Human Herpes Viruses (HHVs)

What does the HHV family Herpesviridae consist of?

8 groups:

• HHV 1 ( Herpes simplex Type 1; HSV-1)

• HHV 2 (Herpes simplex Type 2; HSV-2)

• HHV 3 (Varicella Zoster Virus; VZV)

• HHV 4 (Epstein Barr Virus; EBV)

• HHV 5 (Cytomegalovirus; CMV)

• HHV 6

• HHV 7

• HHV 8 → related to Kaposi’s sarcoma

Which groups of Herpes viruses are in the Alphaherpes group and what are their characteristics?

Alphaherpes viruses consist of HHV1 (HSV-1), HHV2 (HSV-2), HHV3 (VZV)

• Tropism: Infects epithelial cells on skin and mucous membranes

• Site of latency: neurons (sensory ganglia), short reproductive cycles

Which groups of Herpes viruses are in the Betaherpes group and what are their characteristics?

Betaherpes viruses consist of: HHV5 (CMV), HHV6, HHV 7

• Tropism: Infect monocytes, lymphocytes and epithelial cells

• Site of latency: Lymphocytes/monocytes

Which groups of Herpes viruses are in the Gammaherpes group and what are their characteristics?

Gammaherpes viruses consist of: HHV4 (EBV), HHV 8

• Tropism: Infect lymphocytes, B cells and epithelial cells

• Site of latency : B cells, endothelial cells

Common features of herpesviruses:

• Have a lipid bilayer envelope and are linear dsDNA viruses (Baltimore group I)

• Latent infection resulting in lifelong infection:

- Primary infection

- Reactivation of latent (recurrent)

What is involved in the Herpesvirus lifecycle?

• Virus binds specific receptors via glycoproteins, fuses with cell membrane; capsid delivers DNA to the nucleus

Transcription / translation: 3 phases

1. Immediate early- DNA binding proteins that regulate the transcription of early genes

2. Early – DNA polymerase & thymidine kinase (unique in HSV-1/HSV-2, VZV) to facilitate DNA replication

3. Late- structural proteins

• Assembly in nucleus

• Release of virions from cell via exocytosis with host cell death

What is the epidemiology of Herpes Simplex Viruses Type 1 and 2

(HHV 1 and HHV 2)?

- Worldwide distribution; no animal reservoir

- Direct contact with infected oral, genital or skin lesions secretions in a HSV carrier onto damaged mucous membranes or skin

- Both asymptomatic and symptomatic shedders

- HSV-1: acquired young via saliva or secretions from oral/skin lesions

- HSV-2: acquired via sexual contact / genital lesions or by childbirth

Pathogenesis of HHV 1 + 2:

• Entry via epithelial cells in the skin or mucous membranes at inoculation site

• Incubation period 4 – 6 days before clinical lesion appears; local inflammatory response before lesions rupture

• Enters the sensory nerves innervating site of replication and becomes latent in sensory ganglia; minimal gene expression; excellent immune and treatment evasion

• Viremia & dissemination may occur in immunocompromised people

• Reactivation due to stress, UV, immunosuppression; infectious virus travels down nerve and replicates in epithelial cells at nerve ending

What HHV causes gingivostomatitis & cold sores & what are they?

HSV-1

Gingivostomatitis: Primary infection; incubation period 2-12 days; associated with fever, pharyngitis followed by vesicles around and inside the mouth; difficulty feeding; clears 1-2 weeks

Cold sores: Indicative of a reactivation of latent HSV-1 virus; may be

asymptomatic or symptomatic; 1 or 2 episodes on lips per year

What other symptoms are caused by HSV-1?

Herpes gladiatorum (HSV-1)

- Skin to skin contact in contact sports, present as head, neck or trunk lesions, can be linked with primary or re-activated infection

Keratoconjunctivitis (HSV-1)

→ Acute onset of pain, lesions around eye, blurred vision, recurrences can lead to scarring and blindness; treatment urgent; topical acyclovir

Herpes whitlow

→ Infection of fingers by autoinoculation in some cases, or via lesion contact

What is a serious complication of a HSV-1 infection?

Acute sporadic encephalitis in immunocompetent hosts:

linked with Primary infection or reactivation; 2-3 cases/million people /year

• Higher rates in 5-30yo and >50yo

• Sx; Acute onset of fever, confusion, vomiting, altered level of consciousness (LOC), seizures progress to decreased LOC, coma, and death (severe cases)

• Range in severity from mild to severe severe disease

– High mortality (70-90%) and morbidity (<10% normal) in pre-antiviral era

– Urgent IV acyclovir has led to decreased mortalitiy (<20% and 40%) & return to normal neurological function

• High incidence of permanent neurological damage - short-term memory loss, seizures

What are common clinical symptoms associated with genital herpes caused by HSV-2?

• Primary infection is sexually transmitted; fever, headache, myalgias

• In women: local pain and itching, vaginal discharge, lymphadenopathy, vesicles and ulcers on vulva, perineum, vagina, cervix

• In men: vesicles on shaft or glans of penis; may be associated urethritis

• Over 1/2 of primary HSV-2 infections are asymptomatic ie HSV-2 antibody positive no history of disease

• Recurrent genital herpes is frequent in 1st year after primary infection reduces after that

What are common clinical symptoms associated with neonatal herpes caused by HSV-2?

> 85% cases by infection with HSV-2 acquired from maternal genital secretions during delivery; severe risk to child if primary infection occurs during 3rd trimester

• C section for women with active lesions and/or positive cultures

3 major patterns of disease (likely a spectrum)

1. Lesions of skin, eyes, and mouth (SEM)

2. CNS disease – encephalitis with/without SEM

3. Disseminated disease – liver, lungs, CNS (most severe)

What is the treatment for neonatal HSV-2 infection & what occurs if it is untreated?

IV acyclovir is administered for neonates with serious disease:

• Untreated mortality exceeds 80% in disseminated disease, and 50% in CNS disease

• May present with hepatitis, fulminant liver failure, multiorgan failure, seizures, encephalitis, rash

• Incidence varies with prevalence of HSV

What is a complication associated with a primary HSV-2 genital infection?

Aseptic meningitis; incidence of 7% in women & 2% in men

Sx. Fever, headache, vomiting, photophobia about 3-12 days after the appearance of the genital lesion

• Benign, no long term effects if treated

How does recurring HSV present in immunocompetent individuals?

Immunocompetent

– Asymptomatic shedder

– Herpes labialis (“cold sore”)

– Genital HSV (3-9 episodes per year)

– Keratoconjunctivitis

– Encephalitis

How does recurring HSV present in immunocompromised individuals?

Immunocompromised

– Extensive mucocutaneous disease

– Oesophagitis

– Pneumonitis

– Hepatitis

– Encephalitis

How are HSV diagnosed?

Clinical manifestations observed & undergo laboratory confirmation:

E.g. Virus isolation; Swabs from vesicle fluid (skin for cold sores, whitlow)

• Human fibroblasts or other cell types - CPE 24hrs.

• Confirm by IFA

Antigen detection from vesicular fluid

Molecular PCR (genital swabs, CSF for meningitis or encephalitis)

• Direct visualisation from vesicle fluid or swab of base of lesion; EM or Tzanck smear

What is a Tzanck smear?

A diagnostic test used to identify HSV infections by examining fluid from vesicles.

• It involves scraping the base of a lesion and staining the sample to visualise multinucleated giant cells under a microscope.

How are HSV treated?

• Oral/topical Acyclovir, Valacyclovir

• Oral/topical Penciclovir for primary oral and genital infection

• IV Acyclovir for neonates & encephalitis

• Side effects; nausea, diarrhea, headache, tremors

Acyclovir and derivatives: mechanism of action

• It is a guanosine nucleoside analogue that inhibits the replication of HSV-1, HSV-2, VZV

• Phosphorylated by viral thymidine kinase → to acyclovir monophosphate followed by phosphorylation to acyclovir triphosphate by cellular kinases

• Incorporated into viral DNA causing chain termination

What are the 2 distinct clinical syndromes associated with VSV

infections? (alphavirus)

1. Varicella (chickenpox): is the primary disease

• Can have serious consequences in adults and in immunosuppressed

• Included in childhood immunisation programmes in Ireland since October 2025

2. Zoster (Shingles) is the reactivation of latent virus

• Rarely life-threatening

• Causes significant morbidity in the form of post-herpetic neuralgia

(debilitating and difficult to treat)

Epidemiology of VSV:

• VZV is highly infectious (R⁰ 10-12)

• Spread via espiratory droplets or direct contact with vesicular fluids or contact with infected objects

• Peak age of infection in western world is children <5yo

• <10% of adults remain susceptible to infection

• Epidemiology will change due to vaccine

Pathogenesis of primary VZV Infection:

• Spread by respiratory droplets; typical childhood infection

• Incubation period ~ 2 weeks

• Targets epithelial cells in URT before being spread by blood to skin where it infects capillary endothelial cells and adjacent fibroblasts/epithelial cells

• Lesions progress from macules→papules→vesicles then break down with crust formation; mild in children more severe in adults

• Patients considered infectious from 2 days before rash and 4-5 days afterwards until existing vesicles have crusted

Complications of Varicella (chickenpox) - most common → rare

• Secondary bacterial infection of skin lesions

→ Most common complication, especially in children, typically involving streptococci and staphylococci

• Pneumonitis → incidence increased in pregnant women, 10% of smokers, 32% of children with leukaemia (25% mortality)

• Haemorrhagic chickenpox: commonly seen in immunocompromised (uncommon otherwise)

–> Haemorrhage into skin and GIT; hepatitis; thrombocytopenia; ACV and ICU

• Encephalitis

–> 3-4 cases per 10000 children (more common in adults); appears within a week of rash; resolves 2-4 weeks

• 0.1-0.2% more serious- Headache, vomiting, confusion; high mortality (5-20%) and neurological sequelae

Why is Varicella in Pregnancy so serious?

Can lead to severe varicella pneumonia in mother (late 2nd /early 3rd trimester) linked with 2 major problems based on timing of infection:

1. Congenital varicella syndrome (1st trimester)

• Rare:1-2% risk in mothers infected in 1st 20 weeks

• Sx. of skin scarring, limb hypoplasia, rudimentary digits, and CNS defects in newborns

–Mortality rates of 30% in the first few months of life

2. Neonatal varicella infection (Just before or after delivery)

• Highest risk of infection if mother develops varicella one week before to one week after delivery as neonate will have insufficient transferred immunity

• Varicella in pregnant women treated with acyclovir and VZIG

(varicella immunoglobulin); babies exposed to VZV in the first 28 days of life should also receive VZIG

What is VZV Reactivation (Zoster)?

Lifetime risk of developing Zoster is 24-30% following 1º infection, single reactivation can occur decades after initial infection

• Virus reactivates in ganglion, travels down sensory nerve, and forms vesicular rash classically restricted to dermatome supplied by that nerve

• Associated with intense destructive inflammatory changes in ganglion (manifests as severe pain)

What is a complication of VZV Reactivation (Zoster)?

Post herpetic neuralgia; persistent severe pain in the affected dermatome for about a month or more AFTER the zoster has resolved; incidence increases with age

• Immunosuppressed individuals are more likely to experience more than one episode of reactivation

Disseminated disease (through viraemia from original dermatome) also more common

How is VSV treated?

• Using Acyclovir , Valacyclovir, Famciclovir for Herpes Zoster (Shingles)

• Acyclovir +/- VZIg for:

– Varicella or zoster in immunocompromised individuals

– Varicella in pregnancy

– Neonatal varicella

– Varicella pneumonia in normal host

How is VSV prevented?

Passive immunisation:

• Human immunoglobulin with high titres of antibody to VZV (VZIG)

• Recommended for susceptible “at-risk” individuals with “significant” exposure

• Administered ASAP, preferably within 96 hours, but beneficial up to 10 days

• May not prevent infection, but intended to prevent serious forms of disease.

What are examples of active immunisation for VSV?

• Varivax/Varilex; live attenuated vaccine that reduces the severity of varicella with 2 doses at 12months & in junior infants

• Zostavax; live attenuated vaccine that prevents zoster and post herpetic neuralgia; ≥ 50 years

• Shingrix; Subunit vaccine (envelope glycoproteins) that prevents zoster and post herpetic neuralgia; ≥ 50 years; 2 doses 2-6 months apart

• 75% of recipients seroconvert following vaccination

What is the epidemiology of EBV? (HHV 4)

• Infection usually occurs at early age; transmitted in saliva and almost always clinically silent; lifelong carrier

• Latent in a small number of memory B cells in circulation; intermittent virus shedding from mouth and pharynx leading to transmission

• Infection in adolescence can cause Infectious Mononucleosis (Glandular fever) but most have no symptoms when infected

What is Infectious Mononucleosis which is caused by EBV?

Primary infection in adolescents – saliva i.e. kissing a virus shedding carrier

Sx: Sore throat, fever, headache, fatigue, rash uncommon

• Generalised lymphadenopathy is almost always present; marked in cervical region (neck)

• Splenomegaly in about 60% cases; enlarged liver in 10%

• Mild cases resolve in days but 1-4 weeks more common; convalescence

What are the 5 main EBV related cancers?

1. Burkitts lymphoma

2. Hodgkins lymphoma

3. Post transplant lymphomas

4. B cell lymphomas in AIDs patients

5. Nasopharyngeal carcinoma (Chinese)

Burkitts lymphoma

Endemic (African) BL

• Childhood cancer common in equatorial Africa; Jaw tumors

• EBV found in 100% of cases

• Incidence higher in regions in which malaria is hyperendemic

• C- myc translocation leading to high expression of c-myc and high cell proliferation

• Chemotherapy gives excellent results

Hodgkin’s Lymphoma

• Infectious mononucleosis risk factor

• In developed countries 40% of tumour cells contain virus

• Usually involves lymph nodes/abdomen

Nasopharyngeal carcinoma & its prevalence

• Mostly found in the nasopharynx & linked to the EBV virus.

• High prevalence in Southern China and Africa, due to both genetic

and environmental factors

• Chinese diet of a high amount of smoked fish, which contain nitrosamines, well known carcinogens (environmental).

• Nasal obstruction, discharge, bleeding, deafness

• Responds well to radiotherapy; 5 year survival rates of about 50%

EBV Diagnosis

Laboratory diagnosis involves molecular and serological methods:

(Serology)

• Heterophile agglutinins; monospot test to diagnose IM

• ELISA; Detection of IgM and IgG antibodies against EBV antigens.

• PCR can be used for viral DNA detection.

Epidemiology of Cytomegalovirus (HHV 5)

• Latent infection; periodic asymptomatic shedding in saliva, breast milk, urine, semen/cervical secretions; infection spread by contact with these fluids

• Babies: transmits across placenta, within birth canal, breast milk

• Young children: transmission via saliva or urine

• Older people: sexually; present in semen/cervical secretions

• Blood/ solid organ and bone marrow from seropositive donors CMV can transmit the virus

CMV Clinical Symptoms

– Presents as asymptomatic infection in most children and adults

Complications associated with those who are:

• Immunocompromised - Transplant or AIDS patients

• Pneumonitis following bone marrow transplant

• Have AIDS: disseminated disease (retinitis, colitis)

• Pregnant women: primary infection can occur during pregnancy or reactivation of infection

What are the 3 different types of CMV infection in babies?

1. Congenital (most serious) - primary infection in early pregnancy of the mother or reactivation, the virus can spread via the placenta to the foetus

• Primary infection can cause microcephaly, deafness, brain calcification and hepatosplenomegaly; can result in hearing loss or developmental delay

2. Perinatal- during birth

3. Postnatal- breast milk

*Postnatal or perinatal rarely symptomatic or associated with long term problems

What are the 3 main diagnostic approaches of CMV?

1. Culture and DEAFF (Detection of Early Antigen Fluorescent Foci pp65) testing

2. Serological diagnosis:

• Useful for detecting primary infection; CMV specific IgM in the absence of IgG

• In immunocompromised measurement of antibody levels may not be helpful

3. Molecular: PCR to detect and quantify – viral load

How is Valganciclovir used as a treatment for congenital CMV in immunocompromised individuals?

• Nucleoside analogue phosphorylated by VIRAL UL97 protein;

incorporated into viral DNA → chain terminator

• Accumulates in CMV infected cells

• Excreted by kidneys – however toxicity includes neutropenia and renal impairment

• Crosses Blood Brain Barrier

What is a 2nd line therapy of CMV?

Foscarnet second line therapy – competitive inhibitor of the viral polymerase enzyme; used to treat resistant strains of CMV.

What are characteristics of HHV6 and HHV7?

Human herpesvirus 6 (roseola) has two variants, 6A and 6B.

• Found worldwide and in the saliva of >90% of adults; most children infected by 2years.

• Replicates in T and B cells

• HHV 7 predominantly infects CD4+ T cells and can be reactivated by T cell activation; widespread infection of children

What does a primary HHV-6B infection cause in infants and young children?

Roseola infantum or sixth disease;

• 3-5 days of high fever

• Sometimes upper RT symptoms and lymphadenopathy; after fever subsides, a macropapular rash appears on trunk and neck that lasts a few days

What condition is HHV 8 associated with?

Kaposi's sarcoma, primary effusion lymphoma:

• Form of skin cancer that can involve internal organs

• Primarily affects immunocompromised individuals such as those with HIV/AIDS.

• Seroprevalence 1-2.5% in US blood donors

HHV1 targets ____________with latency in the _____ which causes diseases such as ___________

Targets → Mucoepithelia

Latency → In neurons

Disease → Causes oral, ocular lesions, encephalitis etc

HHV2 targets ____________with latency in the _____ which causes diseases such as ___________

Targets → Mucoepithelia

Latency → In neurons

Disease → Genital, ocular, disseminated disease

VZV (HHV3) targets ____________with latency in the _____ which causes diseases such as ___________

Targets → Mucoepithelia

Latency → In neurons

Disease → Chicken pox, shingles

EBV (HHV4) targets ____________with latency in the _____ which causes diseases such as ___________

Targets → B lymphocytes, epithelia

Latency → B lymphocytes

Disease → Infectious mononucleosis, tumours

CMV (HHV5) targets ____________with latency in the _____ which causes diseases such as ___________

Targets → Epithelia, monocytes lymphocytes,

Latency → Monocytes lymphocytes, DC

Disease → Numerous infections incl. congenital disease, pneumonia, retinitis

HHV6 targets ____________with latency in the _____ which causes diseases such as ___________

Targets → T lymphocytes & others (lymphotrophic)

Latency → T lymphocytes

Disease → Roseola in infants

HHV7 targets ____________with latency in the _____ which causes diseases such as ___________

Targets → T lymphocytes (esp CD4+ T cells) & others

Latency → T lymphocytes

Disease → Roseola

HHV8 targets ____________with latency in the _____ which causes diseases such as ___________

Targets → Endothelial cells & B cells

Latency → B lymphocytes

Disease → Kaposi's sarcoma, primary effusion lymphoma