Title: Virology Lecture 4 The Herpesviruses Dr Mike Kotiw Ref: Sherris p503518
1Virology Lecture 4 The HerpesvirusesDr Mike
KotiwRef Sherris p503-518
2Lecture aims
- To be aware of the members of the herpesviridae
- To be able to describe the general structure of
Herpes Simplex viruses - To be able to describe how Herpes Simplex viruses
are classified - To be able to describe how a Herpes Simplex virus
may be diagnosed - To understand the pathogenesis of Herpes Simplex
viruses
3The herpesviruses
- Name from the Greek word Herpein meaning to
creep - 1950s, Burnet demonstrated HSV latency following
a primary infection - Weller (1954) found VZV from chicken pox and
zoster were the same causal agent. - Over 100 Herpesviruses have been isolated
- There is at least one for most animal species
- There are 8 known human Herpesviruses
- The herpesviridae family is divided into 3
sub-families based on host range, cell tropism
and growth rates
4The Herpesvirinae
- Alphaherpesvirinae
- may grow in a number of cell types, rapid and
commonly destroy host cells - Simplexvirus human herpesvirus 1, 2 (HSV-1,
HSV-2) - Varicellovirus human herpesvirus 3 (VZV)
- Betaherpesvirinae
- Tend to grow slowly, have restricted cell type
range - Cytomegalovirus human herpesvirus 5 (HCMV)
- Roseolovirus human herpesvirus 6, 7 (HHV-6,
HHV-7) - Gammaherpesvirinae
- Tend to grow slowly and often immortalize
lymphoid cells of host - Lymphocryptovirus human herpesvirus 4 (EBV)
- Rhadinovirus human herpesvirus 8 (HHV-8) 8
(HHV-8)
5Herpesvirus characteristicsGeneral
- Characteristically large genomes
- may be 180- gt gt200kbp DNA
- Are complex viruses
- may code for more than 30 viral proteins
- Genetically diverse
- all are similar in terms of virus structure and
genome organization - All herpesviruses appear much the same in
electron micrographs
6Herpesviruses Family Classification
- Size 180-200nm
- Envelope present
- Tegument Protein-filled region between capsid
and envelope - Capsid Icosahedral, 95-105nm diameter 162
hexagonal capsomeres - Core DNA bound around protein
- Genome Linear dsDNA 130-235kbp
- Replication Nuclear
- Assembly Nuclear
7HerpesvirusesGenome arrangement
- All herpesvirus genomes have a unique long (UL)
and a unique short (US) region - The unique sequences bound by inverted repeats
- Repeats allow rearrangements of the unique
regions - Consequently Herpesvirus genomes exist as a
mixture of 4 isomers
8HerpesvirusesGenomes
- There are generally 3 genomic types
- 1.
- 2.
- 3.
9HerpesvirusesGenomes
HSV about 150 kbp
VZV about 130 kbp
EBV about 170 kbp
10Type Species Herpes Simplex Virus Classification
- Two members HSV1 and 2 share about
40-50 DNA homology - Systematic names Human Herpes type 1
- Human Herpes type 2
- Sub family Alpha
- Genome size 152kbp
- Genomic isomers 4
- Genome type 1
- GC HHV1 67 HHV2 69
11Herpes SimplexStructure
- Herpesvirus particles are complex
- Core region large DNA genome wound around a
proteinaceous core. - Capsid surrounds the core
- Tegument a protein-filled region which appears
amorphous in electron micrographs which is
outside the capsid - Envelope outside of tegument and contains
glycoproteins - here
12Herpes SimplexStructure
http//www-micro.msb.le.ac.uk/335/Herpesvirus.gif
13Herpes SimplexStructure
Lipid coat
Integument
dsDNA
Glycoprotein
Core protein
Capsid
14Herpes Simplex VirusDiagnosis
- Histology
- Cell culture (embryonated egg)
- Gold standard, form syncytia and inclusion bodies
- Grow well in epithelial cell lines eg BHK
- IFT Useful, needs expertise
- Elisa (IgG IgM)
- EM (including Immune EM)
- PCR
- DNA probes
15Herpes Simplex VirusPathogenesis
- Stability highly infectious even if freeze dried
- Inactivation readily inactivated by ether (2hrs)
or heat ( 560 ) 30 minutes - EpidemiologyUnder natural conditions infects
only humans
16Herpes Simplex VirusPathogenesis
- 2 serological types defined
- HSV1
- Mainly oral infections
- Less frequent in genitalia
- HSV 2
- Mainly genital isolation
- Less frequent orally
17Herpes Simplex Virus PathogenesisHSV1
- Primary infection usually occurs in neonate
- Mainly droplet or contact infection
- Most common sources are maternal and hospital
staff - In youth mainly by contact
- Infection rate is about 50 up to puberty and
gt90 in adult hood
18Herpes Simplex Virus PathogenesisHSV2
- Commences with sexual activity
- About 10-20 of Caucasian population in age group
20 to 30 years are infected - May also be transmitted at birth
- Is more common in Western cultures
19HSV pathogenesisInfectious replication
- 1o exposure of HSV onto mucosal area or
integument defects - Virus shell fuses with cell membrane
- Nucleocapsid reaches cytoplasm and DNA released
- Penetration occurs following fusion with cell
membrane - Viral DNA release occurs in region of nucleopores
- DNA enters cell nucleus and takes on a circular
structure
20HSV pathogenesisInfectious Replication
- Over 30 structural proteins are made
- Replication proceeds in 3 defined stages
- Alpha proteins (early antigens)
- Initiated by an integument protein the viral DNA
is transcribed into alpha proteins - Beta proteins
- Alpha proteins regulate synthesis of beta
proteins - Beta proteins regulate DNA polymerases
- Gamma proteins are late proteins which are
structural proteins and together with new DNA
form new viral particles
21HSV Pathogenesisreplication
- Viral propagation occurs in nucleus.
- Nucleic acid and capsid molecules are formed in
nucleus (nucleus shows inclusion bodies) - Virus gains integument by budding from inner
nuclear membrane - Virus transfers directly to neighbouring cells by
fusing cells to form syncytia CPE - Virus can propagate in the face of an immune
person
22HSV PathogenesisClinical aspects
- Local propagation in epithelial cells virus is
followed by migration by intraaxonal route to
sensory and autonomic ganglia - Usually in the trigeminate ganglion in facial
infection sacral ganglia in genital infections - Lymphohaematogenous dispersion may occur in
immunosuppressed patients - Normally immune responses within about 7 days
usually suppress HSV activity in neurons - Infection then alters from acute to latent
- Both humoral and cell mediated responses
important in recovery
23HSV PathogenesisClinical aspects
- Primary infection
- 90 of patients do not display symptoms
- 9 display minor symptoms
- 1 display clinically significant manifestations
- Superinfection with different strains can occur
24HSV PathogenesisClinical aspects
- Re-activation associated with environmental
triggers - Stress
- UV radiation
- Menstruation
- Fever
- Pregnancy
- Other infections
- Immunosuppression
25HSV PathogenesisClinical aspects
- Re-activation from endogenous infection
associated with virus migrating intraaxonally to
peripheral epithelial cells - Recurrence is not prevented by immune competency
- HSV is re-propagated in target cells forming
highly infectious vesicles - Recurrence may be symptomatic or asymptomatic
- HSV relapses occur in the following frequency
- Genital HSV2 gt oral HSV1 gt genital HSV1 gt oral
HSV2