Fig 1.
The chikungunya virus (CHIKV) replication cycle includes several steps, each offering potential targets for antiviral design.
(Step 1) The E2 glycoprotein of CHIKV binds to cellular attachment factors (e.g., heparan sulfate and phosphatidylserine receptors) and the receptor MXRA8, facilitating viral attachment. (Step 2) CHIKV enters host cells via clathrin-mediated endocytosis. (Step 3) In the endosome, an acidic environment induces a conformational change in the E1 glycoprotein, leading to fusion of the viral envelope with the endosomal membrane and release of viral genomic RNA into the cytoplasm. (Step 4) The genomic RNA is positive-sense single-stranded RNA (+ssRNA), functioning as messenger RNA (mRNA). Translation begins at the 5′ end, producing a large nonstructural polyprotein. (Step 5) This polyprotein is processed by viral proteases, mainly nsP2, into individual nonstructural proteins (nsP1-nsP4). (Step 6) Nonstructural proteins assemble on intracellular membranes to form viral replication complexes (RCs), where +ssRNA serves as a template for synthesizing negative-sense RNA intermediate (−ssRNA). This intermediate is then used to produce full-length +ssRNA and subgenomic +ssRNA. (Step 7) Subgenomic RNA encodes a polyprotein precursor containing structural proteins Capsid–E3–E2–6K–E1, which are processed by host and viral proteases. (Step 8) The capsid protein undergoes autocatalytic cleavage to release itself from the polyprotein and binds full-length +ssRNA to form nucleocapsids. (Step 9) Remaining structural proteins E1 and E2 are co-translationally translocated into the endoplasmic reticulum (ER), where they undergo glycosylation and heterodimer formation before being transported through ER-Golgi intermediate compartment (ERGIC), contributing to viral envelope formation. (Step 10) The nucleocapsid moves to the plasma membrane or membranes derived from the endoplasmic reticulum, where E1 and E2 glycoproteins are incorporated. Budding occurs at these locations, leading to the secretion of virions from the infected cell. This figure created in BioRender. Zhu, Z. (2025) https://BioRender.com/9slnvj3.