Description and characterization of a novel live-attenuated tri-segmented Machupo virus in Guinea pigs.

BACKGROUND: Machupo virus (MACV) is a member of the Mammarenavirus genus, Arenaviridae family and is the etiologic agent of Bolivian hemorrhagic fever, which causes small outbreaks or sporadic cases. Several other arenaviruses in South America Junín virus (JUNV) in Argentina, Guanarito in Venezuela, Sabiá in Brazil and Chapare in Bolivia, also are responsible for human hemorrhagic fevers. Among these arenaviruses, JUNV caused thousands of human cases until 1991, when the live attenuated Candid #1 vaccine, was used. Other than Candid #1 vaccine, few other therapeutic or prophylactic treatments exist. Therefore, new strategies for production of safe countermeasures with broad spectrum activity are needed. FINDINGS: We tested a tri-segmented MACV, a potential vaccine candidate with several mutations, (r3MACV). In cell culture, r3MACV showed a 2-log reduction in infectious virus particle production and the MACV inhibition of INF-1ß was removed from the construct and produced by infected cells. Furthermore, in an animal experiment, r3MACV was able to protect 50% of guinea pigs from a simultaneous lethal JUNV challenge. Protected animals didn't display clinical symptoms nor were virus particles found in peripheral blood (day 14) or in organs (day 28 post-inoculation). The r3MACV provided a higher protection than the Candid #1 vaccine. CONCLUSIONS: The r3MACV provides a potential countermeasure against two South America arenaviruses responsible of human hemorrhagic fever.

Mammarenaviruses deleted from their Z gene are replicative and produce an infectious progeny in BHK-21 cells.

Mammarenaviruses bud out of infected cells via the recruitment of the endosomal sorting complex required for transport through late domain motifs localized into their Z protein. Here, we demonstrated that mammarenaviruses lacking this protein can be rescued and are replicative, despite a 3-log reduction in virion production, in BHK-21 cells, but not in five other cell lines. Mutations of putative late domain motifs identified into the viral nucleoprotein resulted in the almost complete abolition of infectious virion production by Z-deleted mammarenaviruses. This result strongly suggested that the nucleoprotein may compensate for the deletion of Z. These observations were primarily obtained using the Lymphocytic choriomeningitis virus, and further confirmed using the Old World Lassa and New World Machupo viruses, responsible of human hemorrhagic fevers. Z-deleted viruses should prove very useful tools to investigate the biology of Mammarenaviruses.

Past, present and future therapeutic and prophylactic strategies against arenaviruses responsible of human hemorrhagic fever.

For most viral hemorrhagic fevers caused by arenaviruses, no prophylactic vaccine is available yet. Only one therapeutic treatment is currently available and should be administered at the early stages of the infection. This is particularly problematic as these diseases are difficult to diagnose and cure. Lassa fever is the most important pathology caused by arenaviruses, including millions of people at risk in West Africa. For decades, promising studies focusing on the development of vaccine candidates targeting Lassa virus have been published, but no vaccine candidate had reached the clinical phase. The second arenavirus in terms of number of human infections is the Junín virus in Argentina. The Junín infected case number has drastically decreased since the use of the Candid #1 vaccine. This review summarizes past and present experimental studies regarding treatments against arenaviruses responsible for human hemorrhagic fevers from a prophylactic and therapeutic point of view. It also discusses future breakthroughs to get available and effective treatments.