Human herpes virus Flashcards
Structure and classification of Herpesviruses What disease are caused by Herpes viruses How Herpes viruses infect human cells Pathobiology of Herpes simplex virus and Pathobiology of Herpes simplex virus and other Herpes viruses
Herpes virus structure
Herpes – herpeton, Greek for “creep”
Icosahedral capsid surrounding dsDNA
Virus size ~ 120-200 nm
Have around 80 genes coding for approx 100 proteins
HHV classification
α-herpesviruses
β-herpesviruses
γ-herpesviruses
α-herpesviruses
- epidermal/ neuronal viruses with a wide host range
- HHV-1, HHV-2, HHV-3 (VZV)
β-herpesviruses
Slow growth, primarily in T-cells and leukocytes
- HHV-5 (cytomegalovirus)
- HHV-6
- HHV-7
γ-herpesviruses
Primarily B-lymphocytes
- HHV-4 (Epstein-Barr virus)
- HHV-8
Diseases caused by HHV1 & 2
Oropharyngeal and genital herpes
Diseases caused by HHV-3 (VZV)
Chicken-pox (Varicella)/ singles (Zoster)
Diseases caused by Epstein-Barr Virus (HHV-4)
Infectious mononucleosis (glandular fever), burkitt’s lymphoma, nasopharyngeal carcinoma
Diseases caused by cytomegalovirus (HHV-5)
Cytomegalic inclusion disease in utero (newborns and immunocompromised)
Diseases caused by HHV-6
Exanthem Subitum (6th disease) Fatigue syndrome
Diseases caused by HHV-7
Pityriasis rosea?
Diseases caused by HHV-8
Kaposi’s sarcoma (in AIDS pts)
Infection and replication of herpes virus
Virus with glycoproteins sticking out –> stick to receptor on cell surface –> when they bind virus decouples and injects DNA into cell –> dsDNA uncoated, makes its way into nucleus –> co-opts host cell polymerase and DNA starts to transcribe viral genes –> translation –> makes viral proteins including viral factor which goes back to host cell polymerase –> this drives more viral DNA replication –> all bits get put together in nucleus –> viral DNA back into virus –> mature virus –> break out of nucleus –> cells get packed full, cell pops, spread to other cells around or further
Can make proteins out of very little DNA
Herpes Simplex Virus (HSV)
HSV 1
-mainly Oral Infections
HSV 2
-mainly Genital Infections
Herpes Simplex Virus (HSV) infection and reactivation
- Infection: herpetic gingivostomatitis
2. Reactivation: herpes labialis (cold sores)
HSV-1 - oral infections
- Herpes Simplex Infection
- herpetic gingivostomatitis
- virus enterstrigeminal sensory neurones
- migrates to trigeminal ganglion
Herpes Simplex: becomes latent in trigeminal ganglion
In 50% of cases it becomes reactivated
Migrates to peripheral nerve endings
Where active viral particles are shed
Herpes Simplex Reactivation infection caused by
UV light
Stress
Illness
Immunosuppression
Herpes labialis
Coldsores
Lesion resolves
Virus lays dormant again in trigeminal ganglion until reactivated
Natural history of HSV infections
Source of virus:
- skin lesions, saliva (usually HSV-1)
- genital lesions, genital secretions (usually HSV-2)
- passive immunity from maternal antibody in infancy
- -> primary infection (90-99% asymptomatic, 1-10% symptomatic)
- ->establishment of latent infection
- ->reactivation of latent virus and secondary/ recurrent infection
Herpetic gingivostomatitis incidence
Primary HSV Very common Mainly affects young children -usually mild, may go unnoticed Sometimes young adults -often more severe
Herpetic gingivostomatitis clinical features
Incubation period 3-10 days Duration 5-14 days Multiple vesicles - rupture to form extensive sloughing ulcers Gingivitis with erythema and sloughing Malaise, pyrexia, lymphadenopathy
Herpetic gingivostomatitis diagnosis
Typical clinical appearance
Main diagnostic difficulty with erythema multiforme
Herpetic gingivostomatitis investigation
Not normally done
Rising antibody titre/ presence of IgM antibodies
Viral culture or now mainly PCR
Polymerase chain reaction: basic method (DIAGRAMS)
- Denature DNA to single strands
- Annealing of specific primers to DNA
- Extension by polymerase
- Repeat 30-35 times
Polymerase chain reaction
At the end of each cycle, the amount of DNA has doubled
By end of 30 cycles, you will have ~1 billion molecules from original one you started with
Band if positive, nothing if negative
Management of herpetic gingivostomatitis
Acyclovir (200mg 5x daily for 5 days) if found early in immunocompromised Fluids and soft diet Analgesics/ antipyretics (paracetamol) Local antiseptics e.g. chlorhexidine Topical analgesics e.g. Difflam X-infection control
Action of acyclovir
HSV thymidine kinase (TK) phosphorylates guanosine (G) when HSV DNA replicates
Human cells cannot phosphorylate ACV very well
In HSV-infected cells, ACV is phosphorylated by viral T enzyme to ACV-P
ACV-P then inhibits virus replication
-get incorporated into replicating viral DNA but further bases cannot be added as ACV-P lack a terminal hydroxyl gp. It is a chain terminator
-ACV-P acts on virus DNA complex and inhibits the activity of 1 or more of these enzymes, so virus DNA manufacture is markedly slowed up
Clinical features of herpes labialis
Prodromal irritation
Vesicles at or near mucocutaneous junction of lips
Crusting lesions lasting 7-10 days
Usually re-occurs at same sites
Rarely: may occur, intra-orally, in nose or elsewhere on skin
Management of herpes labialis
Acyclovir cream 5% if used v early
OTC drying and antibacterial agents
Prophylactic treatment of herpes labialis
Rarely justified
Prophylactic acyclovir will prevent lesions in immunocompormised or those susceptible or those susceptible to erythema multiforme
Value of acyclovir in herpes labialis
Prophylactic - oral ACV (600-1000mg/day in 2 doses) is effective
- < duration of pain by 1.4 days
- < time to lesion crusting by 2.1 days
- < occurrence of new lesions by at least 50%
- > mean time to next recurrence from 46-118 days
- < mean number of reccurrences over 4 - month observation period
Herpetic Whitlow features
Herpetic infection of fingers from handling oral tissues of someone active HSV1 or HSV 2 simplex lesions (mainly dentists)
Very painful
Very difficult to treat
Prevention better than cure - wear gloves
HSV encephalitis
Mainly affects frontal loves of brain
70-80% mortality if untreated
Of survivors, only 3% return to normal
Usually only people >50 years (HSv-1) and neonates (HSV-2) affected
HSV encephalitis - adults (HSV-1)
Headache and behavioural changes over several days
Fever
Only 11% of cases have history of recurrent HSV infections
HSV encephalitis - neonates (HSV-2)
Skin rash, lesions and CNS symptoms
Virus present in liver, lung and adrenal glands
Respiratory distress
Fits and convulsions
> intracranial p
Incidence approx 1 in 300,000 live births in UK
HSV-2
Mainly genital infections
Multiple vesicles
-rupture to form extensive sloughing ulcers
HHV-3 (VZV)
Many similarities in structure and infection to HSV-1 and 2 Primary infection -chicken pox (varicella) Secondary infection -herpes zoster (shingles)
HHV-3 pathway
Chicken pox/ varicella (1. HZV) –> dormant in dorsal root/ trigeminal ganglia
- ->reactivation (age [70% >50yrs], stress, illness, immunosuppression) –>herpes zoster (2. HZV) seldom reoccurs
- ->remains dormant
Incubation period of chicken pox
14 days
Natural infection of the nasopharynx - day 0
Viral replication in lymph nodes - day 4
Primary viraemia - day 6
Viral replication in host tissues - day 9
-viral antigens displayed on tissue cells and antigen presenting cells
HHV-3 (VZV) - 1. infection
Mild or severe versions
Herpes zoster - 2. infection
Most commonly affects chest and back
Classical “shingles” rash like belt around chest
Blisters –> rash –> release and heal
Herpes zoster - oral disease
Most commonly affects of the divisions of the trigeminal N. 3 phases -pre-herpetic neuralgia -rash -post-herpetic neuralgia
Pre-herpetic neuralgia
Pain in distribution of affected division of trigeminal nerve
Prior to development of rash
May mimic dental pain
Rash (herpes zoster)
Unilateral in distribution of branch of trigeminal nerve -ophthalmic -maxillary -mandibular Vesicles break down to form -ulcers (mucosa) -crusting lesions (skin) Last 2-3 weeks
Herpes zoster - eye involvement
Problems caused by zoster include glaucoma, cataract, double vision and scarring of the cornea
Management of herpes zoster
Acyclovir 800mg 5x daily for 7 days if seen soon after lesions develop
Analgesics
Ophthalmic referral if eye involved
Avoid contact with children
New alternatives to acyclovir
Valaciclovir
-1g 3x daily for 7 days
Famciclovir
-250mg 3x daily for 7 days
Post-herpetic neuralgia
10% of pts go on to get extremely unpleasant intractable burning pain in distribution of affected nerve
More common in elderly
Effective early treatment of zoster may decrease risk of neuralgia
Treat pain with tricyclic anti-depressants and neuropathic pain drugs
HHV-4 - Epstein-Barr Virus (EBV) associated with
Infectious Mononucleosis (glandular fever) -acute primary infection with EBV Burkitt's lymphoma -a B-cell malignancy Nasopharyngeal carcinoma -an epithelial cell malignancy Oral hairy leukoplakia -seen in AIDS pts and some transplant recipients
HHV-4 - Epstein-Barr Virus (EBV)
Primary infection EBV replicates in oro-pharyngeal epithelial cells but then establishes latency in B-lymphocytes
EBV latent infection of B-lymphocytes is necessary for virus persistance, subsequent replication in epithelial cells and release of infectious virus into saliva
Infectious mononucleosis (EBV)
About 95% of the world’s population are infected with EBV Most infections are asymptomatic Symptoms include sore throat, swollen cervical lymph nodes and mild fever Infections in the western world are usually seen in young adults The disease can run a prolonged, episodic course, interfering with physical and scholastic performance (good excuse for poor exam results )
Oral infectious mononucleosis
Petechiae on soft palate
Creamy exudates on fauces
Cervical lymphadenopathy
Burkitt’s lymphoma
A malignant, B-cell lymphoma of high
prevalence in children in tropical Africa at
elevations below 1500m where malaria is
present
EBV infects most children sub-clinically in
these areas
Severe, clinical EBV infections early in
childhood predispose to Burkitt’s Lymphoma
– EBV immortalises B cells
Treatment – cyclophosphamide (chemo)
Uually affects jaw bone - tumour mass
HHV-5 - cytomegalovirus (CMV)
In healthy individuals In healthy individuals rarely causes: Glandular fever-like illness Salivary gland swelling In immunocompromised / AIDS can cause: Large ragged oral mucosal ulcers Salivary gland swelling Retinitis
HSV-8
In AIDS pts can cause
-Kaposi’s sarcoma
Chicken pox rash timeline
Secondary viraemia: day 0
-skin rash/ fever
-natural killer cell activity
Cessation of fever; skin lesions +ve for virus: day 2/3
Cessation of new lesion formation; virus absent from skin lesions: day 5 to 6 weeks
-neutralising Ab to virus proteins present; cell-mediated immunity (CMI) present
Chicken pox recovery and latent phase timeline
Months –> years: exposure to VZV; asymptomatic reactivation of latent virus
-maintenance of CMI; persistance of IgG antibody; disappearance of IgM antibody
Chicken pox reactivation timetline
Ole age: reactivation of latent VZV to give clinical zoster
-decline of CMI
