relatively normal until the later phases of HIV disease and full-blown AIDS. I I I II I I V Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 49. * Diagnosis of HIV Infection • Testing based on detection of antibodies specific to the virus in serum or other fluids; done at 2 levels • Initial screening – ELISA, latex agglutination, and rapid antibody tests – Rapid results but may result in false positives • Follow up with Western blot analysis to rule out false positives • False negatives can also occur; persons who may have been exposed should be tested a second time 3-6 months later
  • 50. * Diagnosis of AIDS is made when a person meets the criteria: 1. Positive for the virus, and 2. They fulfill one of the additional criteria: • They have a CD4 count of fewer than 200 cells/ml of blood • Their CD4 cells account for fewer than 14% of all lymphocytes • They experience one or more of a CDC-provided list of AIDS-defining illnesses Diagnosis of AIDS
  • 51. * AIDS -Defining Illnesses Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 52. * Preventing and Treating HIV • No vaccine available – Monogamous sexual relationships – Condoms – Universal precautions • No cure; therapies slow down the progress of the disease or diminish the symptoms – Inhibit viral enzymes: reverse transcriptase, protease, integrase – Inhibit fusion – Inhibit viral integration – Highly active anti-retroviral therapy HIV protease Protease inhibitor AZT ssRNA molecule Cytoplasm Location of reaction External to cell Reverse transcriptase Viral DNA Reverse transcriptase No complete viral DNA (a) Reverse transcriptase blockers. A prominent group of drugs (AZT, ddI, 3TC) act as nucleoside analogs to inhibit reverse transcriptase. They are inserted in place of the natural nucleotide by reverse transcriptase but block further action of the enzyme and synthesis of viral DNA. Virus cannot produce new infections Defective virus Uncut viral proteins (b) Protease inhibitors that cause abnormal viruses to be released. Protease inhibitors plug into the active sites on HIV protease.This enzyme is necessary to cut long HIV protein strands and produce smaller protein units. During budding viruses incorporate this uncut nonfunctioning protein. The resultant viruses are unable to mount an infection. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 53. * Adult T-Cell Leukemia and Hairy-Cell Leukemia Leukemia is a malignant disease of the white blood cell forming elements in bone marrow • 2 leukemias are thought to be viral: • Adult T-Cell leukemia – HTLV-I; signs include cutaneous T-cell lymphoma with lymphadenopathy and dissemination of the tumors to other organs • HTLV II – may be a factor in certain neurodegenerative conditions
  • 54. Concept Check: Which of the following cells is a target of HIV infection? A. Dendritic cells B. Monocytes C. Helper T cells D. All of these can support infection
  • 55. * Nonenveloped Nonsegmented ssRNA Viruses: Picornaviruses and Caliciviruses • Picornaviruses – Enterovirus – poliovirus, HAV – Rhinovirus – rhinovirus – Cardiovirus – infects heart and brain Capsi d RNA core (a) (b) © Science VU/CDC/Visuals Unlimited Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 57. * Poliovirus and Poliomyelitis Poliomyelitis (polio) – acute enteroviral infection of the spinal cord that can cause neuromuscular paralysis • Poliovirus – naked capsid; resistant to acid, bile, and detergents; can survive stomach acids when ingested • Worldwide vaccination programs have reduced the number of cases; eradication is expected
  • 58. * • Transmitted by fecal- oral route • Polioviruses adhere to receptors of mucosal cells in oropharynx and intestine, multiply in number and shed in throat and feces, some leak into blood • Most infections are short-term, mild viremia Pathogenesis of Poliomyelitis (a) (c) (d) (b) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 59. * • Some develop mild nonspecific symptoms of fever, headache, nausea, sore throat, and myalgia • If viremia persists, virus spreads to spinal cord and brain • If nervous tissue is infected but not destroyed – muscle pain and spasm, meningeal inflammation, and vague hypersensitivity Pathogenesis of Poliomyelitis (a) (c) (d) (b) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 60. * • Invasion of motor neurons causes flaccid paralysis • Decades later post-polio syndrome (PPS) – progressive muscle deterioration; occurs in 25-50% of patients infected with polioviruses in childhood Pathogenesis of Poliomyelitis (a) Anterior horn of spinal cord Asymptomati c Aseptic meningitis Minor non-CNS illness Paralyti c 0 20 Percen t 40 60 80 100 Anterior horn cells, normal © Cabisco/Visuals Unlimited (b1) Anterior horn cells, damaged © Science VU/Charles W. Stratton/Visuals Unlimited (b2) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 61. * Treatment and Prevention • Treatment is largely supportive for pain and suffering; respiratory failure may require artificial ventilation; physical therapy may be needed • Prevention is vaccination: – Inactivated polio vaccine (IPV) Salk vaccine – Oral polio vaccine (OPV) Sabin vaccine, attenuated virus – no longer recommended in the U.S. • Worldwide eradication is being attempted
  • 62. * Nonpolio Enteroviruses • Most common – Coxsackieviruses A and B – Echoviruses – Nonpolioenteroviruses • Similar to poliovirus in epidemiological and infectious characteristics but less virulent • Responsible for respiratory infections, conjunctivitis, and hand-foot-mouth disease • Rare cases of coxsackievirus and echovirus paralysis, aseptic meningitis, and encephalitis
  • 63. * Hepatitis A Virus and Infectious Hepatitis • Cubical picornavirus relatively resistant to heat and acid • Not carried chronically, principal reservoirs are asymptomatic, short-term carriers or people with clinical disease • Fecal-oral transmission; multiplies in small intestine and enters the blood and is carried to the liver • Most infections subclinical or vague, flu-like symptoms occur; jaundice is seldom present
  • 64. * • No specific treatment once the symptoms begin • Inactivated viral vaccine • Attenuated viral vaccine • Pooled immune serum globulin for those entering into endemic areas Hepatitis A Virus and Infectious Hepatitis
  • 65. Concept Check: Poliomyelitis is generally acquired via A. Sexual Contact B. Insect Vector C. Ingestion D. Inhalation
  • 66. * Human Rhinovirus (HRV) • More than 110 serotypes associated with the common cold • Unique molecular surface makes development of a vaccine unlikely • Many strains circulating in the population at one time; acquired from contaminated hands and fomites Rhinovirus particle Antibod y (b) (a) Knob antigen Pocket antigen Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 67. * • Sensitive to acidic environments; optimum temperature is 33oC • Headache, chills, fatigue, sore throat, cough, nasal drainage • Treat the symptoms • Handwashing and care in handling nasal secretions Human Rhinovirus (HRV)
  • 68. * Caliciviruses • Norwalk agent best known; believed to cause 1/3rd of all viral gastroenteritis cases • Transmitted by fecal-oral route • Infection in all ages at any time of year • Acute onset, nausea, vomiting, cramps, diarrhea, chills • Rapid and complete recovery
  • 69. * Nonenveloped Segmented dsRNA Viruses: Reoviruses Unusual double-stranded RNA genome Two best known: • Reovirus – cold-like upper respiratory infection, enteritis • Rotavirus – oral-fecal transmission; primary viral cause of mortality and morbidity resulting from diarrhea in infants and children Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display. (a) (b) Bryon Skinner/CDC From Farrar and Lambert, Pocket Guide for Nurses: Infectious Diseases, 1984. Williams and Wilkins, Baltimore, MD. Reprinted by permission of Dr. William Edmund Farrar, Jr.
  • 70. * Prions and Spongiform Encephalopathies Prions – proteinaceous infectious particles; highly resistant to chemicals, radiation, and heat • Cause transmissible spongiform encephalopathies (TSEs) in humans and animals – Neurodegenerative diseases with long incubation periods
  • 72. * • Creutzfeldt-Jakob Disease (CJD) – alteration in the structure of normal PrP protein found in the brain – Abnormal PrP converts normal PrP into abnormal form • Abnormal PrP results in nerve cell death, spongiform damage, and severe loss of brain function • Transmission is through direct or indirect contact with infected brain tissue or CSF Human TSE Neurons Glial cells © M. Abbey/Photo Researchers, Inc. Neuron Spongifor m lesions © Pr. J.J. Hauwl/ISM/Phototake (a) (b) Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.
  • 73. * • Variant CJD became apparent in the late 1990s after eating meat from cattle afflicted with bovine spongiform encephalopathy • Difficult to diagnose; requires examination of biopsied brain or nervous tissue • Prevention relies on avoidance of contaminated tissue • Treatment focuses on easing symptoms Human TSE
  • 74. Concept Check: Which of the following enzymes would degrade the causative agent for Cruetzfeldt-Jakob? A. Nucleases that degrade nucleic acids B. Proteases that degrade proteins C. Both Nucleases and Proteases D. Neither will affect it