Progress in the experimental therapy of severe arenaviral infections
Institute for Antiviral Research & Department of Animal, Dairy & Veterinary Sciences, Utah State University, Logan, UT, USA. Future Microbiology
(Impact Factor: 4.28).
12/2011; 6(12):1429-41. DOI: 10.2217/fmb.11.132
A number of viruses in the family Arenaviridae cause severe illness in humans. Lassa virus in West Africa and a number of agents in South America produce hemorrhagic fever in persons exposed to aerosolized excretions of the pathogens' rodent hosts. Because arenaviruses are not transmitted by arthropods, and person-to-person spread is rare, human infections occur singly and sporadically, and are usually not diagnosed until the patient is severely ill. Because the arenaviruses are naturally transmitted by the airborne route, they also pose a potential threat as aerosolized bioterror weapons. The broad-spectrum antiviral drug ribavirin was shown to reduce mortality from Lassa fever, and has been tested against Argentine hemorrhagic fever, but it is not an approved treatment for either disease. Human immune convalescent plasma was proven to be effective for Argentine hemorrhagic fever in a controlled trial. New treatments are needed to block viral replication without causing toxicity and to prevent the increased vascular permeability that is responsible for hypotension and shock. In this paper, we review current developments in the experimental therapy of severe arenaviral infections, focusing on drugs that have been tested in animal models, and provide a perspective on future research.
Available from: Brett Hurst
- "There are presently 7 arenaviruses known to cause viral HF. The group includes 5 New World viruses (Junin, Machupo, Guanarito, Sabia, and Chapare) present in areas of South America, and two Old World viruses (Lassa and Lujo) found in defined regions of Western and South Africa
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ABSTRACT: Tacaribe virus (TCRV) is a less biohazardous relative of the highly pathogenic clade B New World arenaviruses that cause viral hemorrhagic fever syndromes and require handling in maximum containment facilities not readily available to most researchers.AG129 type I and II interferon receptor knockout mice have been shown to be susceptible to TCRV infection, but the pathogenic mechanisms contributing to the lethal disease are unclear.
To gain insights into the pathogenesis of TCRV infection in AG129 mice, we assessed hematologic and cytokine responses during the course of infection, as well as changes in the permeability of the vascular endothelium. We also treated TCRV-challenged mice with MY-24, a compound that prevents mortality without affecting viral loads during the acute infection, and measured serum and tissue viral titers out to 40 days post-infection to determine whether the virus is ultimately cleared in recovering mice.
We found that the development of viremia and splenomegaly precedes an elevation in white blood cells and the detection of high levels of proinflammatory mediators known to destabilize the endothelial barrier, which likely contributes to the increased vascular permeability and weight loss that was observed several days prior to when the mice generally succumb to TCRV challenge. In surviving mice treated with MY-24, viremia and liver virus titers were not cleared until 2--3 weeks post-infection, after which the mice began to recover lost weight. Remarkably, substantial viral loads were still present in the lung, spleen, brain and kidney tissues at the conclusion of the study.
Our findings suggest that vascular leak may be a contributing factor in the demise of TCRV-infected mice, as histopathologic findings are generally mild to moderate in nature, and as evidenced with MY-24 treatment, animals can survive in the face of high viral loads.
Available from: avc.sagepub.com
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Junín virus (JUNV) and several other clade B New World arenaviruses cause human disease ranging from mild febrile illness to severe viral haemorrhagic fever. These viruses pose a significant threat to national security and safe and effective therapies are limited except in Argentina, where immune plasma is the standard of care for treating JUNV infection in cases of Argentine haemorrhagic fever.
An in vitro screen of the Chemtura library identified several compounds with activity against Tacaribe virus (TCRV), a clade B arenavirus closely related to JUNV. Of these compounds, D746, a phenolic dibenzylsulfide, was further pursued for additional in vitro studies and evaluated in the AG129 mouse TCRV infection model.
D746 was found to act during an early to intermediate stage of the TCRV replication cycle and μM range activity was confirmed by virus yield reduction assays with both TCRV and JUNV. Although intraperitoneal twice daily treatment regimens were found to be highly effective when started 2 h prior to TCRV challenge in AG129 mice, post-exposure treatment initiated 3 days after infection was not efficacious. Interestingly, despite the pre-exposure treatment success, D746 did not reduce serum or tissue virus titres during the acute infection. Moreover, D746 elicited ascites fluid accumulation in mice during, as well as independent of, infection.
Our findings suggest that D746 may be altering the host response to TCRV infection in AG129 mice in a way that limits pathogenesis and thereby protects mice from otherwise lethal infection in the absence of measurable reductions in viral burden.
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ABSTRACT: Two series of imidazo[2,1-b]thiazoles substituted on C-3 or C-5 with an unprotected carbohydrate moiety were synthesized. Different protective groups for position 3 of the carbohydrate moiety were tested (acetyl, tert-butyldimethylsilyl (TBDMS), and p-methoxybenzyl (PMB)) and the latter turn out to be the best strategy to obtain the desired products. Full deprotection of the carbohydrate was performed successfully in only one step.
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