Herpes Simplex Virus, Structure,Pathogenesis, Clinical Feature and Lab Diagnosis

Herpes virus

-         Establish lifelong persistent infections / undergo periodic reactivation

-         Reactivated infection different from disease caused by primary infection.

Structure

Virion: spherical, 150-200 nm diameter ( icosahedral), 162 capsomers

Structure of Herpes Simplex Virus (HSV-1)

Envelope: derived from nuclear membrane of infected cell

-         contains viral glycoprotein spikes (8nm long)

Tegument: amorphous, asymmetric structure between capsid and envelope.

Genome: ds DNA, linear, 124-235 kbp, reiterated sequences

Proteins: 35 proteins involved in structure of virion.

-         Genome encodes atleast 100 different proteins.

Replication: nucleus, bud from nuclear membrane.

HERPES- SIMPLEX VIRUSES

-         grow rapidly and are highly cytolytic

-         latent infection in nerve cells
HSV Type I: oropharyngeal lesions / recurrent attacks of fever blisters
                      spread by contact ( infected saliva)
HSV Type II: infects genital mucosa
                       transmitted sexually, vertically

-         growth cycle – 8- 16 hours

-         genome: 150kbp; can encode atleast 70 polypeptides

-         Atleast 11 glycoproteins known.

·         gD: most potent inducer of neutralizing antibody

·        gC: c3b binding protein

·        gE: Fc receptor (IgG)

·        gG: type specific and allow for antigenic discrimination.

·        gH: involved in release of virions.

 

Pathogenesis

-         cytolytic infection due to necrosis of infected cells and inflammation
response

-         Ballooning of infected cells, production of Cowdry type A intranuclear
inclusion bodies.

-         Margination of chromatin, formation of multinucleated giant cells.

-         Cell fusion provides for cell to cell spread

-         Virus must encounter mucosal surfaces / broken skin to initiate infection
HSV-1: respiratory droplets / contact with infected saliva
HSV-2: genital routes

-         Replication occurs first at site of infection
virus invades local nerve endings

Transported by retrograde axonal flow in the dorsal root ganglion
 ( sensory) to the nerve body ( neurone), where latency is established.

- Typical lesion produced is the vesicle ( ballooning degeneration
 of intra-      epithelial    cells).

-         Underlying layer (basal epithelium) is intact.

-         Base of vesicle contains multinucleate cells ( Tzanck cells) and eosinophilic

 inclusion bodies in the infected nuclei.

-         Roof of vesicle breaks down, ulcer forms with crusts over forming a scab
 and then heals.

-         There is insertion of viral gp into cell membrane and also secreted to ECF.

LATENT INFECTION

-  HSV- 1: latent infection in the trigeminal ganglia
    HSV-2: latent infection in the sacral ganglia

- Neurons continue to harbour viral genome ( non- replicating state)

- Only a few viral genes expressed; persistence is life long.

- In latency, viral DNA exists as free circular episomes ( abt 20 copies / cell)

- Infected neurons not recognized by immune system.

REACTIVATION / RECRUDESCENCE

-         virus DNA passes along the nerve axon back to nerve ending
where infection of epithelial cells may occur.

-         Many recurrences asymptomatic ( viral shedding in secretions)
. when symptomatic – cold sores ( fever blisters) near the lip
. recurrent infection less extensive / less severe
. increase CD8+ suppressor cell activity / local increase in
prostaglandin level / decrese CMI
. induced by UV light, fever, trauma, stress. Eg bone marrow
 transplant, increase dose chemotherapy

-         Interval between stimulus and appearance of lesion: 2-5 days.

CLINICAL FEATURE

Primary infection: - in those with no antibody; mostly clinically anapparent

-         result in antibody production and establishment of latent infection

-         usually involves mucous membrane, of mouth, may include lips,
skin of face, nose, eye and genital tract

Recurrence / recrudescence:
           prodrome → pain / paraesthesia of the site
                                                ↓

                                erythema / papule with in 24 hours

                                                 ↓

       Vesicle / ulcer / subsequent crusting ( 8-12 days) / healing

                            → cold sores / fever blisters

-         on mucocutaneous junction of lip

-         Severe pain, extensive mucosal ulceration and delayed healing in compromised patients ( Greenwood).

A. ORAL INFECTION
- 1⁰ – HSV-1 infection usually asymptomatic; episode attributed to teething or mistaken for thrush

- Symptomatic disease frequent in small children ( 1-6 years)

            → Acute, febrile gingivostomatitis

            → Incubation period; 3-5 days ( range of 2-12 days), clinical illness → 2-3 weeks in adults → associated mononucleosis, pharyngitis / tonsillitis

-         recurrent disease → vesicles at border of lip

-         viraemia rare except in pregnancy or in neonate.

B. SKIN INFECTION

- Contamination of skin abrasions

- Herpetic whitlow → hand infection in toddlers, hospital personnel

- Eczema herpeticum → severe form of cutaneous herpes in children
with atopic eczema or with burns.

             - extensive ulceration → viraemia

C. EYE INFECTION

- Keratoconjunctivitis : mostly HSV- 1

- Branching or dendritic corneal ulcer found and recur resulting in corneal
 scarring and impairment of vision ( opacification of corneal stroma)

D. CNS INFECTION

- Mostly due to central spread from trigeminal ganglia

- Most common cause of fatal, sporadic encephalitis, ↑ mortality rate

- prodrome→ fever, malaise → headache / behavioural change
                  → seizure / paralysis  → coma → death

- Virus replication in neurons and oedema( inflammation response)

                                              ↓

                        Haemorrhagic necrosis and space – occupying nature

-         CSF collected in acute stages sent to lab for PCR

E. GENITAL INFECTION : mostly by HSV-2

·        acquired by auto- inoculation from lesions, but mostly by sexual contact

·        1⁰- infection severe, illness lasting about 3 weeks

·        Vesiculoulcerative lesion of penis, cervix, vulva, vagina, perineum

·        Incubation period: 2-20 days ( average:7 days).

·        1⁰- infection severe → fever, malaise, dysuria, urithritis, inguinal
lymphadenopathy, vaginal discharge.
                               → complication : extragenital lesion, aseptic meningitis.

·        Viral excretion persists for about 3 weeks.

·        Recurrent infection common and mild.
→ limited vesicles appear and heal in about 10 days
→ virus shedding asymptomatic
→ vertical transmission is seen

·        Significant in immuno suppressed patients.

F. NEONATAL HERPES (about 75% by HSV-2)

o       Acquired in utero, during birth or after birth.

o       In about 1 in 5000 deliveries, CFR > 60%

o       50% transmission rate with 1⁰- infection in mother during delivery

o       Infection usually present about 6^th day post partum; 3 categories of disease:
- lesions localized to skin, eye and mouth
- encephalitis with or with out localized skin involvement.
- disseminated disease, involving multiple organs, including CNS

o       Worst prognosis (mortality rate about 80%)
    ↓
pneumonia, jaundice, liver- failure, IV coagulopathy → death.

o       Can be acquired postnatally by exposure to either HSV-1 or HSV-2.

o       Sources→ family members / hospital personnel shedding virus.

7. INFECTION IN IMMUNOCOMPROMISED HOST(jawetz)

Immunity

-         Passively acquired maternal antibody lasts for 6 months.

-         Period of greatest susceptibility to 1⁰- herpes infection → 6 months – 2 yrs

-         During 1⁰- infection; IgM appear transiently; followed by IgG / IgA → persist longer.

-         CMI and non- specific host factors (NK cells, IFN) important in controlling infection.

Lab diagnosis

1. CYTOPATHOLOGY
   - stain scrapings obtained from base of vesicle ( giemsa stain)
   - presence of multinucleated giant cells indicate HSV-1, HSV-2 or VZV.
2. Isolation and identification of virus
   - isolated from lesions; also from throat washings, CSF and stool.
   - Inoculation of tissue cultures ( human diploid fibroblast).
   - Identification by Nt- test or immunofluorescence staining with specific antiserum.
   - typing done by using monoclonal antibody or by RE analysis of viral DNA
3. PCR: most sensitive / specific
   - detection of amplified viral DNA by PCR in CSF or other samples
   - typing done by using type- specific primers, or using common primers
    followed by RE analysis or hybridization probes.
4. Serology
   - antibody appear in 4-7 days after infection, reach peak in 2-4 weeks.
   - CFT measures total antibody, not differentiating type- specific antibody.
   - EIA more efficient than CFT; type- specific antigen (gG) used to detect
    type – specific antibody.
   - diagnostic valve limited by multiple Ag shared by HSV-1 and HSV-2;
   also heterotypic anamnestic responses to VZV in HSV infection and vice- versa.

Epidemiology (book)

Treatment / prevention / control (book)