Junín Virus Pathogenesis and Virus Replication

Grant, Ashley; Seregin, Alexey; Huang, Cheng; Kolokoltsova, Olga A.; Brasier, Allan R.; Peters, C. J.; Paessler, Slobodan

doi:10.3390/v4102317

Cited by 80 publications

(74 citation statements)

References 101 publications

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“…In NHPs, LNS has been reported in multiple species with mortality near 100%, which is highly comparable to the IFN-␣␤/␥ R Ϫ/Ϫ model reported here. One of the most common complications in humans after infection with various hemorrhagic arenaviruses, including Machupo and Junin viruses, is the presence of LNS, which can be lethal or result in transient or permanent neurological sequelae (57,58). In addition, a portion of patients who have recovered from Lassa fever develop a long-term hearing loss, showing a potential neurological impact of Old World arenaviruses.…”

Section: Discussionmentioning

confidence: 99%

Rescue of a Recombinant Machupo Virus from Cloned cDNAs and In Vivo Characterization in Interferon (αβ/γ) Receptor Double Knockout Mice

Patterson

Seregin

Huang

et al. 2014

J Virol

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Machupo virus (MACV) is the etiological agent of Bolivian hemorrhagic fever (BHF), a reemerging and neglected tropical disease associated with high mortality. The prototypical strain of MACV, Carvallo, was isolated from a human patient in 1963, but minimal in vitro and in vivo characterization has been reported. To this end, we utilized reverse genetics to rescue a pathogenic MACV from cloned cDNAs. The recombinant MACV (rMACV) had in vitro growth properties similar to those of the parental MACV. Both viruses caused similar disease development in alpha/beta and gamma interferon receptor knockout mice, including neurological disease development and high mortality. In addition, we have identified a novel murine model with mortality and neurological disease similar to BHF disease reported in humans and nonhuman primates.

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Section: Discussionmentioning

confidence: 99%

Rescue of a Recombinant Machupo Virus from Cloned cDNAs and In Vivo Characterization in Interferon (αβ/γ) Receptor Double Knockout Mice

Patterson

Seregin

Huang

et al. 2014

J Virol

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“…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.…”

mentioning

confidence: 99%

“…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).…”

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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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“…As an endemic virus spread by native ineradicable rodent populations, JUNV could be acquired during natural outbreaks for bioterror purposes and could naturally spread outside of its current range. The relatively slow onset of AHF with its unspecific symptoms that may delay diagnosis, coupled with its debilitating hemorrhagic phase, make JUNV a serious threat to public health (1,2). With the use of an attenuated vaccine manufactured in Argentina (3) in high-risk individuals, the incidence of AHF has declined, but cases continue to be reported.…”

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confidence: 99%

Monoclonal antibody therapy for Junin virus infection

Zeitlin

Geisbert

Deer

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Countermeasures against potential biothreat agents remain important to US Homeland Security, and many of these pharmaceuticals could have dual use in the improvement of global public health. Junin virus, the causative agent of Argentine hemorrhagic fever (AHF), is an arenavirus identified as a category A high-priority agent. There are no Food and Drug Administration (FDA) approved drugs available for preventing or treating AHF, and the current treatment option is limited to administration of immune plasma. Whereas immune plasma demonstrates the feasibility of passive immunotherapy, it is limited in quantity, variable in quality, and poses safety risks such as transmission of transfusion-borne diseases. In an effort to develop a monoclonal antibody (mAb)-based alternative to plasma, three previously described neutralizing murine mAbs were expressed as mouse-human chimeric antibodies and evaluated in the guinea pig model of AHF. These mAbs provided 100% protection against lethal challenge when administered 2 d after infection (dpi), and one of them (J199) was capable of providing 100% protection when treatment was initiated 6 dpi and 92% protection when initiated 7 dpi. The efficacy of J199 is superior to that previously described for all other evaluated drugs, and its high potency suggests that mAbs like J199 offer an economical alternative to immune plasma and an effective dual use (bioterrorism/public health) therapeutic.Junin | therapy | immunotherapy | hemorrhagic fever

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Junín Virus Pathogenesis and Virus Replication

Cited by 80 publications

References 101 publications

Rescue of a Recombinant Machupo Virus from Cloned cDNAs and In Vivo Characterization in Interferon (αβ/γ) Receptor Double Knockout Mice

Rescue of a Recombinant Machupo Virus from Cloned cDNAs and In Vivo Characterization in Interferon (αβ/γ) Receptor Double Knockout Mice

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

Monoclonal antibody therapy for Junin virus infection

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