Varicella-Zoster Virus (VZV / HHV-3) · Human Engineering Atlas

Classification & Structure

Order / Family	Herpesvirales / Herpesviridae
Subfamily / Genus	Alphaherpesvirinae / Varicellovirus
Common names	HHV-3; chickenpox virus (varicella); shingles virus (zoster)
Genome	~125 kb linear dsDNA; unique long (U_L) and unique short (U_S) regions flanked by terminal and internal repeats (TRL/IRL, IRS/TRS); 71 predicted open reading frames
Virion morphology	Enveloped, 150–200 nm; icosahedral capsid (T=16) enclosing the genome; tegument layer (including ORF9 — VP22, IE62, ORF47 kinase); lipid envelope with at least 6 glycoproteins (gB, gC, gE, gH, gI, gK, gL, gM, gN)
Key glycoproteins	gE — major surface antigen; forms gE/gI heterodimer acting as Fc receptor (binds IgG Fc, inhibiting ADCC); gB — membrane fusion; gH/gL — fusion complex; gC — heparan sulfate binding; gE/gI critical for cell-to-cell spread
Immediate-early proteins	IE62 (ORF62) — major transactivator, packaged in tegument; IE63 (ORF63) — anti-apoptotic, critical for latency establishment; IE4 (ORF4), IE61 (ORF61) — additional transactivators/ubiquitin ligase
Latency reservoir	Dorsal root ganglia (DRG) and trigeminal ganglia (TG) sensory neurons; rarely cranial nerve ganglia. Virus establishes lifelong latency after primary varicella infection.
Latency transcripts	VLT (VZV latency transcript) — antisense to IE61; low-level ORF63 protein in latent neurons; no productive replication in latency. VLT·ORF63 fusion transcript upon reactivation.
Transmission	Highly contagious (R₀ ~12); respiratory droplets/aerosol from vesicular fluid; direct contact with lesions; contagious 1–2 d before rash until all lesions crust (~5–7 d after rash onset)

Infection Mechanism

Step 1 — Respiratory entry & tonsillar replication VZV infects respiratory mucosal epithelium; gB and gH/gL mediate fusion, gC binds heparan sulfate for initial attachment. The virus replicates in tonsillar T cells (CD4+ and CD8+) — an obligate step for systemic dissemination. Infected T cells mediate viraemia, delivering VZV to skin and other tissues. gE/gI facilitate cell-to-cell spread, bypassing extracellular antibody neutralisation.
Step 2 — Skin tropism & varicella rash Skin keratinocytes and dermal fibroblasts are infected via infected T cells. Full replication cycle produces characteristic vesicular lesions: intranuclear inclusion bodies (Cowdry type A), ballooning degeneration, multinucleated giant cells. Lesions appear in crops (successive waves of viraemia) in characteristic centripetal distribution — trunk-face-limbs. ~200–500 lesions typical in unvaccinated children.
Step 3 — Retrograde axonal transport & latency establishment From skin nerve endings, VZV undergoes retrograde axonal transport to sensory ganglia (DRG, TG). In neurons, lytic gene expression is suppressed — only VLT and low-level ORF63 (IE63) are expressed. IE63 blocks apoptosis (inhibits pro-apoptotic signals) and suppresses NF-κB-dependent ISG expression. Viral DNA circularises as an episome (~50–100 copies/neuron) and persists for the host's lifetime without productive replication.
Step 4 — IE62 / IE63 innate immune evasion IE62, the major tegument transactivator, suppresses IFN-β promoter activity by interfering with IRF3 activation. IE63 blocks STAT1 phosphorylation downstream of IFN-α/β receptor signalling. ORF61 (IE61) acts as a ubiquitin ligase targeting PML (promyelocytic leukaemia) nuclear bodies — host antiviral structures — for degradation. The gE/gI Fc receptor sequesters IgG to inhibit Fc-mediated effector functions (ADCC, complement activation).
Step 5 — Reactivation & anterograde spread to skin (herpes zoster) Waning cell-mediated immunity (ageing, immunosuppression, stress) allows VZV reactivation. Productive replication resumes in the ganglion neuron; anterograde axonal transport carries virus to the skin territory of that dermatome. Inflammation of the ganglion (ganglionitis) causes the prodromal pain before rash. The characteristic dermatomal vesicular eruption of shingles follows. Reactivation can spread to the anterior horn (motor zoster), eye (zoster ophthalmicus — CN V1), or ear (Ramsay Hunt syndrome — facial nerve / CN VII). Post-herpetic neuralgia (PHN) results from inflammatory neuronal damage and impaired pain modulation.

Host Immune Response

IFN-α/β (plasmacytoid DC — early) NK cell cytotoxicity Macrophage / DC activation Complement via gC binding inhibition VZV-specific IgG (gE, gB, gH targets) CD4+ T cell proliferation (critical for control) CD8+ CTL (IE62, gE epitopes) Memory T cells maintain latency Secretory IgA (mucosal) VZV-specific T cell immunity declines with age Immunosuppression → risk of zoster / dissemination IE63 blocks STAT1 → suppressed ISG expression

Disease Spectrum

Syndrome	Key Features	Severity
Varicella (chickenpox)	Pruritic vesicular rash in crops; fever; self-limited ~1 week in healthy children	Low (children)
Adult varicella	More severe; pneumonitis (varicella pneumonia) in ~1/400 adults; higher mortality	Moderate–High
Varicella in pregnancy	Maternal pneumonia; congenital varicella syndrome (limb hypoplasia, microcephaly, chorioretinitis) if <20 weeks; neonatal varicella if near term	Severe
Herpes zoster (shingles)	Dermatomal vesicular rash; prodromal pain/allodynia; risk increases steeply with age (>50)	Moderate
Post-herpetic neuralgia (PHN)	Persistent burning/stabbing pain >90 days post-rash; 10–15% of zoster cases; debilitating in elderly	Severe (chronic)
Zoster ophthalmicus	CN V1 involvement; keratitis, uveitis, acute retinal necrosis; risk of blindness	Severe
Ramsay Hunt syndrome	Geniculate ganglion; facial palsy, auricular vesicles, vertigo, hearing loss	Severe
Disseminated zoster	Immunocompromised; >20 lesions outside primary/adjacent dermatomes; visceral involvement (pneumonia, hepatitis, encephalitis); high mortality if untreated	Critical

Treatment & Prevention

Acyclovir	Guanosine analogue; phosphorylated by VZV thymidine kinase (TK); inhibits viral DNA polymerase (ORF28). IV acyclovir for severe/disseminated varicella and immunocompromised patients (10–12.5 mg/kg q8h). Oral acyclovir (800 mg 5×/day) for uncomplicated zoster if started within 72h of rash onset. Foundation of anti-VZV therapy since 1982.
Valaciclovir	L-valyl ester prodrug of acyclovir; much improved oral bioavailability (~55% vs ~15–20%). 1 g TID × 7 days for zoster; also used for varicella prophylaxis in exposed immunocompromised contacts. Preferred oral agent due to compliance advantage.
Famciclovir	Prodrug of penciclovir; 500 mg TID × 7 days for zoster. Similar efficacy to valaciclovir. Also reduces PHN duration when started early.
Foscarnet	Pyrophosphate analogue; inhibits viral DNA polymerase without requiring TK activation. Reserved for acyclovir-resistant VZV (TK-deficient mutants) in severely immunocompromised patients (HIV, haematopoietic stem cell transplant). Nephrotoxic — requires careful monitoring.
Post-herpetic neuralgia management	Topical lidocaine patches / capsaicin 8% patch; gabapentin or pregabalin (first-line); tricyclic antidepressants (amitriptyline); opioids as adjunct. Early effective antiviral treatment is the best preventive strategy for PHN.
VZV immunoglobulin (VariZIG)	Post-exposure prophylaxis for immunocompromised susceptible individuals and neonates exposed within 96h. Reduces severity of varicella if administered promptly.
Varivax (live-attenuated, Oka strain)	Two-dose schedule (12–15 months; 4–6 years); ~98% efficacy against moderate/severe varicella. Recommended for all healthy children. Contraindicated in immunocompromised. Vaccinated individuals can rarely develop varicella or zoster from vaccine-strain virus.
Shingrix (RZV — recombinant zoster vaccine)	Adjuvanted recombinant subunit vaccine: VZV glycoprotein E (gE) + AS01B adjuvant system (MPL + QS-21 saponin). Two IM doses 2–6 months apart. >90% efficacy against zoster across all age groups ≥50; >90% efficacy against PHN. Replaces Zostavax (live-attenuated) due to far superior efficacy, especially in elderly. Can be given to previously vaccinated or immunocompromised individuals.

Connections

Establishes latency → Dorsal root ganglia Primary site → Skin keratinocytes Targets → T lymphocytes (viraemia) Damages → Lungs (varicella pneumonia) Damages → Sensory neurons (PHN) Damages → Cornea/retina (zoster ophthalmicus) Prevented by → Shingrix (RZV) Prevented by → Varivax (Oka strain) Treated by → Acyclovir / Valaciclovir Family → Herpesviridae (HHV-3)

Key References

Cohen JI (2013). Herpes zoster. NEJM 369, 255–263. DOI
Depledge DP et al. (2018). A spliced latency-associated VZV transcript maps antisense to the viral transactivator gene 61. Nat Commun 9, 1167. DOI
Arvin AM (1996). Varicella-zoster virus. Clin Microbiol Rev 9, 361–381. DOI
Lal H et al. (2015). Efficacy of an adjuvanted herpes zoster subunit vaccine (ZOE-50 trial). NEJM 372, 2087–2096. DOI
Oxman MN et al. (2005). A vaccine to prevent herpes zoster and postherpetic neuralgia (Shingles Prevention Study). NEJM 352, 2271–2284. DOI
Gershon AA et al. (2015). Varicella zoster virus infection. Nat Rev Dis Primers 1, 15016. DOI
Kennedy PGE & Gershon AA (2018). Clinical features of varicella-zoster virus infection. Viruses 10, 609. DOI

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