Herpes Virus Family

The Herpesviridae are large, enveloped, double-stranded DNA viruses united by one defining biological trait: lifelong latency after primary infection, with periodic reactivation. Eight human herpesviruses (HHV-1 to HHV-8) cause disease ranging from cold sores to malignancy. This is a perennial NEET PG favourite for its inclusion bodies, latency sites, and antiviral pairings.

General properties (the unifying theme)

All human herpesviruses share a common architecture: an icosahedral nucleocapsid (162 capsomeres), a protein tegument, and a lipid envelope with glycoprotein spikes, enclosing a linear dsDNA genome. The envelope makes them labile — easily destroyed by lipid solvents, acids, drying and heat — which is why transmission needs close mucosal/secretory contact.

High-yield: The single most important shared feature is latency — the virus persists in a non-replicating state in specific host cells and reactivates under stress, immunosuppression or fever.

The viruses are classified into three subfamilies based on host range, growth cycle and latency site:

Subfamily	Members	Latency site	Growth cycle
Alphaherpesvirinae	HSV-1, HSV-2, VZV	Sensory (dorsal root/trigeminal) ganglia — neurons	Rapid, cytolytic
Betaherpesvirinae	CMV, HHV-6, HHV-7	Monocytes, lymphocytes, secretory glands, kidney	Slow, cytomegalic
Gammaherpesvirinae	EBV, HHV-8 (KSHV)	Lymphocytes (B cells)	Lymphoproliferative

A simple memory hook for latency: "Alpha = neuron, Beta = mononuclear/secretory, Gamma = lymphocyte."

HSV-1 and HSV-2 (HHV-1 and HHV-2)

Pathophysiology and latency

Herpes simplex viruses infect mucosal/epithelial surfaces, travel retrograde up sensory nerve axons, and establish latency in ganglia: HSV-1 in the trigeminal ganglion, HSV-2 in the sacral (S2–S4) ganglia. Reactivation triggers (sunlight/UV, fever — hence "fever blisters" — stress, menstruation, immunosuppression) cause anterograde travel back to the skin/mucosa producing recurrent lesions.

The classic histopathology is the Cowdry type A intranuclear inclusion with multinucleated giant cells — demonstrable on a Tzanck smear (scraping from the base of a fresh vesicle).

Clinical features

• HSV-1 (oral, "above the waist"): gingivostomatitis (children), herpes labialis/cold sores, herpetic whitlow (finger, classically in dentists/health workers), herpes gladiatorum (wrestlers), and the dreaded herpetic keratitis with a dendritic corneal ulcer (leading infectious cause of corneal blindness).
• HSV-2 (genital, "below the waist"): painful genital vesicles/ulcers, recurrent genital herpes, and neonatal herpes acquired during vaginal delivery (high mortality; C-section indicated for active lesions).
• HSV encephalitis: HSV-1 is the commonest cause of sporadic fatal viral encephalitis in adults, classically affecting the temporal lobe (haemorrhagic necrosis), causing fever, behavioural change, aphasia and seizures.
• Eczema herpeticum (Kaposi varicelliform eruption): disseminated HSV in atopic dermatitis.

High-yield: HSV encephalitis → temporal lobe involvement on MRI, RBCs/lymphocytes in CSF, and PCR of CSF is the diagnostic investigation of choice. Start IV acyclovir empirically before confirmation — do not wait.

Diagnosis

Tzanck smear → fast but only shows giant cells (cannot distinguish HSV from VZV). PCR is now the gold standard for CSF and lesions; viral culture (cytopathic effect in 1–3 days), DFA, and serology are supportive. Type-specific glycoprotein G (gG1/gG2) serology distinguishes HSV-1 from HSV-2.

Management

Acyclovir is the drug of choice. It is a guanosine analogue, selectively phosphorylated first by viral thymidine kinase (then host kinases) into acyclovir triphosphate, which inhibits viral DNA polymerase and acts as a chain terminator — explaining its selectivity for infected cells.

Condition	Drug / route
Mucocutaneous/genital HSV	Oral acyclovir, valacyclovir, famciclovir
HSV encephalitis / neonatal / disseminated	IV acyclovir
Herpes keratitis	Topical trifluridine / ganciclovir gel
Acyclovir-resistant (TK-deficient) HSV	Foscarnet (no TK needed)

Varicella-Zoster Virus (VZV / HHV-3)

VZV causes two distinct diseases: chickenpox (varicella) on primary infection and shingles (herpes zoster) on reactivation.

Chickenpox

Spread by respiratory droplets/airborne route (highly contagious). After a 10–21 day incubation, a prodrome is followed by a generalised, pruritic, centripetal (trunk > limbs) rash in successive crops — so lesions in different stages (macule → papule → vesicle → crust) coexist ("dew drops on a rose petal"). This pleomorphism distinguishes it from smallpox (all lesions same stage, centrifugal).

High-yield: Chickenpox lesions are in different stages simultaneously; smallpox lesions are all in the same stage. This single line has been asked repeatedly.

Herpes zoster (shingles)

Reactivation from dorsal root ganglia produces a painful dermatomal (unilateral, does not cross midline) vesicular eruption. Thoracic dermatomes are most common. Important variants:

• Herpes zoster ophthalmicus — V1 (ophthalmic) division; Hutchinson's sign (vesicle on nose tip → nasociliary nerve → risk of ocular involvement).
• Ramsay Hunt syndrome — geniculate ganglion of facial nerve → ear vesicles + facial palsy + loss of taste.
• Post-herpetic neuralgia — most common complication, especially in the elderly.

Complications

Reye syndrome — encephalopathy with fatty liver, classically when aspirin is given to children during varicella or influenza (hence aspirin is contraindicated; use paracetamol). Other complications: secondary bacterial superinfection (group A Streptococcus), varicella pneumonia (severe in adults and pregnancy), and congenital varicella syndrome (limb hypoplasia, cicatricial skin scarring) if infection occurs in the first/second trimester.

High-yield: Aspirin + varicella/influenza in a child → Reye syndrome. Give paracetamol instead.

Management and prophylaxis

• Acyclovir / valacyclovir / famciclovir for zoster (start within 72 hours), severe varicella, and immunocompromised patients.
• VZIG (varicella-zoster immunoglobulin) for post-exposure prophylaxis in susceptible high-risk contacts (neonates, pregnant women, immunocompromised).
• Live attenuated vaccines: varicella vaccine (Oka strain); recombinant subunit zoster vaccine (Shingrix) is now preferred over the live zoster vaccine for older adults.

Cytomegalovirus (CMV / HHV-5)

The largest human herpesvirus genome; a betaherpesvirus latent in monocytes/macrophages and secretory glands. It is shed in virtually every body fluid (saliva, urine, breast milk, semen, blood, cervical secretions).

Signature cytopathology

"Owl's eye" intranuclear inclusion — a large basophilic inclusion surrounded by a clear halo, with smaller cytoplasmic inclusions; the affected cell is enlarged (cytomegaly).

High-yield: Owl-eye inclusion = CMV. A classic single-answer recall.

Clinical syndromes

• Congenital CMV — the commonest congenital viral infection and the leading infectious cause of congenital sensorineural deafness. Features: periventricular calcification, microcephaly, hepatosplenomegaly, jaundice, "blueberry muffin" rash, chorioretinitis, intrauterine growth restriction.
• Immunocompetent: usually asymptomatic; can cause a heterophile-negative mononucleosis (versus EBV's heterophile-positive picture).
• Immunocompromised / transplant: the most important opportunistic reactivation — CMV retinitis (AIDS, CD4 <50; "pizza-pie" retinopathy), pneumonitis, oesophagitis/colitis, and a major cause of transplant morbidity.

Congenital infection	Calcification pattern	Clue
CMV	Periventricular	Deafness, microcephaly
Toxoplasma	Diffuse / scattered	Hydrocephalus, chorioretinitis

Diagnosis and treatment

Diagnosis: CMV PCR / pp65 antigenemia / DNA quantification in blood; histology of owl-eye cells; shell-vial culture. Treatment: Ganciclovir / valganciclovir are the drugs of choice. Alternatives: foscarnet and cidofovir (used in ganciclovir resistance; both nephrotoxic). Foscarnet and cidofovir do not require viral phosphorylation, so they work against thymidine-kinase-deficient resistant strains.

Epstein-Barr Virus (EBV / HHV-4)

A gammaherpesvirus that infects B lymphocytes via the CD21 (CR2) complement receptor, also using it to enter pharyngeal epithelium. Latency in B cells underlies both benign and malignant disease.

Infectious mononucleosis ("kissing disease")

Triad of fever, pharyngitis, and lymphadenopathy (posterior cervical), often with splenomegaly and fatigue. Blood film shows atypical lymphocytes (Downey cells) — these are reactive CD8+ T cells, not infected B cells.

High-yield: Giving ampicillin/amoxicillin to a patient with EBV mononucleosis (often misdiagnosed as bacterial pharyngitis) provokes a characteristic maculopapular rash — a classic exam vignette.

Diagnostic tests

• Heterophile antibodies — IgM antibodies that agglutinate sheep/horse RBCs. Detected by the Paul-Bunnell test and the Monospot test. May be negative in young children.
• EBV-specific serology (more specific): anti-VCA IgM (acute), anti-VCA IgG (past/recent), and anti-EBNA (appears late — implies past infection).

Antibody	Appears	Interpretation
Heterophile (Paul-Bunnell)	Early	Screening; non-specific
Anti-VCA IgM	Acute	Current infection
Anti-EBNA	6–12 weeks (late)	Past / convalescent

EBV-associated malignancies

• Burkitt lymphoma — endemic (African, jaw mass) form; t(8;14) translocation with c-myc activation; "starry-sky" histology.
• Nasopharyngeal carcinoma — strong association in Southeast Asia/China.
• Hodgkin lymphoma, primary CNS lymphoma in AIDS, and post-transplant lymphoproliferative disorder (PTLD).
• Oral hairy leukoplakia in HIV (corrugated white tongue lesions, EBV-driven, non-scrapable).

High-yield: EBV → Burkitt lymphoma (t(8;14), c-myc), nasopharyngeal carcinoma, Hodgkin lymphoma, oral hairy leukoplakia, PTLD.

Management of uncomplicated mono is supportive; avoid contact sports for ~3 weeks due to splenic rupture risk. Antivirals are not routinely indicated.

HHV-6, HHV-7 and HHV-8

• HHV-6 (and HHV-7) — betaherpesviruses causing roseola infantum (exanthem subitum / sixth disease): high fever for 3–4 days that defervesces just as a maculopapular rash appears on the trunk; classically in infants, can trigger febrile seizures.
• HHV-8 (Kaposi sarcoma-associated herpesvirus, KSHV) — gammaherpesvirus and cause of Kaposi's sarcoma (AIDS-defining; purplish vascular skin/visceral lesions, spindle cells), primary effusion lymphoma, and multicentric Castleman disease.

High-yield: HHV-6 → roseola infantum; HHV-8 → Kaposi sarcoma. Frequent one-liner matches.

The latency-and-disease flow (stepwise)

Primary mucosal/epithelial infection → local replication → retrograde axonal (or lymphocyte) spread → establishment of latency in ganglion/lymphocyte → trigger (immunosuppression, UV, fever, stress) → reactivation → anterograde spread → recurrent localised disease.

A practical diagnostic approach to a suspected herpesvirus lesion:

1. Vesicular skin/mucosal lesion? → Tzanck smear (giant cells = HSV or VZV) → confirm with PCR/DFA for typing.
2. Encephalitis with temporal lobe signs? → CSF PCR for HSV → start IV acyclovir empirically.
3. Owl-eye cells / retinitis in immunocompromised? → CMV → ganciclovir.
4. Pharyngitis + posterior cervical nodes + atypical lymphocytes? → heterophile/Paul-Bunnell → EBV.
5. Purple vascular skin nodules in HIV? → HHV-8 → Kaposi sarcoma.

Inclusion bodies and antiviral pairings (consolidated)

Virus	Inclusion / hallmark	Latency site	Drug of choice
HSV-1/2	Cowdry A; multinucleate giant cells (Tzanck)	Trigeminal / sacral ganglia	Acyclovir (foscarnet if resistant)
VZV	Cowdry A; giant cells	Dorsal root ganglia	Acyclovir / valacyclovir
CMV	Owl-eye intranuclear inclusion	Monocytes, glands	Ganciclovir / valganciclovir
EBV	Atypical (Downey) lymphocytes	B lymphocytes	Supportive
HHV-8	Spindle cells (Kaposi)	B lymphocytes	ART + chemotherapy

Mnemonic for HSV antiviral mechanism — "TK turns on the drug": Acyclovir needs viral Thymidine Kinase for its first phosphorylation; loss of TK → acyclovir resistance → switch to Foscarnet (a pyrophosphate analogue that directly inhibits DNA polymerase, bypassing TK).

Complications worth remembering

• HSV: keratitis/blindness, encephalitis, neonatal disseminated disease, eczema herpeticum.
• VZV: post-herpetic neuralgia, Reye syndrome (with aspirin), pneumonia in adults/pregnancy, congenital varicella syndrome, Ramsay Hunt syndrome.
• CMV: congenital deafness/calcification, retinitis, transplant rejection-mimicking disease.
• EBV: splenic rupture, malignancies, PTLD.
• HHV-8: visceral Kaposi, primary effusion lymphoma.

Key differentials

• Chickenpox vs smallpox: stages (mixed vs uniform), distribution (centripetal vs centrifugal).
• EBV vs CMV mononucleosis: EBV is heterophile-positive; CMV mononucleosis is heterophile-negative with milder pharyngitis.
• HSV vs VZV vesicle: Tzanck cannot separate them — PCR/DFA needed; distribution helps (dermatomal = zoster).
• CMV vs Toxoplasma congenital infection: periventricular vs diffuse calcification.
• Herpangina (Coxsackie A) vs herpetic gingivostomatitis (HSV-1): posterior oropharynx vs anterior mouth/gingiva.

Recently asked / exam angle

• Owl-eye inclusion body → identify the virus (CMV) — repeatedly tested image/match question.
• Drug of choice for CMV retinitis (ganciclovir/valganciclovir) and for acyclovir-resistant HSV (foscarnet).
• Latency sites: HSV-1 trigeminal, HSV-2 sacral, VZV dorsal root ganglia — direct one-liners.
• Paul-Bunnell / Monospot test and heterophile antibodies linked to EBV; ampicillin rash vignette.
• Burkitt lymphoma t(8;14), c-myc and EBV association.
• Reye syndrome trigger (aspirin in varicella/influenza in children).
• HSV encephalitis → temporal lobe + CSF PCR + empiric IV acyclovir.
• Tzanck smear finding (multinucleated giant cells) and its inability to distinguish HSV from VZV.
• HHV-6 = roseola, HHV-8 = Kaposi match-the-following pairs.
• Receptor for EBV entry into B cells: CD21 (CR2).

Rapid revision

1. Herpesviruses are enveloped, dsDNA, icosahedral viruses defined by lifelong latency.
2. Alpha → ganglia (HSV, VZV); Beta → monocytes/glands (CMV, HHV-6/7); Gamma → B lymphocytes (EBV, HHV-8).
3. HSV-1 latency = trigeminal ganglion; HSV-2 = sacral ganglion. Tzanck smear shows multinucleated giant cells.
4. HSV encephalitis = temporal lobe; CSF PCR is investigation of choice; treat empirically with IV acyclovir.
5. Acyclovir is activated by viral thymidine kinase; resistance (TK-deficient) → use foscarnet.
6. Chickenpox = lesions in different stages, centripetal; smallpox = same stage, centrifugal.
7. Aspirin + varicella/influenza in children → Reye syndrome; use paracetamol.
8. Herpes zoster ophthalmicus → Hutchinson's sign; Ramsay Hunt = geniculate ganglion + facial palsy.
9. CMV = owl-eye inclusion; commonest congenital infection; periventricular calcification + deafness; treat with ganciclovir/valganciclovir.
10. EBV infects B cells via CD21; causes heterophile-positive mono (Paul-Bunnell/Monospot), atypical lymphocytes; ampicillin → rash.
11. EBV malignancies: Burkitt (t(8;14), c-myc), nasopharyngeal carcinoma, Hodgkin, oral hairy leukoplakia, PTLD.
12. HHV-6 → roseola infantum; HHV-8 → Kaposi sarcoma, primary effusion lymphoma, Castleman disease.