New World arenaviruses

The New World arenaviruses are the American branch of the arenavirus family, and their medically important members cause the South American haemorrhagic fevers. Five closely related viruses account for these diseases, each named for the country or region where it emerged: Junin virus (Argentine haemorrhagic fever), Machupo virus (Bolivian haemorrhagic fever), Guanarito virus (Venezuelan haemorrhagic fever), Sabia virus (Brazilian haemorrhagic fever) and Chapare virus. All five belong to a single genetic subgroup, clade B, and all are maintained in nature by cricetid rodents of the Americas, each virus tied to its own reservoir species, with human infection an accidental and largely rural spillover.

The group is best understood alongside the Old World arenaviruses of Africa. Where the Old World pathogens Lassa and Lujo enter cells through alpha-dystroglycan, the pathogenic New World viruses use a different door, human transferrin receptor 1, and their disease carries a more prominent haemorrhagic and neurological picture from the outset. Two features set the group apart clinically: for Argentine haemorrhagic fever there is a licensed live vaccine and an established immune-plasma treatment, countermeasures that do not exist for most haemorrhagic fevers, while the other four agents remain without specific prevention. All are handled only at maximum laboratory containment, and several are recognised biosecurity concerns.

Discovery and historical significance

The New World haemorrhagic fever viruses were discovered one after another as agriculture and settlement brought people into contact with new rodent reservoirs across the twentieth century. Junin virus was identified in the late 1950s as the cause of a haemorrhagic fever among agricultural workers on the Argentine pampas, the first of the group to be characterised. Machupo virus followed in 1963, when a team led by Karl Johnson identified it during an outbreak of Bolivian haemorrhagic fever in the Beni region, an investigation that also pinned the disease to a rodent reservoir and ended one outbreak by trapping the mice.

The pattern continued as further agents emerged. Guanarito virus was recognised in Venezuela in 1989, and Sabia virus in Brazil in 1990, the latter notable for causing laboratory-acquired infections, one after a centrifuge accident, which underlined the hazard of working with these viruses. Chapare virus was identified in Bolivia in the early 2000s. A near relative, Tacaribe virus, holds a special place: isolated from bats in Trinidad in 1956, it is the one clade-B member that is not a rodent virus and does not cause human disease, and it has been used as a safer laboratory surrogate for its dangerous cousins.

Classification, structure, and genome

Classification

The New World arenaviruses form the Tacaribe serocomplex within the genus Mammarenavirus, family Arenaviridae, the counterpart of the Old World Lassa and lymphocytic choriomeningitis complex. They are carried by cricetid rodents of the Americas and divide genetically into several clades, of which clade B contains all the human pathogens; the other clades hold viruses of no known human disease. This split matters because pathogenicity in the group is concentrated so tightly: a virus’s clade, its reservoir and its ability to use the human receptor together predict whether it threatens people.

The medically important members, their diseases and reservoirs are summarised below.

Virus	Disease	Country	Reservoir rodent	Approximate case fatality
Junin	Argentine haemorrhagic fever	Argentina	Calomys musculinus	~15 to 30% untreated
Machupo	Bolivian haemorrhagic fever	Bolivia	Calomys callosus	~15 to 30%
Guanarito	Venezuelan haemorrhagic fever	Venezuela	Zygodontomys brevicauda	~30%
Sabia	Brazilian haemorrhagic fever	Brazil	Unknown	~a third of very few cases
Chapare	Chapare haemorrhagic fever	Bolivia	Unknown	High in small clusters

The New World and Old World groups differ in more than geography, and the contrast is a useful clinical map: the New World clade-B viruses use transferrin receptor 1 rather than alpha-dystroglycan, are carried by cricetid rather than murid rodents, and tend to a more haemorrhagic and neurological illness. The division predicts the classical pattern rather than an invariable rule, since human pathogenicity arose separately in the two lineages.

Virion structure

The particles are typical arenaviruses: pleomorphic and enveloped, studded with glycoprotein spikes, and carrying host ribosomes incorporated during assembly that give the family its grainy appearance.

Genome organisation

The genome is the standard arenavirus bisegmented, ambisense, negative-sense RNA in a small and a large segment, encoding the nucleoprotein and glycoprotein precursor on the small segment and the polymerase and Z matrix protein on the large. The receptor-binding subunit GP1 is the part that determines the group’s defining use of the human transferrin receptor.

Replication cycle

Entry is the step that separates the pathogenic New World viruses from their relatives. Their GP1 subunit binds human transferrin receptor 1, a protein the body uses to take up iron, and it is the fit to the human version of this receptor, rather than to the rodent version each virus normally uses, that lets a clade-B virus infect people. After receptor binding the virion enters by clathrin-mediated endocytosis and fuses with the endosomal membrane at low pH to release the genome. From there replication follows the common arenavirus route: cytoplasmic transcription and replication with cap-snatching, and budding from the plasma membrane directed by the Z protein. Because each virus is adapted to the transferrin receptor of its own reservoir rodent, its capacity to spill over to humans depends on how well it also engages the human receptor.

Pathogenesis

The pathogenesis of the South American haemorrhagic fevers resembles that of the other arenaviruses in outline but differs in emphasis. As with Lassa, the early targets are the antigen-presenting cells, and severe disease reflects increased vascular permeability and platelet dysfunction rather than wholesale tissue destruction, with thrombocytopenia and leucopenia characteristic. Injury to the small vessels produces the capillary leak, and a prominent neurological component distinguishes these diseases from Lassa fever.

The immunology, however, is mirror-imaged. Where recovery from Lassa fever depends on the T-cell response, control of the New World haemorrhagic fevers depends chiefly on antibody, which is why passive transfer of immune plasma is effective in Argentine haemorrhagic fever. At the same time an inflammatory response contributes to severe disease, and in Argentine haemorrhagic fever raised levels of interferon and tumour necrosis factor correlate with a worse outcome, so the picture is one of both insufficient early control and harmful late inflammation.

Epidemiology

Each New World haemorrhagic fever is confined to the range of its reservoir rodent, and human disease is largely rural and occupational, concentrated in agricultural workers exposed to rodents or their excreta in the field. Argentine haemorrhagic fever is by far the best documented: it emerged on the fertile pampas and, before vaccination, caused up to several hundred cases a year in a season that tracked the maize harvest, with the drylands vesper mouse Calomys musculinus as its reservoir. Its historical burden runs to tens of thousands of cases.

The others are more focal. Bolivian haemorrhagic fever occurs in the Beni department of Bolivia, carried by Calomys callosus, and Venezuelan haemorrhagic fever in the states of Portuguesa and Barinas, carried by the cane mouse Zygodontomys brevicauda. Sabia and Chapare viruses are known from only a handful of cases each, their reservoirs still unidentified, but they remain active: a fatal Chapare infection was confirmed in La Paz, Bolivia, in late 2024. Person-to-person spread is generally limited, but it is well documented for some of the group. Machupo virus has caused nosocomial and household transmission, and a 2019 cluster of Chapare virus in La Paz spread to healthcare workers, with fatalities, showing that these viruses are not always dead-end infections.

Natural history

After an incubation of about 6 to 14 days, the illness begins gradually rather than abruptly, with fever, malaise and myalgia, and most patients then improve. In the untreated, a substantial minority, of the order of a fifth to a third, deteriorate in the second week into severe haemorrhagic and neurological disease and shock, which is when death occurs. Survival is followed by recovery that is usually complete, driven by the developing antibody response, though convalescence may be prolonged, and for Argentine haemorrhagic fever treated with immune plasma a distinctive late neurological syndrome can appear weeks after apparent recovery.

Clinical presentations and complications

The clinical syndrome is broadly shared across the group and is best defined for Argentine haemorrhagic fever. After the gradual onset, the first week brings fever, malaise, myalgia and headache with facial flushing, conjunctival injection and a petechial or maculopapular rash, together with falling platelet and white cell counts. Around a fifth to a third of patients progress to severe disease in the second week, with mucosal bleeding and, characteristically, a prominent neurological picture of tremor, ataxia, and in severe cases delirium and seizures that is more marked than in the Old World diseases. Bleeding tends to be mucosal and the total blood loss modest; hypovolaemic shock and neurological deterioration, rather than exsanguination, drive the fatal cases.

Some features vary between the agents. The aspartate aminotransferase is usually normal or only mildly raised, in contrast to Lassa fever, and pharyngitis is prominent in Venezuelan haemorrhagic fever, while Bolivian and Venezuelan disease can leave a transient hearing loss in convalescence. Sabia and Chapare are described from too few cases to define a distinct clinical signature, but both have caused severe haemorrhagic disease with the same general pattern.

Diagnosis

Diagnosis rests on reverse transcription polymerase chain reaction and antigen detection in the acute phase, since the antibody response develops too slowly to help early, and all culture and confirmatory work is confined to maximum-containment laboratories. Serology, by immunofluorescence or enzyme immunoassay, is useful later and for surveillance but is limited by cross-reaction among the related viruses. The clinical differential is wide and includes dengue, which these diseases can resemble early, leptospirosis, and the other viral haemorrhagic fevers, and in every case malaria must be excluded in parallel where it is a possibility.

Management

Treatment is principally intensive supportive care, with careful attention to fluid balance, bleeding and the neurological complications. Two specific measures apply. Ribavirin has activity against the group and is used in severe disease, with evidence of benefit in Bolivian and other infections. For Argentine haemorrhagic fever, transfusion of immune convalescent plasma is an established treatment and, given within the first week or so of illness, reduces mortality substantially, from the untreated range to a low single-figure percentage. Its one recognised drawback is a late neurological syndrome, a self-limiting illness with fever and cerebellar signs, that develops some weeks later in about a tenth of treated patients.

Prevention and public health

Vaccination

The outstanding preventive success against this group is the live-attenuated Candid #1 vaccine against Junin virus, developed for Argentine haemorrhagic fever and in use in Argentina since the early 1990s. Vaccination of the at-risk rural population has cut the incidence of Argentine haemorrhagic fever dramatically, and the vaccine is thought to give some cross-protection against Bolivian haemorrhagic fever. There is no licensed vaccine against the other New World agents, and none is in wide use, so prevention of Bolivian, Venezuelan, Brazilian and Chapare disease depends on avoiding exposure.

Infection prevention and control

Because several of these viruses can spread from person to person, a suspected case is managed under viral haemorrhagic fever precautions: isolation, appropriate personal protective equipment, and safe handling of blood, body fluids and sharps. The 2019 Chapare cluster, in which the virus reached hospital staff, is the standing reminder that nosocomial transmission is a real risk. Reduction of contact with reservoir rodents is the mainstay of community prevention, though it is difficult where the reservoir is a field rodent rather than a house-dwelling one.

Surveillance and notification

The New World haemorrhagic fevers are notifiable events in their endemic countries and trigger contact tracing and rodent surveillance. Their emergence over successive decades, and the continued appearance of Chapare cases, means surveillance for undiagnosed haemorrhagic fever remains important for detecting both known and novel agents.

South African context

The New World arenaviruses are South American viruses with no reservoir or transmission in South Africa, so they are not part of the endemic disease picture. Their relevance to South African practice is limited to the rare possibility of an imported case in a traveller returning from an endemic rural area of South America, an event that has essentially never been recorded but that would be approached exactly as any other suspected viral haemorrhagic fever. Such a case would enter the national viral haemorrhagic fever pathway of early recognition, strict isolation, safe specimen handling and confirmatory testing at maximum containment, the same system used for Lassa, Lujo, Marburg and the other high-consequence agents. Neither the Candid #1 vaccine nor immune plasma has any routine place in South Africa, since the diseases they address do not occur there.

References and recommended reading

• Bausch DG. Arenaviruses. In: Richman DD, Whitley RJ, Hayden FG (eds.), Clinical Virology, 4th edition. Washington: ASM Press; 2016. The source for the individual South American haemorrhagic fevers, their reservoirs and clinical courses, and the ribavirin and immune-plasma evidence.
• Radoshitzky SR, Buchmeier MJ, de la Torre JC. Arenaviridae: The Viruses and Their Replication. In: Fields Virology, 7th edition. Philadelphia: Wolters Kluwer; 2022. The reference for classification, the clade structure, transferrin-receptor-1 entry and the replication cycle.
• Hewson R. Understanding Viral Haemorrhagic Fevers: Virus Diversity, Vector Ecology, and Public Health Strategies. Pathogens. 2024;13(10):909. Current taxonomy, reservoir ecology and the vaccine and countermeasure landscape.