Abstract
Defective interfering particles (DIPs) are naturally occurring products during virus replication in infected cells. DIPs contain defective viral genomes (DVGs) and interfere with replication and propagation of their corresponding standard viral genomes by competing for viral and cellular resources, as well as promoting innate immune antiviral responses. Consequently, for many different viruses, including mammarenaviruses, DIPs play key roles in the outcome of infection. Due to their ability to broadly interfere with viral replication, DIPs are attractive tools for the development of a new generation of biologics to target genetically diverse and rapidly evolving viruses. Here, we provide evidence that in cells infected with the Lassa fever (LF) vaccine candidate ML29, a reassortant that carries the nucleoprotein (NP) and glycoprotein (GP) dominant antigens of the pathogenic Lassa virus (LASV) together with the L polymerase and Z matrix protein of the non-pathogenic genetically related Mopeia virus (MOPV), L-derived truncated RNA species are readily detected following infection at low multiplicity of infection (MOI) or in persistently-infected cells originally infected at high MOI. In the present study, we show that expression of green fluorescent protein (GFP) driven by a tri-segmented form of the mammarenavirus lymphocytic choriomeningitis virus (r3LCMV-GFP/GFP) was strongly inhibited in ML29-persistently infected cells, and that the magnitude of GFP suppression was dependent on the passage history of the ML29-persistently infected cells. In addition, we found that DIP-enriched ML29 was highly attenuated in immunocompetent CBA/J mice and in Hartley guinea pigs. Likewise, STAT-1-/- mice, a validated small animal model for human LF associated hearing loss sequelae, infected with DIP-enriched ML29 did not exhibit any hearing abnormalities throughout the observation period (62 days).
Highlights
The mammarenavirus Lassa virus (LASV) is endemic to Western Africa, where it is estimated to infect hundreds of thousands of individuals yearly, resulting in a high number of cases of Lassa fever (LF), a febrile disease associated with significant morbidity and a case fatality rate as high as 69% among hospitalized confirmed patients [1]
We show that in Vero cells persistently infected with ML29, expression of the green fluorescent protein (GFP) reporter gene directed by a recombinant tri-segmented lymphocytic choriomeningitis virus (LCMV) was strongly inhibited and the level of inhibition was greater in cells with higher cell passage number
Defective interfering particles (DIPs)-associated defective viral genomes (DVGs) originate from wild-type viral genomes and act by competition with viral genomes for replication or packaging, or both
Summary
The mammarenavirus Lassa virus (LASV) is endemic to Western Africa, where it is estimated to infect hundreds of thousands of individuals yearly, resulting in a high number of cases of Lassa fever (LF), a febrile disease associated with significant morbidity and a case fatality rate as high as 69% among hospitalized confirmed patients [1]. LASV was discovered more than 50 years ago in Nigeria, one of the most populated African countries, and appears to have moved west to become endemic in West. There are no approved vaccines to control LF in West Africa, and therapeutic options are limited to an off-label use of ribavirin that is only partially effective, has a narrow therapeutic window, and can cause significant side effects [5,6]. The high genetic diversity of LASV [7] poses a significant challenge for the development of pan-LASV vaccine with “full coverage” [8,9,10]
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