Chikungunya Virus: In Vitro Response to Combination Therapy With Ribavirin and Interferon Alfa 2a

Gallegos, Karen M.; Drusano, George L.; D’Argenio, David Z.; Brown, Ashley N.

doi:10.1093/infdis/jiw358

Cited by 48 publications

(51 citation statements)

References 14 publications

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“…The intensity or duration of pain during the acute phase has been correlated with high viral loads, providing clues that viral clearance should be hastened. Ribavirin and IFNα have shown synergistic antiviral activity against chikungunya virus in vitro; however, neither of these are recommended for daily use due to the risk of side effects . Favipiravir (T‐705), a viral RNA polymerase inhibitor licensed in Japan for the treatment of influenza, was also found to inhibit chikungunya virus replication in vitro and could become the focus of studies assessing its usefulness in treating chikungunya virus.…”

Section: Clinical Care Of Chikungunya Virus Patients: Lessons Learnedmentioning

confidence: 99%

Review: Chikungunya Arthritis: Implications of Acute and Chronic Inflammation Mechanisms on Disease Management

Zaid

Gérardin

Taylor

et al. 2018

Arthritis & Rheumatology

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In the past decade, arboviruses-arthropod-borne viruses-have been the focus of public health institutions worldwide following a spate of devastating outbreaks. Chikungunya virus, an arbovirus that belongs to the alphavirus genus, is a reemerging arthritogenic virus that has caused explosive outbreaks since 2006, notably on Réunion Island, and more recently in the Caribbean, South America, India, and Southeast Asia. The severity of arthritic disease caused by chikungunya virus has prompted public health authorities in affected countries to develop specific guidelines to tackle this pathogen. Chikungunya virus disease manifests first as an acute stage of severe joint inflammation and febrile illness, which later progresses to a chronic stage, during which patients may experience debilitating and persisting articular pain for extended periods. This review aims to provide a broad perspective on current knowledge of chikungunya virus pathogenesis by identifying key clinical and experimental studies that have contributed to our understanding of chikungunya virus to date. In addition, the review explores the practical aspects of treatment and management of both acute and chronic chikungunya virus based on clinical experience during chikungunya virus outbreaks. Finally, recent findings on potential therapeutic solutions-from antiviral agents to immunomodulators-are reviewed to provide both viral immunologists and clinical rheumatologists with a balanced perspective on the nature of a reemerging arboviral disease of significant public health concern, and insight into future therapeutic approaches to better address the treatment and management of chikungunya virus.

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Section: Clinical Care Of Chikungunya Virus Patients: Lessons Learnedmentioning

confidence: 99%

Review: Chikungunya Arthritis: Implications of Acute and Chronic Inflammation Mechanisms on Disease Management

Zaid

Gérardin

Taylor

et al. 2018

Arthritis & Rheumatology

View full text Add to dashboard Cite

show abstract

“…To expand on these findings, we addressed whether atovaquone could inhibit CHIKV, an arbovirus transmitted by Aedes mosquitoes and capable of causing severe human disease and significant outbreaks (48)(49)(50). Importantly, CHIKV has been shown to be inhibited by nucleotide biosynthesis inhibitors (27,51,52), and thus we hypothesized that it would be inhibited by atovaquone. We infected Vero cells with a CHIKV expressing a ZsGreen reporter in the presence of increasing concentrations of atovaquone and quantified the number of ZsGreen-positive cells after treatment by microscopy.…”

mentioning

confidence: 99%

Atovaquone Inhibits Arbovirus Replication through the Depletion of Intracellular Nucleotides

Kottkamp

Jesus

Grande

et al. 2019

J Virol

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Arthropod-borne viruses represent a significant public health threat worldwide, yet there are few antiviral therapies or prophylaxes targeting these pathogens. In particular, the development of novel antivirals for high-risk populations such as pregnant women is essential to prevent devastating disease such as that which was experienced with the recent outbreak of Zika virus (ZIKV) in the Americas. One potential avenue to identify new and pregnancy-acceptable antiviral compounds is to repurpose well-known and widely used FDA-approved drugs. In this study, we addressed the antiviral role of atovaquone, an FDA Pregnancy Category C drug and pyrimidine biosynthesis inhibitor used for the prevention and treatment of parasitic infections. We found that atovaquone was able to inhibit ZIKV and chikungunya virus virion production in human cells and that this antiviral effect occurred early during infection at the initial steps of viral RNA replication. Moreover, we were able to complement viral replication and virion production with the addition of exogenous pyrimidine nucleosides, indicating that atovaquone functions through the inhibition of the pyrimidine biosynthesis pathway to inhibit viral replication. Finally, using an ex vivo human placental tissue model, we found that atovaquone could limit ZIKV infection in a dose-dependent manner, providing evidence that atovaquone may function as an antiviral in humans. Taken together, these studies suggest that atovaquone could be a broad-spectrum antiviral drug and a potential attractive candidate for the prophylaxis or treatment of arbovirus infection in vulnerable populations, such as pregnant women and children.IMPORTANCE The ability to protect vulnerable populations such as pregnant women and children from Zika virus and other arbovirus infections is essential to preventing the devastating complications induced by these viruses. One class of antiviral therapies may lie in known pregnancy-acceptable drugs that have the potential to mitigate arbovirus infections and disease, yet this has not been explored in detail. In this study, we show that the common antiparasitic drug atovaquone inhibits arbovirus replication through intracellular nucleotide depletion and can impair ZIKV infection in an ex vivo human placental explant model. Our study provides a novel function for atovaquone and highlights that the rediscovery of pregnancy-acceptable drugs with potential antiviral effects can be the key to better addressing the immediate need for treating viral infections and preventing potential birth complications and future disease.

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“…To expand on these findings, we addressed if atovaquone could inhibit chikungunya virus (CHIKV), an arbovirus transmitted by Aedes mosquitoes and capable of causing severe human disease and significant outbreaks [45], [46], [47]. Importantly, CHIKV has been shown to be inhibited by nucleotide biosynthesis inhibitors [22], [48], [49], and thus we hypothesized it would be inhibited by atovaquone. We infected Vero cells with a CHIKV expressing a ZsGreen reporter in the presence of increasing concentrations of atovaquone and quantified the number of ZsGreen positive cells after treatment by microscopy.…”

Section: Resultsmentioning

confidence: 99%

The antiparasitic drug atovaquone inhibits arbovirus replication through the depletion of intracellular nucleotides.

Kottkamp

Jesus

Grande

et al. 2018

Preprint

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Arthropod-borne viruses represent a significant public health threat worldwide yet there are few antiviral therapies or prophylaxis targeting these pathogens. In particular, the development of novel antivirals for high-risk populations such as pregnant women is essential to prevent devastating disease such as that which was experienced with the recent outbreak of Zika virus (ZIKV) in the Americas. One potential avenue to identify new and pregnancy friendly antiviral compounds is to repurpose well-known and widely used FDA approved drugs. In this study, we addressed the antiviral role of atovaquone, a FDA Pregnancy Category C drug and pyrimidine biosynthesis inhibitor used for the prevention and treatment of parasitic infections. We found that atovaquone was able to inhibit ZIKV and chikungunya virus virion production in human cells and that this antiviral effect occurred early during infection at the initial steps of viral RNA replication. Moreover, we were able to complement viral replication and virion production with the addition of exogenous pyrimidine nucleosides indicating that atovaquone is functioning through the inhibition of the pyrimidine biosynthesis pathway to inhibit viral replication. Finally, using an ex vivo human placental tissue model, we found that atovaquone could limit ZIKV infection in a dose-dependent manner providing evidence that atovaquone may function as an antiviral in humans. Taken together, these studies suggest that atovaquone could be a broad-spectrum antiviral drug and a potential attractive candidate for the prophylaxis or treatment of arbovirus infection in vulnerable populations, such as pregnant women.

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Chikungunya Virus: In Vitro Response to Combination Therapy With Ribavirin and Interferon Alfa 2a

Abstract: These studies illustrate the promise of RBV plus IFN alfa as a potential therapeutic strategy for the treatment of CHIKV infections.

Cited by 48 publications

References 14 publications

Review: Chikungunya Arthritis: Implications of Acute and Chronic Inflammation Mechanisms on Disease Management

Review: Chikungunya Arthritis: Implications of Acute and Chronic Inflammation Mechanisms on Disease Management

Atovaquone Inhibits Arbovirus Replication through the Depletion of Intracellular Nucleotides

The antiparasitic drug atovaquone inhibits arbovirus replication through the depletion of intracellular nucleotides.

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