RESUMEN
Hemorrhagic fevers (HF) resulting from pathogenic arenaviral infections have traditionally been neglected as tropical diseases primarily affecting African and South American regions. There are currently no FDA-approved vaccines for arenaviruses, and treatments have been limited to supportive therapy and use of non-specific nucleoside analogs, such as Ribavirin. Outbreaks of arenaviral infections have been limited to certain geographic areas that are endemic but known cases of exportation of arenaviruses from endemic regions and socioeconomic challenges for local control of rodent reservoirs raise serious concerns about the potential for larger outbreaks in the future. This review synthesizes current knowledge about arenaviral evolution, ecology, transmission patterns, life cycle, modulation of host immunity, disease pathogenesis, as well as discusses recent development of preventative and therapeutic pursuits against this group of deadly viral pathogens.
Asunto(s)
Infecciones por Arenaviridae , Arenavirus/inmunología , Brotes de Enfermedades , Fiebres Hemorrágicas Virales , Tolerancia Inmunológica , Ribavirina/uso terapéutico , África/epidemiología , Infecciones por Arenaviridae/tratamiento farmacológico , Infecciones por Arenaviridae/epidemiología , Infecciones por Arenaviridae/inmunología , Fiebres Hemorrágicas Virales/tratamiento farmacológico , Fiebres Hemorrágicas Virales/epidemiología , Fiebres Hemorrágicas Virales/inmunología , Humanos , América del Sur/epidemiologíaRESUMEN
Our previous studies reported the inhibitory action against arenaviruses of antiretroviral zinc finger-reactive compounds provided by the National Cancer Institute (USA). These compounds were able to inactivate virions as well as to reduce virus yields from infected cells. Here, the inactivation of the arenavirus Junín (JUNV), agent of Argentine hemorrhagic fever, by the aromatic disulfide NSC20625 was analyzed. The treatment of purified JUNV with this compound eliminated infectivity apparently through irreversible modifications in the matrix Z protein detected by: (a) alterations in the electrophoretic migration profile of Z under non-reducing conditions; (b) an electrodense labeling in the internal layer beneath the envelope and around the matrix Z protein, in negatively stained preparations; (c) changes in the subcellular localization of Z in cells transfected with a recombinant fusion protein JUNVZ-eGFP. The infection of Vero cells with JUNV inactivated particles was blocked at the uncoating of viral nucleocapsid from endosomes, providing new evidence for a functional role of Z in this stage of arenavirus cycle. Furthermore, the inactivated JUNV particles retained the immunoreactivity of the surface glycoprotein GP1 suggesting that this disulfide may be useful in the pursuit of an inactivating agent to obtain a vaccine antigen or diagnostic tool.
Asunto(s)
Infecciones por Arenaviridae/tratamiento farmacológico , Compuestos Azo/farmacología , Disulfuros/farmacología , Guanidinas/farmacología , Virus Junin/efectos de los fármacos , Virión/efectos de los fármacos , Dedos de Zinc , Animales , Fármacos Anti-VIH/farmacología , Infecciones por Arenaviridae/metabolismo , Proteínas Portadoras/biosíntesis , Proteínas Portadoras/genética , Chlorocebus aethiops , Proteínas Fluorescentes Verdes , Virus Junin/genética , Microscopía Electrónica de Transmisión , Proteínas de la Nucleocápside/metabolismo , Proteínas Recombinantes de Fusión/biosíntesis , Células Vero , Virión/ultraestructura , Inactivación de VirusRESUMEN
BACKGROUND: In the present study, a series of N-substituted acridone derivatives was synthesized and evaluated against two haemorrhagic fever viruses (HFV). METHODS: Compounds were tested against Junin virus (JUNV), an arenavirus agent of Argentine haemorrhagic fever, and dengue virus (DENV), a flavivirus agent of the most prevalent arthropod-borne viral disease in humans. RESULTS: Among tested compounds, two N-allyl acridones (derivatives 3c and 3f) elicited a potent and selective antiviral activity against JUNV (strain 1V4454) and DENV-2 (strain NGC) with 50% effective concentration values between 2.5 and 5.5 microM, as determined by virus yield inhibition. No cytotoxicity was detected at concentrations up to 1,000 microM, resulting in selectivity indices >181.8-400.0. Both acridones were effective against a wide spectrum of arenaviruses and the four serotypes of DENV. Furthermore, 3c and 3f failed to inactivate virus before cell infection as well as to induce a refractory state by cell pretreatment, indicating that the inhibitory effect was exerted through a blockade in virus multiplication during the infectious process. CONCLUSION: These data are the first demonstration that acridone derivatives have a potent antiviral activity that block in vitro multiplication of HFV belonging to Arenaviridae and Flaviviridae, such as JUNV and DENV.