Animal Models, Prophylaxis, and Therapeutics for Arenavirus Infections

Vela, Eric M.

doi:10.3390/v4091802

Cited by 36 publications

(29 citation statements)

References 86 publications

(135 reference statements)

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“…JUNV is endemic in regions of Argentina and West Africa and is the cause of severe episodes of hemorrhagic fever with high mortality rates. The search for effective therapeutics to treat arenavirus infections, particularly those caused by Junin and Lassa viruses, has been an active area of research for many years (8,(27)(28)(29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). More recent efforts in the field of antiviral therapeutics for emerging RNA viruses have focused on identifying host factors or virus-host interactions, rather than solely viral proteins, as targets for novel antivirals (6, 8-13, 39, 40, 43, 44).…”

Section: Discussionmentioning

confidence: 99%

A Host-Oriented Inhibitor of Junin Argentine Hemorrhagic Fever Virus Egress

Han

Liu

et al. 2014

J Virol

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IMPORTANCE There are currently no FDA-approved vaccines or therapeutics to prevent or treat Argentine hemorrhagic fever (AHF). The causative agent of AHF is Junin virus (JUNV); a New World arenavirus classified as an NIAID/CDC category A priority pathogen.Here, we describe a prototype therapeutic that blocks budding of JUNV and has the potential to function as a broad-spectrum antiviral drug. J unin virus (JUNV) is a New World arenavirus endemic in Argentina that causes severe Argentine hemorrhagic fever and significant mortality in humans (1). The virus is present in excreta from infected rodents and is typically spread to humans via aerosolization (1). JUNV is important because it is a biosafety level 4 pathogen with potential use as a bioterror agent, for which there are no U.S. Food and Drug Administration (FDA)-approved vaccines or therapeutics. JUNV is an enveloped, bisegmented negative-sense RNA virus that encodes four proteins: surface glycoprotein precursor (GPC), RNA polymerase (L), nucleoprotein (NP), and small RING finger matrix protein (Z). The Z protein of arenaviruses plays a key role in promoting virus egress and spread and is capable of budding independently from mammalian cells in the form of virus-like particles (VLPs) (2-6). Efficient separation of arenavirus Z VLPs from the plasma membrane is promoted by viral L domains within the Z protein (for a review, see reference 7). L domains function by recruiting host proteins that facilitate efficient virus-cell separation ("pinching-off") (7). JUNV Z protein contains a single PTAP type L domain which interacts with host Tsg101, a component of the endosomal sorting complexes required for transport (ESCRT) machinery (5-7). L-domain-mediated recruitment of host proteins by virus represents a potential target for the development of novel antiviral inhibitors to disrupt virus egress from infected cells to reduce virus dissemination and disease progression (3,6,(8)(9)(10)(11)(12)(13).Based upon the known nuclear magnetic resonance structure of the Tsg101-PTAP interaction site, we conducted an in silico screen for competitive binding inhibitors. We identified several compounds, and the most potent (compound 0013) blocks both Z VLP and live JUNV egress at nanomolar concentrations. Moreover, compound 0013 specifically blocks PTAP-Tsg101 interactions. Intriguingly, since L-domain-containing matrix proteins are generally required for efficient virus-cell separation of emerging RNA viruses (filoviruses, arenaviruses, henipaviruses, rhabdoviruses, paramyxoviruses, and retroviruses), we speculate that inhibitors of this virus-host interaction could represent broadspectrum antiviral drugs against a range of enveloped RNA viruses. MATERIALS AND METHODSCell lines, virus, and antibodies. VeroE6 and HEK293T cells were grown in Dulbecco modified Eagle medium supplemented with 10% fetal calf serum. The Candid-1 vaccine strain of JUNV was kindly provided by Robert B. Tesh (University of Texas Medical Branch, Galveston, TX) via

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Section: Discussionmentioning

confidence: 99%

A Host-Oriented Inhibitor of Junin Argentine Hemorrhagic Fever Virus Egress

Han

Liu

et al. 2014

J Virol

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“…Humans usually become infected through contact with infected rodents or inhalation of infectious rodent excreta or secretions [2]. Animal models, such as hamsters, mice, guinea pigs, and non-human primates, have been used to study the pathogenicity of mammarenaviruses and to measure vaccine or drug efficacy [12]. Viral infections have been identified in many organs, including the spleen, liver, adrenal gland, placenta, and lungs [10,[13][14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Prevalence of Wēnzhōu virus in small mammals in Yunnan Province, China

et al. 2019

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Background Mammarenaviruses are associated with human hemorrhagic fever diseases in Africa and America. Recently, a rodent mammarenavirus, Wēnzhōu virus (WENV) and related viruses, have been reported in China, Cambodia, and Thailand. Moreover, in Cambodia, these viruses were suspected to be associated with human disease. In China, Yunnan Province is famous for its abundant animal and plant diversity and is adjacent to several South-eastern Asia countries. Therefore, it is necessary to know whether WENV-related viruses, or other mammarenaviruses, are prevalent in this province. Methodology/Principal findings Small mammals were trapped, euthanized, and sampled. Mammarenavirus RNA was detected using a nested reverse transcription polymerase chain reaction (RT-PCR) and quantified by real-time RT-PCR. A total of 1040 small mammals belonging to 13 genera and 26 species were trapped in Yunnan Province. WENV-related mammarenaviruses were detected in 41 rodent liver samples, mainly in brown rats ( Rattus norvegicus ) and oriental house rats ( R . tanezumi ).Viral nucleocapsid protein was detected in liver sections by indirect immunofluorescence assay. Full-length-genomes were amplified by RT-PCR and used for phylogenetic analysis with the MEGA package. Recombination analysis was performed using the SimPlot and Recombination Detection Program. Conclusions/Significance WENV related viruses circulated in small mammals in Yunnan Province. Whole genome sequence analysis of five selected viral strains showed that these viruses are closely related to WENVs discovered in Asia and form an independent branch in the phylogenetic tree in the WENV clade. Paying attention to investigate the influence of these viruses to public health is essential in the epidemic regions.

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“…In the U.S., ribavarin is approved for the treatment of HCV and respiratory syncytial virus. Although ribavirin was reported to benefit the resolution of many emerging viral infections preclinically (2), it yielded marginal to no benefit in the clinic. Ribavirin is today administered together with interferon, a soluble immune factor that is active against most vertebrate-infecting viruses and that was approved for HCV treatment in 1991 (3).…”

mentioning

confidence: 99%

Combating emerging viral threats

Bekerman

Einav

2015

Science

180

182

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Synopsis Most approved antiviral therapeutics selectively inhibit proteins encoded by a single virus, thereby providing a “one drug-one bug” solution. As a result of this narrow spectrum of coverage and the high cost of drug development, therapies are currently approved for fewer than ten viruses out of the hundreds known to cause human disease. This perspective summarizes progress and challenges in the development of broad-spectrum antiviral therapies. These strategies include targeting enzymatic functions shared by multiple viruses and host cell machinery by newly discovered compounds or by repurposing approved drugs. These approaches offer new practical means for developing therapeutics against existing and emerging viral threats.

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Animal Models, Prophylaxis, and Therapeutics for Arenavirus Infections

Cited by 36 publications

References 86 publications

A Host-Oriented Inhibitor of Junin Argentine Hemorrhagic Fever Virus Egress

A Host-Oriented Inhibitor of Junin Argentine Hemorrhagic Fever Virus Egress

Prevalence of Wēnzhōu virus in small mammals in Yunnan Province, China

Combating emerging viral threats

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