viral Flashcards
basic virus structure
•DNA or RNA forms the core, which is surrounded by a
protein coat.
•Protein coat or capsid comprises protein units or
capsomeres
•Together the nucleic acid core and capsid form the
nucleocapsid
•In some viruses, the nucleocapsid is surrounded by an
- *envelope, a lipid bilayer of host cell origin**.
- envelope is studded with virus-encoded glycoproteins.
‘spikes’ in the viral envelope
attach virus to cell surface
mediate virus entry into cells
targets for antibodies
has carbohydrate side chain & transmembrane anchor
viral life cycle
extracellular phase in which virus particle
(“virion”) is metabolically inert and
intracellular phase in which virus genome
expression occurs; this, together with
involvement of host proteins (animal, plant or bacteria)
and other host functions, achieves production of
new progeny virions.
Viruses are obligate intracellular pathogens
enveloped vs nonenveloped
Non-enveloped “naked” viruses tend to survive well
(& may be bile resistant)
– e.g_. picorna (polio; hepatitis A) norovirus_
• Enveloped viruses often survive transiently outside
host. Spread by close or intimate contact
– e.g_. Influenza, HIV, Hepatitis B virus_
virus classification criteria
- Type of nucleic acid (DNA or RNA).
- • Symmetry of nucleocapsid
- • Lipid envelope (presence or absence).
- • Number of strands of nucleic acid (ss/ds) & their physical construction (e.g. segmented)
- • Polarity of viral genome (e.g. + or - strand RNA).
DNA viruses
enveloped:
poxvirus
baculovirus
herpesvirus
naked:
adenovirus
viral replication steps
- Attachment - to susceptible target cells
- Penetration - to cell interior (traverse membrane)
- Uncoating - primes for transcription
-
Transcription - production of viral RNA
* *5. Translation** - viral proteins produced - Replication - DNA or RNA, driven by viral proteins
- Assembly - new virions formed
- Release - & dissemination or transmission
key point: many critical functions and activities
are provided by the infected hos cell
how DNA virus replicates its genome
DNA viruses with large genomes e.g. poxviruses, herpesviruses encode 100 or more genes, including many of the enzymes required for genomic
replication (e.g. DNA polymerase) and are
more “autonomous”
DNA Viruses with small genomes e.g. papillomaviruses
encode only a few genes and use the host cell DNA polymerase etc
how RNA viruses replicate
Most RNA viruses encode their own
RNA-dependent RNA polymerase,
which uses complementary RNA as template
- *Retroviruses (& DNA Hepadnaviruses) ** encode Reverse Transcriptase - RNA-dependent DNA polymerase =>
- make dsDNA from RNA, for new genome synthesis
RNA dependent polymerases lack proofreading ability,
→ RNA viruses mutate quickly (& often replicate faster)
PLUS-STRAND RNA
Positive-stranded RNA is:
equivalent to mRNA and can often be immediately translated into proteins once the viral genome gains entry into the cytoplasm.
Therefore, protein synthesis is the first step, and
_one of the proteins synthesized is the viral
polymerase._The _polymerase then synthesizes
a *negative-strand copy of the +veRNA*, which is
then copied back into +veRNA messages._
Translation of these messages produces
structural proteins that are used to package
progeny +veRNA into virions.
MINUS-STRAND RNA
Negative-stranded RNA:
must first be converted into +veRNA (mRNA) by the RNA-dependent RNA polymerase (RDRP) incorporated in the virion.
The mRNA can then be translated into proteins.
Replicative enzymes (RDRP) synthesize a negative-strand copy of the +veRNA.
Structural proteins translated from the mRNA are
then used to package progeny -veRNA and RDRP into virions.
These types of viruses must package a polymerase into the viral capsid, because cells lack enzymes that will make a +veRNA copy of the viral -veRNA strand.
outcome after viral infection of cell
- *• Clearance** following acute phase of cell death
e. g. influenza, viral gastroenteritis, poliovirus, measles
• Persistent infection with continued production of infectious virus and immune evasion
e.g. hepatitis B, HIV
• Latent infection with virus persistence after initial clearance, and asymptomatic or symptomatic reactivation
e.g. Herpes viruses – herpes simplex, varicella zoster
latent virus infections
Viral DNA persists but does not replicate to
produce new infectious virus
• May never cause signs of disease.
• May activate on one or more occasions, and be
asymptomatic or cause disease.
• Some latent infections may lead to malignant
disease.
exposure
potential physical contact with virus
tropism
which cells/tissues (or host) are susceptible?
virulence
capacity to cause disease
VIral pathogenesis mechanisms
Cell death:
- Lytic infection, apoptosis,
- Immune mediated e.g. AIDS is attributable to the progressive loss of helper T cells
Interference with cellular function
– hepatitis, myocarditis, neuralgia
Body’s response to cell damage
– INCREASED mucous production in respiratory tract infections
Cell transformation and oncogenesis
Local effects of the immune response
– swelling, congestion, arthropathy, rashes
Systemic effects of the immune response
– fever
Immunosuppression
– Cytomegalovirus
– Measles
Triggering autoimmune response
– post-infectious encephalomyelitis
Defence:
Innate mechanisms
macrophages, neutrophils, NK, complement, interferon
defence: antibodies do what?
neutralise further spread
Viral mechanisms of Immune Evasion
Interference with cytokine network
mimic cytokine receptors - poxviruses
mimic inhibitory cytokines - EBV
inhibit interferon - adenovaccinia, influenza
suppress m-derived cytokines- measles
immune escape - antigen variation
mutation of epitopes RNA viruses > DNA viruses
antigenic “shift”/reassortment : influenza virus
ECLIPSE PHASE
Period from virus entry until new infectious virions released
INCUBATION PERIOD
Interval between exposure and appearance of rash/sign
PRODROME
Non-specific symptoms appearing before more specific features (usually rash)
REPRODUCTIVE NO R0
INFECTIOUSNESS
Average number of secondary cases arising from a single index
case in a totally susceptible population
family HERPESVIRIDAE
Structure
• Members share common architecture →
morphologically identical under EM
• Large double-stranded DNA genome
– EBV 162 kB; CMV 360 kB
• Icosahedral capsid
• Lipid envelope derived from host cell bearing
virus-encoded glycoproteins
Over 100 herpesviruses have been identified
• Biological properties and genomic structure
Sub-families alpha-, beta-, gamma- herpesvirinae
• Viruses of each species are numbered in
chronological order of discovery
• Eight human herpes viruses have been identified to
date
Herpesviruses species
Alphaherpesvirinae:
Herpes simplex virus type 1 HSV-1
Herpes simplex virus type 2 HSV-2
Varicella zoster virus VZV
Betaherpesvirinae
Cytomegalovirus CMV
Human herpesvirus 6 HHV-6
Human herpesvirus 7 HHV-7
Gammaherpesvirinae
Epstein-Barr virus EBV
Human herpes virus 8 HHV-8
natural history of herpes v infections
• Primary infections are frequently asymptomatic
• Virus is not cleared but persists in a latent state
• Reactivation may be clinical or sub-clinical
• Infection is usually widespread in the natural
host
Seropositive status indicates____
infection, not immunity
antiviral agents do what against herpes viruses?
e.g. Aciclovir, Ganciclovir can control
productive herpes virus infections but cannot
eradicate/control latent infection
what does varicella zoster virus do?
• Primary infection causes chickenpox
(varicella)
• Latent in dorsal root or cranial nerve
ganglia
• Reactivation causes shingles (zoster)
• During reactivation virus travels down
sensory nerves and produce painful
vesicles in the area of skin served by
infected ganglion
P{rimary VZV infection
Peak incidence in early childhood
• Only 5% over 18’s remain susceptible in
temperate zones
• 50% over 24 year olds in the tropics are
susceptible
• Incidence of varicella high in susceptible visitors
to temperate zones
varicella clinical features
• Incubation period 10-21d
• Asymptomatic infection uncommon
• Prodromal symptoms: fever, pharyngitis, malaise
• Itchy/painful lesions appear in crops
• Macule →papule → vesicle → pustule → crusts
• More severe in adults / immunocompromised
• Varicella vaccine is licensed for routine childhood
immunisation in the USA
varicella complications
Children
Acute cerebellar ataxia - 1:4000 cases (15y)
Adults
Pneumonia - 1:400 cases > hospital admission
Zoster
Common condition
• Reactivation of latent VZV
• Pain at site may precede eruption of painful
vesicles
• Unilateral; 1-2 dermatomes involved
• _Ophthalmic division of trigeminal nerve →
involvement of eye in 50%_
• Post-herpetic neuralgia especially in the elderly
• Incidence increases with age and in the i.c. host
• Immunocompetent rarely suffer at most 2 attacks
decades apart during a lifetime
zoster in immunocompromised host
More severe, extensive, prolonged rash.
Risk of disseminated infection
6-10 days after onset of localised rash
- cutaneous
- visceral
pneumonitis; hepatitis; meningoencephalitis
VZV horicontal transmission
• Varicella is spread by respiratory route,
commencing 48h before onset of rash.
• Skin lesions of varicella and zoster are
infectious until crusted over.
VZV vertical transmission
Congenital Varicella
Maternal varicella in the first 20 weeks of gestation
results in foetal defects in <2% of cases.
Maternal shingles does not damage the foetus
Neonatal Varicella
_Maternal varicella occurring within 7 days before or 7
days after delivery_is associated with a high mortality in
the newborn infant
Post-exposure prophylaxis
Varicella zoster hyperimmune globulin - VZIG
Indicated for susceptible individuals at risk of severe
VZV infection following a significant exposure
incident
• Pregnant
• Immunosuppressed
• Neonate of seronegative mother
VZV antiviral therapy?
• Not routine in uncomplicated childhood
varicella
• Advised for varicella in adults and in
immunocompromised individuals
• Recommended for treatment of zoster
• Ophthalmic zoster: mandatory
ophthalmological assessment
VZV first line treatment
Aciclovir po or iv
Valaciclovir po
• Famciclovir po
These are also the first line agents for HSV, but as
VZV is less susceptible, higher doses are required
Oka varicella vaccine
• Live attenuated vaccine
• Part of routine childhood vaccination
schedule in USA
• 2 dose schedule
• Recommended in UK for
– susceptible healthcare workers
– Susceptible household contacts of
immunocompromised patients
Viruses in general often interfere with immune system processes
HIV
EBV
HSV
- HIV overwhelmingly most important
- Uses CD4 molecule to invade host cell : T-cells, also macrophages and glial cells
- Also uses chemokine receptors CCR5/ CXCR4
- Decline in CD4+ cell numbers inexorable whilst virus proliferates
- Major defects in immunity follow loss of CD4 T cells: Lower IL-2, INF, B cell growth factors
Epstein Barr virus (EBV) : infects B cells and causes random proliferation
Herpes simplex virus (HSV): down-regulates MHC in the cells it infects
retrovirus
enveloped
RNA
ss+
icosahedral
orthomyxovirus
enveloped
RNA
ss-
helical
herpesvirus
enveloped
DNA
ds
icosohedral
DNA viruses
- poxoviridae
- herpesviridae
- adenoviridae
- hepadenaviridae
- papovaviridae
- parvoviridae
