Classification & Structure
| Order / Family | Amarillovirales / Flaviviridae |
|---|---|
| Genus / Species | Flavivirus / Zika virus; closest relatives: Spondweni virus (serogroup); distantly related to dengue, West Nile, yellow fever, Japanese encephalitis viruses |
| Lineages | African lineage (ancestral; Uganda 1947 isolate, Rhesus 766 strain); Asian lineage (emerged Pacific/Americas epidemic strains; Micronesia 2007, French Polynesia 2013–14, Brazil 2015–16). Asian lineage associated with microcephaly. |
| Genome | ~10.8 kb positive-sense single-stranded RNA; 5′ cap (type I), no poly-A tail; single ORF encoding ~3,423 aa polyprotein flanked by 5′ and 3′ UTRs with stem-loop structures important for replication and immune evasion |
| Polyprotein processing | Co- and post-translational cleavage by host signal peptidase + viral NS2B-NS3 serine protease yields: 3 structural proteins (C, prM/M, E) + 7 non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, NS5) |
| Virion morphology | Enveloped, icosahedral, 40–65 nm; 180 copies of E and M proteins arranged in head-to-tail dimers (T=1 pseudo-T=3); E protein domain III mediates receptor binding; prM in immature virions cleaved by furin to M during egress |
| Entry receptors | AXL (Gas6-dependent TAM receptor) — primary on neural progenitor cells, trophoblasts, endothelium, macrophages; TYRO3 — neurons/glia; TIM-1 (HAVCR1) — mucus-producing cells; DC-SIGN (CD209) — dendritic cells; Integrin αvβ5; TYRO3 redundant with AXL in skin fibroblasts |
| Transmission routes | Mosquito-borne (primary): Aedes aegypti and Ae. albopictus; Sexual transmission (male→female, male→male; virus persists in semen weeks-months post-infection); Transplacental (vertical — cause of congenital Zika syndrome); Blood transfusion (rare); Breastfeeding (RNA detected in milk; transmission unconfirmed) |
| Geographic spread | Africa (1947, endemic); Asia/Pacific (expansion 2007–2015); Americas (2015–2016 pandemic, WHO PHEIC declared Feb 2016); now endemic/hyperendemic in tropical/subtropical belt; declining but ongoing low-level circulation |
Infection Mechanism
- Step 1 — Mosquito inoculation & dermal cell entry Aedes mosquito deposits saliva containing ZIKV into dermal tissue. Skin-resident dendritic cells, Langerhans cells, keratinocytes, and fibroblasts are initial targets. AXL and TYRO3 (TAM receptor tyrosine kinases) bind virus-associated phosphatidylserine via bridging ligands Gas6 and Protein S, enabling "apoptotic mimicry" entry — a mechanism shared with other flaviviruses. Virus-receptor complex is internalised via clathrin-mediated or micropinocytosis endocytosis.
- Step 2 — Endosomal fusion, uncoating & polyprotein translation In acidified endosomes, E protein domain II undergoes pH-dependent conformational change (dimer → trimer), inserting the fusion loop into the endosomal membrane. Genome RNA is released into the cytoplasm. Host ribosomes translate the single ORF; NS2B-NS3 serine protease and NS3 NTPase/helicase are essential for polyprotein processing and RNA replication. Replication occurs on ER-derived membranous webs (invaginations induced by NS4A/NS4B).
- Step 3 — NS5 STAT2 degradation — innate immune evasion NS5 (the viral RdRp + MTase) directly binds human STAT2 and recruits the UBR4 E3 ubiquitin ligase for proteasomal degradation. This efficiently blocks IFN-α/β signalling downstream of IFNAR1/2, preventing ISG induction. NS4B additionally suppresses STING and RIG-I pathways. The IFN antagonism is more effective in human cells than murine cells — explaining why mouse models require immunocompromised (IFNAR-KO) backgrounds to model Zika disease. Result: prolonged high-level viraemia despite antiviral immune activation.
- Step 4 — Neural progenitor cell (NPC) tropism & microcephaly mechanism In the developing fetal brain, NPCs highly express AXL and TYRO3. ZIKV preferentially infects radial glia (primary NPCs) lining the ventricular zone, which normally divide to generate all cortical neurons. Intracellular mechanisms driving microcephaly: (1) ANKLE2 interaction — ZIKV NS4A/NS4B dysregulate the lipid kinase PI3K/Akt pathway by interacting with ANKLE2, a regulator of nuclear lamina, causing mitotic catastrophe in NPCs; (2) G2/M cell cycle arrest — viral proteins cause checkpoint arrest, reducing NPC proliferation; (3) p53-dependent apoptosis — ZIKV activates caspase-3 in NPCs, depleting the progenitor pool; (4) symmetric → asymmetric division shift — alters cortical neurogenesis timing. Net result: profound cortical thinning, ventriculomegaly, simplified gyral pattern (lissencephaly/pachygyria), congenital microcephaly.
- Step 5 — GBS molecular mimicry & peripheral nerve injury ZIKV envelope protein and NS1 share structural/sequence homology with human gangliosides (GM1, GD1a, GD1b expressed on peripheral nerve myelin). Post-infectious antibody cross-reactivity triggers complement-mediated and T-cell-mediated attack on peripheral myelin and axons. The predominant GBS subtype is acute motor axonal neuropathy (AMAN) — distinct from post-dengue, post-EBV GBS which tends to be AIDP. Onset typically 1–4 weeks after acute Zika infection. Molecular mimicry with ZIKV NS1 and myelin proteins is supported by serologic cross-reactivity data.
Host Immune Response
Disease Spectrum
| Syndrome | Key Features | Severity |
|---|---|---|
| Asymptomatic infection | ~80% of infections; detectable viraemia 1–7 days; infectious to mosquitoes and sexual partners | None |
| Acute Zika fever | Maculopapular rash, low-grade fever, non-purulent conjunctivitis, arthralgia/myalgia; self-limited ~5–7 days | Mild |
| Congenital Zika syndrome (CZS) | Microcephaly; cerebral calcifications (periventricular, cortical/subcortical); cortical dysplasia; ventriculomegaly; cerebellar hypoplasia; limb contractures; hearing loss; retinal abnormalities. Worst outcomes with 1st-trimester infection. | Critical |
| Guillain-Barré syndrome (GBS) | Ascending flaccid paralysis 1–4 weeks post-infection; AMAN subtype predominant; ~1/4,000 infections; 5–8% require mechanical ventilation; most recover but residual weakness common | Severe |
| Encephalitis / meningitis | Rare in adults; fever, altered consciousness, CSF pleocytosis; reported in immunocompromised and elderly | Severe |
| Acute myelitis | Spinal cord inflammation; motor/sensory/autonomic dysfunction; rare but well-documented in outbreaks | Severe |
| Testicular inflammation | Orchitis; prolonged viral persistence in semen (up to 6 months); risk of sexual transmission window | Moderate |
Treatment & Prevention
| Supportive care (acute infection) | No approved antiviral exists. Management is symptomatic: antipyretics (acetaminophen preferred; aspirin/NSAIDs avoided until dengue excluded due to haemorrhage risk), hydration, rest. Serology-confirmed ZIKV: monitor for neurological symptoms and counsel regarding sexual transmission and pregnancy risk. |
|---|---|
| GBS management | Intravenous immunoglobulin (IVIg) — 2 g/kg over 5 days; reduces disease severity and accelerates recovery by neutralising pathogenic autoantibodies. Plasmapheresis — equivalent efficacy to IVIg; removes circulating anti-ganglioside antibodies. ICU-level respiratory monitoring; intubation if FVC <20 mL/kg. Physical/occupational rehabilitation essential for recovery. |
| Congenital Zika syndrome — supportive | No disease-modifying therapy. Management: multidisciplinary neurodevelopmental assessment; antiepileptics for seizures; feeding support (nasogastric/gastrostomy); physiotherapy; ophthalmologic/audiologic follow-up. Outcomes vary by severity of cortical malformation. |
| Vector control | Aedes mosquito control: elimination of standing water (breeding sites); insecticide-treated bed nets; DEET/IR3535 repellents; release of Wolbachia-infected or sterile male mosquitoes (population suppression programs, e.g., World Mosquito Program). |
| Sexual transmission prevention | WHO recommends consistent condom use or abstinence for ≥3 months after return from Zika-endemic areas (men) and ≥2 months (women) to prevent sexual transmission. Particularly critical for pregnant partners or those planning pregnancy. |
| mRNA vaccine candidates (Phase I/II) | mRNA-1893 (Moderna) — LNP-encapsulated mRNA encoding prM/E; Phase II completed; demonstrates seroconversion >90% and neutralising antibody titers. Two-dose 50 µg IM regimen. Safety profile consistent with other mRNA vaccines. |
| DNA vaccine candidates (Phase I/II) | VRC5283 (NIAID/VRC) and GLS-5700 — plasmid DNA encoding prM/E; Phase II (NCT02887482); immunogenic with electroporation delivery. Lower immunogenicity than mRNA platform alone; require 3-dose regimens. |
| Purified inactivated virus (ZPIV) | ZPIV (Walter Reed Army Institute) — alum-adjuvanted inactivated ZIKV; Phase II; strong neutralising antibody response; requires 2-dose prime + boost; established safety. Traditional platform with well-understood regulatory path. |
| Vaccine development status (2025) | No vaccine has reached Phase III efficacy trial, primarily due to: waning epidemic (reducing endpoint events), challenge of testing in pregnant women, ADE (antibody-dependent enhancement) concerns given dengue co-circulation, and complex correlates of protection for fetal outcomes. mRNA-1893 considered furthest along. Active WHO/CEPI priority pathogen designation. |
Connections
Infects → Neural progenitor cells (fetal brain)
Damages → Peripheral nerves (GBS — AMAN)
Crosses → Placental barrier (vertical transmission)
Entry → Skin DCs / fibroblasts (mosquito bite)
Evades → IFN-I pathway (NS5 → STAT2 degradation)
Persists → Testes / semen (sexual transmission)
Cross-reacts → Dengue antibodies (ADE risk)
Binds → AXL / TYRO3 TAM receptors
Vector → Aedes aegypti mosquito
Causes → Congenital microcephaly
Triggers → Guillain-Barré syndrome (post-infectious)
Key References
- Brasil P et al. (2016). Zika virus infection in pregnant women in Rio de Janeiro. NEJM 375, 2321–2334. DOI
- Tang H et al. (2016). Zika virus infects human cortical neural progenitors and attenuates their growth. Cell Stem Cell 18, 587–590. DOI
- Cao-Lormeau VM et al. (2016). Guillain-Barré syndrome outbreak associated with Zika virus infection in French Polynesia. Lancet 387, 1531–1539. DOI
- Grant A et al. (2016). Zika virus targets human STAT2 to inhibit type I interferon signaling. Cell Host Microbe 19, 882–890. DOI
- Driggers RW et al. (2016). Zika virus infection with prolonged maternal viremia and fetal brain abnormalities. NEJM 374, 2142–2151. DOI
- Abbink P et al. (2016). Protective efficacy of multiple vaccine platforms against Zika virus challenge in rhesus monkeys. Science 353, 1129–1132. DOI
- Musso D & Gubler DJ (2016). Zika virus. Clin Microbiol Rev 29, 487–524. DOI
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