A Tri-Segmented RNA Genome Encoding Three Key Proteins

The HTNV genome is composed of three negative-sense RNA segments — S (small), M (medium), and L (large) — each encapsidated by nucleocapsid protein N to form a ribonucleoprotein (RNP) complex, the functional template for transcription and replication.^[4]

The M segment encodes the glycoprotein precursor (GPC), co-translationally cleaved by host signal peptidase into mature Gn (G1) and Gc (G2). Gn mediates receptor binding, membrane fusion, and viral morphogenesis. Gc forms homotetramers with Gn at the virion surface and attaches to host cell receptors via integrins ITGAV/ITGB3.^[4] Antibodies targeting Gn and Gc exhibit potent neutralizing activity and confer lasting protection in vivo, making them the primary targets for vaccine and therapeutic antibody development.^[4]

The S segment encodes the Nucleocapsid protein N (NP, ~50 kDa) — the most conserved and abundantly expressed structural protein during infection. NP is essential for viral RNA replication and is the dominant immunogenic antigen, triggering strong humoral and cellular immune responses detectable early in the acute phase of HFRS.^[2,5]

The L segment encodes the RNA-dependent RNA polymerase (RdRp), the largest viral protein, responsible for genome replication and mRNA transcription. Uniquely, the hantavirus RdRp can recombine homologous RNA sequences, enabling viral evolution through superinfection.^[4]

Endothelial Targeting & Type I Interferon Suppression

HTNV preferentially infects endothelial cells via integrin ITGAV/ITGB3-mediated entry — triggering increased vascular permeability, the hallmark of HFRS pathophysiology — without causing direct cytopathic lysis of the host cell.^[1] Loss of endothelial barrier integrity drives the capillary leakage, hemorrhage, and renal dysfunction that define the clinical course.

A key virulence mechanism involves active suppression of innate antiviral immunity. A study published in Virology (2024) demonstrated that HTNV NP and Gc proteins both inhibit host type I interferon (IFN-I) production by targeting the RIG-I–like receptor (RLR) signaling pathway. Mechanistically, NP and Gc interact with TRIM25 to competitively block its association with RIG-I/MDA-5, suppressing downstream IFN-I signaling — with Gc exerting a stronger inhibitory effect than NP.^[7]

On the adaptive immunity side, HTNV glycoprotein-specific CD4⁺ T-cell responses — both Th1 (polyfunctional cytokine secretion) and ThGranzyme B⁺ (cytotoxic mediators) — inversely correlate with plasma HTNV RNA load. Broader epitope targeting and stronger CD4⁺ T-cell responses associate with milder disease outcomes.^[8] The nucleocapsid protein is simultaneously the dominant target for early CD8⁺ T-cell responses.^[9]