Review maps hepatitis E receptor networks and immune evasion

A 2026 review concludes that hepatitis E virus (HEV) does not depend on one universal receptor or a single immune-evasion pathway. Instead, available evidence points to overlapping host attachment factors, entry cofactors, endosomal trafficking machinery and lysosomal processing enzymes, together with immune-modulatory activities associated with HEV’s three principal open reading frames. The synthesis offers a provisional framework for understanding the pathogen’s broad cellular and animal host range, its clinical diversity and its ability to establish chronic infection in some immunocompromised people. It also emphasizes that much of the evidence comes from separate cell-culture, virus-like-particle and ectopic-expression systems that have not yet been tested together in a physiologically relevant model.

HEV is a small, positive-sense RNA virus in the Hepeviridae family, with a genome of roughly 7.2 kilobases encoding ORF1, ORF2 and ORF3. Genotype 1 also carries an overlapping ORF4. The pathogen occurs in two biologically important particle forms: non-enveloped HEV, released into bile and feces, and quasi-enveloped HEV, which acquires a host-derived lipid membrane and can circulate in blood and cell-culture supernatants. These forms share some entry machinery but differ in their initial attachment factors and intracellular routes. ORF1 encodes the replication polyprotein, ORF2 forms the capsid and has a secreted immunomodulatory isoform, and ORF3 promotes quasi-enveloped particle release while affecting host signaling. The review treats these as interacting modules rather than isolated proteins, while noting that the proposed organization of ORF1 into separately processed domains remains controversial.

No single high-affinity HEV receptor has been established, unlike the receptor network defined for hepatitis C virus. Instead, infectious virus and recombinant capsid particles implicate a layered portfolio of host factors. Cell-surface heparan sulfate proteoglycans, particularly syndecans with 6-O-sulfated glycans, provide low-affinity electrostatic attachment for the non-enveloped capsid; removing heparan sulfate reduces capsid binding and infection. The quasi-enveloped form does not depend on this exposed-capsid interaction in the same way because its lipid cloak shields the capsid. Phosphatidylserine exposed on that cloak instead supports entry through the phosphatidylserine-binding factor TIM1, also known as HAVCR1. Both forms enter through clathrin- and dynamin-dependent endocytosis, but downstream routing differs: non-enveloped particles pass through Rab11-positive recycling endosomes, while quasi-enveloped particles proceed through Rab5a-positive early endosomes and Rab7-positive late endosomes.

Several lysosomal factors support the final stages of entry. Niemann–Pick C1 and lysosomal acid lipase contribute to disassembly of the quasi-envelope, while cathepsin L mediates capsid proteolysis and genome release. In hepatocytes, the asialoglycoprotein receptor directly binds the ORF2 ectodomain and facilitates attachment and entry, but it is better described as an entry-associated factor than an obligatory receptor. Epidermal growth factor receptor (EGFR) presents an especially important qualification: it assists entry after attachment, yet HEV-driven EGFR downregulation can subsequently favor replication, release and immune escape. EGFR therefore has stage-dependent effects across the life cycle, and an intervention that reduces initial entry may increase extracellular virus at later stages. Candidate factors such as GRP78, HSC70 and ATP5B have less complete functional validation and remain less firmly characterized than the factors supported by infectious-virus and gene-manipulation experiments.

Based on these findings, the review proposes a dual-module heuristic for organizing HEV tropism. A broadly expressed core includes heparan-sulfate-mediated attachment, clathrin and dynamin uptake, Rab-regulated trafficking, and NPC1- and cathepsin-dependent endolysosomal processing. A liver-enriched ASGPR–EGFR amplifier adds preferential access to hepatocytes, while the TIM1 route permits quasi-enveloped HEV to bypass the exposed capsid. The authors stress that this is a hypothesis assembled from separate studies, not a validated causal model. The framework also may not extend across the entire Hepeviridae. Rat HEV, classified within Rocahepevirus ratti, binds and enters human liver and intestinal cells efficiently through a capsid spike-domain determinant, unlike virus-like particles from ferret, bat and avian viruses. This lineage-specific behavior means receptor evidence from classical Paslahepevirus genotypes should not automatically be extrapolated to rat HEV.

HEV’s broad clinical and animal host range is likewise unlikely to result from a single factor. Genotypes 1 and 2 are human-restricted and spread mainly through contaminated water in endemic regions, whereas genotypes 3 and 4 circulate in pigs and other animals and can reach people through food, animal contact or environmental exposure. Genotypes 5 and 6 have been detected in wild boar, genotype 7 in dromedary camels and genotype 8 in Bactrian camels. A chimeric HEV-3 carrying the genotype 1 capsid P domain failed to infect swine cells, highlighting capsid determinants in host restriction. Residues 490 and 492 of ORF2 affect selective antibody binding and attachment, but they are not the only determinants. Other evidence points to the ORF1 hypervariable region and to differences in post-entry replication compatibility. A broadly conserved entry network may therefore permit initial infection, while viral genetics, intracellular conditions and host immunity determine whether infection becomes productive or sustained.

Following entry, HEV is recognized principally by the cytosolic sensors RIG-I and MDA5 and by Toll-like receptors. RIG-I and MDA5 signal through MAVS, TBK1 and IRF3, while Toll-like receptor pathways converge on IRF3 and NF-κB. These routes stimulate type I and type III interferons and the expression of interferon-stimulated genes. The response is cell-type dependent: hepatocytes can show a predominant type III interferon response, whereas enterocytes can favor type I interferon. Type III signaling appears particularly important in hepatocytes because depletion of its receptor IFNLR1, but not IFNAR1, enhanced HEV replication in one experimental system. Yet the antiviral effect remains incomplete. Interferon-stimulated genes accumulate, and individual effectors including Mx proteins, OAS/RNase L, PKR, ISG20 and IFIT1 restrict replication, yet HEV can continue to replicate. ISG15 may act as a brake on type I interferon sensitivity, and the viral RNA-dependent RNA polymerase can sequester IFIT1 away from HEV RNA.

The three viral proteins interfere with this response at different levels. Within ORF1, the methyltransferase region, X domain and putative papain-like cysteine protease region reduce RIG-I- or MDA5-dependent interferon induction, interfere with IRF3 and NF-κB activation, and antagonize TBK1-dependent signaling. The putative protease region has also been reported to remove K63-linked ubiquitin chains from RIG-I and TBK1, although its status as a catalytically active enzyme is disputed. ORF2 produces both the capsid protein and a more abundant secreted glycosylated form, ORF2S, which acts as an antigen decoy for anti-capsid antibodies without blocking cell entry. Studies using ectopically expressed proteins also indicate that ORF2 can reduce NF-κB signaling by limiting degradation of IκBα and by attenuating induction of TNFAIP3 and IL6. Evidence for these effects comes partly from expression systems that may not reproduce the abundance or timing of proteins during authentic infection.

ORF3 has an equally context-dependent role. It can transiently activate NF-κB early in infection but suppress the pathway later, in part through reduced TRAF6 and NOD2 activity and diminished IKKε and NF-κB phosphorylation. Other experiments report inhibition of STAT1 or TLR7-associated signaling, whereas one system found enhanced RIG-I ubiquitination and interferon induction. These apparently conflicting results may reflect differences in cell type, expression level, duration or experimental system rather than a single uniform function. ORF3 also recruits the ESCRT machinery through a PSAP late-domain motif and localizes with multivesicular bodies, enabling quasi-enveloped particles to leave cells through an exosomal route. The acquired membrane can shield viral antigens from antibodies, while reported viroporin-like activity and effects on mitochondrial physiology may help preserve cellular conditions conducive to prolonged particle production.

The review identifies several priorities for resolving the remaining uncertainty. Authentic infectious-virus studies, polarized or three-dimensional hepatocyte cultures, organoids and organ-derived explants are needed to test the dual-module model and distinguish productive extrahepatic replication from passive circulation of viral material. Infectious-clone approaches could clarify how ORF3 affects signaling under natural protein stoichiometry and determine whether ORF1 is processed, processed only in limited settings, or functions as a monomeric multifunctional polyprotein. The central picture is that HEV combines distributed receptor use with layered interference in sensing, interferon induction, inflammatory signaling and particle release. This architecture can support acute infection, cross-species spillover and persistent disease under immunosuppression, but its components remain to be tested together in models that reproduce human tissues and physiological viral exposure.

Subject of Research: Hepatitis E virus cell entry, tissue tropism and innate immune evasion

Article Title: Host receptor networking and molecular mechanisms of innate immune evasion in hepatitis E virus pathogenesis

Article References: Zohaib, A., Yamin, M., Butt, M. U., Ge, X.-Y., Aljedani, S. S., & Abdulal, R. H. (2026). Host receptor networking and molecular mechanisms of innate immune evasion in hepatitis E virus pathogenesis. Frontiers in Microbiology, 17, Article 1938537. https://doi.org/10.3389/fmicb.2026.1938537

Image Credits: AI Generated

DOI: 10.3389/fmicb.2026.1938537

Keywords: hepatitis E virus, viral entry, host receptors, innate immunity, immune evasion, interferon signaling, tissue tropism, zoonosis, viral genomics, Host, receptor, networking