The historical roots of hantavirus research trace back to the Korean War in the early 1950s, when thousands of United Nations soldiers developed a severe febrile illness later identified as Korean hemorrhagic fever. The causative agent, Hantaan virus, was not isolated until 1978 near the Hantan River in South Korea, giving rise to the name hantavirus. Since that discovery, numerous hantavirus species have been identified worldwide, each tightly associated with a specific rodent or small mammal reservoir. Today, hantaviruses are classified within the order Bunyavirales and the family Hantaviridae, a taxonomic revision that reflects their unique genetic and biological characteristics compared with other bunyaviruses. The genus Orthohantavirus contains the majority of species pathogenic to humans, including Hantaan virus, Seoul virus, Puumala virus, Dobrava-Belgrade virus, Sin Nombre virus, and Andes virus.

Structurally, hantaviruses form spherical virions measuring approximately 80 to 120 nanometers in diameter, enclosed by a lipid envelope studded with glycoprotein spikes that mediate host cell recognition, attachment, and membrane fusion. The genome consists of three segments of negative-sense single-stranded RNA designated large, medium, and small. The large segment encodes the RNA-dependent RNA polymerase responsible for transcription and replication, the medium segment encodes the precursor of the envelope glycoproteins Gn and Gc, and the small segment encodes the nucleocapsid protein that binds and protects viral RNA. Beyond its structural role, the nucleocapsid protein contributes to immune evasion by interfering with host innate immune responses. Critically, the segmented genome permits genetic reassortment when multiple strains co-infect the same host cell, a mechanism that enhances viral diversity and can generate novel strains with altered virulence and host range.

The replication cycle of hantaviruses is entirely cytoplasmic, distinguishing them from many other RNA viruses that involve nuclear stages. Viral entry is initiated through interactions between surface glycoproteins and host cell receptors, including β3 integrins, β1 integrins, decay-accelerating factor, and protocadherin-1, the latter identified as a particularly critical entry receptor for New World hantaviruses such as Andes virus, Sin Nombre virus, and Laguna Negra virus. Following receptor engagement, virions enter cells predominantly through clathrin-mediated endocytosis, and endosomal acidification triggers conformational changes that facilitate membrane fusion. The viral polymerase employs a cap-snatching mechanism, cleaving short capped fragments from host messenger RNAs to prime viral mRNA synthesis, a strategy that ensures efficient translation while contributing to host protein synthesis shutoff and immune evasion. Virion assembly occurs primarily at the Golgi apparatus before mature particles are released via the secretory pathway.

Epidemiologically, hantaviruses impose two distinct clinical syndromes shaped by geography and viral species. Hemorrhagic fever with renal syndrome, caused by Old World viruses such as Hantaan, Seoul, Puumala, and Dobrava-Belgrade, predominates in Europe and Asia and follows a classically five-phase course encompassing febrile, hypotensive, oliguric, polyuric, and convalescent stages, with mortality ranging from less than 1 percent in mild Puumala infections to roughly 15 percent in severe Dobrava-Belgrade cases. Hantavirus cardiopulmonary syndrome, driven by New World viruses in the Americas, presents with fulminant respiratory compromise, pulmonary edema, and cardiogenic shock, with case-fatality rates reaching 40 to 50 percent despite intensive supportive care. China bears the highest global burden of hemorrhagic fever with renal syndrome, while Puumala virus drives cyclical outbreaks across Northern and Central Europe tied to fluctuations in bank vole populations. In the Americas, Andes virus stands apart as the only hantavirus with well-documented person-to-person transmission, primarily among household members, sexual partners, and caregivers during the prodromal phase when viral loads are high but symptoms remain nonspecific.

Transmission to humans occurs overwhelmingly through inhalation of aerosolized viral particles from contaminated rodent urine, feces, and saliva, particularly in enclosed or poorly ventilated spaces. Secondary routes include contact with contaminated fomites, rodent bites, and consumption of contaminated food or water. High-risk groups encompass farmers, forestry workers, military personnel, laboratory workers, and outdoor enthusiasts. Rodent population dynamics, governed by climatic fluctuations such as El Niño Southern Oscillation events, deforestation, agricultural expansion, and urban encroachment into wildlife habitats, strongly modulate spillover risk. Despite public concern, the review emphasizes that hantaviruses lack efficient airborne transmission comparable to influenza or SARS-CoV-2, and human-to-human spread remains rare and largely restricted to Andes virus, a constraint that limits widespread global dissemination even as localized outbreaks with serious consequences persist.

Pathogenically, hantavirus disease is defined by profound vascular permeability resulting from endothelial dysfunction rather than direct cytopathic injury. The viruses preferentially infect vascular endothelial cells and persist without causing overt cell lysis, meaning that host immune responses, not viral-mediated death, drive tissue injury. Pattern-recognition receptors including Toll-like receptors 3 and 7 and cytosolic sensors RIG-I and MDA5 initiate type I interferon signaling, yet many hantaviruses encode mechanisms to blunt this response, delaying antiviral defenses. Subsequent adaptive immunity, characterized by cytotoxic T lymphocyte expansion and neutralizing antibodies against the Gn and Gc glycoproteins, can clear infection, but dysregulated or excessive responses generate a cytokine storm phenotype that disrupts endothelial barrier integrity. This delicate balance between viral control and immunopathology shapes disease severity and informs therapeutic strategies aimed at restoring antiviral control while tempering hyperinflammation.

Diagnosis relies on a combination of clinical suspicion, exposure history, and laboratory confirmation, with serological assays detecting virus-specific IgM and IgG antibodies remaining the most widely used approach, complemented by reverse transcription polymerase chain reaction for early viral RNA detection and genome sequencing for strain identification. However, nonspecific early symptoms, a narrow window of viremia, serological cross-reactivity among related species, and limited access to molecular diagnostics in resource-constrained settings continue to impede accurate case recognition, particularly in Africa and many low- and middle-income countries. Treatment remains fundamentally supportive, encompassing oxygen supplementation, mechanical ventilation, extracorporeal membrane oxygenation, hemodynamic stabilization, and renal replacement therapy as needed. Ribavirin has shown partial efficacy against certain Old World hantaviruses when administered early, while favipiravir, monoclonal antibodies, and nanotechnology-based delivery platforms represent promising but still investigational avenues. No universally approved vaccine exists; licensed inactivated formulations are restricted to China and South Korea for selected Old World strains, and next-generation platforms including DNA, mRNA, recombinant viral vector, and virus-like particle vaccines are under development to achieve broader cross-protection.

The review operationalizes a One Health framework into concrete prevention and control actions, calling for integrated human-animal-environment surveillance, targeted rodent reservoir monitoring, environmental sampling, and formal intersectoral coordination mechanisms. Primary prevention centers on environmental sanitation, rodent-proofing, proper ventilation of enclosed spaces before cleaning, wet-cleaning methods that minimize aerosol generation, and personal protective equipment for occupationally exposed individuals. Community education campaigns play a critical role in improving risk perception and encouraging early medical consultation after high-risk exposures. Genomic surveillance, combined with climate modeling and ecological forecasting, enables more precise outbreak reconstruction and proactive preparedness, while artificial intelligence-assisted prediction models may further enhance the integration of ecological, climatic, and epidemiological data.

Looking ahead, the author identifies persistent controversies and knowledge gaps, including the determinants of reservoir competence, the sensitivity of current surveillance systems, and the limits of predictive models, alongside unresolved questions about the biological basis of Andes virus transmissibility and whether other hantavirus species harbor undetected human-to-human potential. Although a COVID-19-like global pandemic caused by hantaviruses currently appears unlikely given their transmission dynamics, the review concludes that increasing ecological disruption and global connectivity demand sustained interdisciplinary collaboration among virologists, epidemiologists, ecologists, clinicians, and public health authorities. Strengthening early warning systems, expanding genomic surveillance, developing pan-hantavirus vaccines and broad-spectrum antivirals, and formalizing One Health coordination mechanisms are framed as essential pillars for preventing future high-consequence hantavirus events in an era of accelerating environmental change.

Subject of Research: Hantavirus zoonotic spillover risk, molecular virology, and One Health preparedness

Article Title: Hantaviruses at an inflection point: scientific evidence, spillover risk, and One Health approach

Article References: Zatla, I. (2026). Hantaviruses at an inflection point: scientific evidence, spillover risk, and One Health approach. Frontiers in Virology, 6, Article 1883348. https://doi.org/10.3389/fviro.2026.1883348

Image Credits: AI Generated

DOI: 10.3389/fviro.2026.1883348

Keywords: hantavirus, zoonosis, rodent reservoirs, Andes virus, One Health, hemorrhagic fever with renal syndrome, hantavirus cardiopulmonary syndrome, spillover, genomic surveillance, vaccine development, antiviral therapy, public health preparedness