scholarly journals Favipiravir Does Not Inhibit Chikungunya Virus Replication in Mosquito Cells and Aedes aegypti Mosquitoes

2021 ◽  
Vol 9 (5) ◽  
pp. 944
Author(s):  
Sofie Jacobs ◽  
Lanjiao Wang ◽  
Ana Lucia Rosales Rosas ◽  
Ria Van Berwaer ◽  
Evelien Vanderlinden ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Aedes Aegypti ◽  
Chikungunya Virus ◽  
Active Form ◽  
Metabolic Activation ◽  
Vero Cells ◽  
Mosquito Vector ◽  
Chikv Infection ◽  
Mosquito Cells

Favipiravir (T-705) is a broad-spectrum antiviral drug that inhibits RNA viruses after intracellular conversion into its active form, T-705 ribofuranosyl 5′-triphosphate. We previously showed that T-705 is able to significantly inhibit the replication of chikungunya virus (CHIKV), an arbovirus transmitted by Aedes mosquitoes, in mammalian cells and in mouse models. In contrast, the effect of T-705 on CHIKV infection and replication in the mosquito vector is unknown. Since the antiviral activity of T-705 has been shown to be cell line-dependent, we studied here its antiviral efficacy in Aedes-derived mosquito cells and in Aedes aegypti mosquitoes. Interestingly, T-705 was devoid of anti-CHIKV activity in mosquito cells, despite being effective against CHIKV in Vero cells. By investigating the metabolic activation profile, we showed that, unlike Vero cells, mosquito cells were not able to convert T-705 into its active form. To explore whether alternative metabolization pathways might exist in vivo, Aedes aegypti mosquitoes were infected with CHIKV and administered T-705 via an artificial blood meal. Virus titrations of whole mosquitoes showed that T-705 was not able to reduce CHIKV infection in mosquitoes. Combined, these in vitro and in vivo data indicate that T-705 lacks antiviral activity in mosquitoes due to inadequate metabolic activation in this animal species.

scholarly journals Defective viral genomes from chikungunya virus are broad-spectrum antivirals and prevent virus dissemination in mosquitoes

2021 ◽  
Vol 17 (2) ◽  
pp. e1009110
Author(s):  
Laura I. Levi ◽  
Veronica V. Rezelj ◽  
Annabelle Henrion-Lacritick ◽  
Diana Erazo ◽  
J Boussier ◽  
...  
Keyword(s):  
Aedes Aegypti ◽  
Broad Spectrum ◽  
Chikungunya Virus ◽  
Rna Virus ◽  
Viral Genomes ◽  
Mosquito Cells ◽  
Spectrum Activity ◽  
Broad Spectrum Activity

Defective viral genomes (DVGs) are truncated and/or rearranged viral genomes produced during virus replication. Described in many RNA virus families, some of them have interfering activity on their parental virus and/or strong immunostimulatory potential, and are being considered in antiviral approaches. Chikungunya virus (CHIKV) is an alphavirus transmitted by Aedes spp. that infected millions of humans in the last 15 years. Here, we describe the DVGs arising during CHIKV infection in vitro in mammalian and mosquito cells, and in vivo in experimentally infected Aedes aegypti mosquitoes. We combined experimental and computational approaches to select DVG candidates most likely to have inhibitory activity and showed that, indeed, they strongly interfere with CHIKV replication both in mammalian and mosquito cells. We further demonstrated that some DVGs present broad-spectrum activity, inhibiting several CHIKV strains and other alphaviruses. Finally, we showed that pre-treating Aedes aegypti with DVGs prevented viral dissemination in vivo.

scholarly journals Favipiravir and Ivermectin Showed in Vitro Synergistic Antiviral Activity against SARS-CoV-2

2021 ◽  
Author(s):  
Kunlakanya Jitobaom ◽  
Chompunuch Boonarkart ◽  
Suwimon Manopwisedjaroen ◽  
Nuntaya Punyadee ◽  
Suparerk Borwornpinyo ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Synergistic Effects ◽  
Active Form ◽  
Cell Types ◽  
Vero Cells ◽  
Clear Cut ◽  
Clinical Benefits ◽  
Repurposed Drugs

Abstract Despite the urgent need for effective antivirals against SARS-CoV-2 to mitigate the catastrophic impact of the COVID-19 pandemic, there are still no proven effective and widely available antivirals for COVID-19 treatment. Favipiravir and Ivermectin are among common repurposed drugs, which have been provisionally used in some countries. There have been clinical trials with mixed results, and therefore, it is still inconclusive whether they are effective or should be dismissed. It is plausible that the lack of clear-cut clinical benefits was due to the finding of only marginal levels of in vivo antiviral activity. An obvious way to improve the activity of antivirals is to use them in synergistic combinations. Here we show that Favipiravir and Ivermectin had the synergistic effects against SARS-CoV-2 in Vero cells. The combination may provide better efficacy in COVID-19 treatment. In addition, we found that Favipiravir had an additive effect with Niclosamide, another repurposed anti-parasitic drug with anti-SARS-CoV-2 activity. However, the anti-SARS-CoV-2 activity of Favipiravir was drastically reduced when tested in Calu-3 cells. This suggested that this cell type might not be able to metabolize Favipiravir into its active form, and that this deficiency in some cell types may affect in vivo efficacy of this drug.

scholarly journals In vitro and in vivo studies reveal α-Mangostin, a xanthonoid from Garcinia mangostana, as a promising natural antiviral compound against chikungunya virus

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Poonam Patil ◽  
Megha Agrawal ◽  
Shahdab Almelkar ◽  
Manish Kumar Jeengar ◽  
Ashwini More ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Antiviral Activity ◽  
Chikungunya Virus ◽  
In Vivo Studies ◽  
Therapeutic Effects ◽  
Garcinia Mangostana ◽  
Chikv Infection ◽  
Antiviral Compound

Abstract Background Chikungunya virus (CHIKV), a serious health problem in several tropical countries, is the causative agent of chikungunya fever. Approved antiviral therapies or vaccines for the treatment or prevention of CHIKV infections are not available. As diverse natural phenolic compounds have been shown to possess antiviral activities, we explored the antiviral activity of α-Mangostin, a xanthanoid, against CHIKV infection. Methods The in vitro prophylactic and therapeutic effects of α-Mangostin on CHIKV replication in Vero E6 cells were investigated by administering it under pre, post and cotreatment conditions. The antiviral activity was determined by foci forming unit assay, quantitative RT-PCR and cell-based immune-fluorescence assay. The molecular mechanism of inhibitory action was further proposed using in silico molecular docking studies. Results In vitro studies revealed that 8 µM α-Mangostin completely inhibited CHIKV infectivity under the cotreatment condition. CHIKV replication was also inhibited in virus-infected mice. This is the first in vivo study which clearly showed that α-Mangostin is effective in vivo by significantly reducing virus replication in serum and muscles. Molecular docking indicated that α-Mangostin can efficiently interact with the E2–E1 heterodimeric glycoprotein and the ADP-ribose binding cavity of the nsP3 macrodomain. Conclusions The findings suggest that α-Mangostin can inhibit CHIKV infection and replication through possible interaction with multiple CHIKV target proteins and might act as a prophylactic/therapeutic agent against CHIKV.

scholarly journals Sequential Infection of Aedes aegypti Mosquitoes with Chikungunya Virus and Zika Virus Enhances Early Zika Virus Transmission

Insects ◽  
2018 ◽  
Vol 9 (4) ◽  
pp. 177 ◽  
Author(s):  
Tereza Magalhaes ◽  
Alexis Robison ◽  
Michael Young ◽  
William Black ◽  
Brian Foy ◽  
...  
Keyword(s):  
Aedes Aegypti ◽  
Blood Meal ◽  
Zika Virus ◽  
Chikungunya Virus ◽  
Vector Competence ◽  
Virus Transmission ◽  
Mosquito Vector ◽  
Molecular Aspects ◽  
Virus Interactions ◽  
Sequential Infection

In urban settings, chikungunya, Zika, and dengue viruses are transmitted by Aedes aegypti mosquitoes. Since these viruses co-circulate in several regions, coinfection in humans and vectors may occur, and human coinfections have been frequently reported. Yet, little is known about the molecular aspects of virus interactions within hosts and how they contribute to arbovirus transmission dynamics. We have previously shown that Aedes aegypti exposed to chikungunya and Zika viruses in the same blood meal can become coinfected and transmit both viruses simultaneously. However, mosquitoes may also become coinfected by multiple, sequential feeds on single infected hosts. Therefore, we tested whether sequential infection with chikungunya and Zika viruses impacts mosquito vector competence. We exposed Ae. aegypti mosquitoes first to one virus and 7 days later to the other virus and compared infection, dissemination, and transmission rates between sequentially and single infected groups. We found that coinfection rates were high after sequential exposure and that mosquitoes were able to co-transmit both viruses. Surprisingly, chikungunya virus coinfection enhanced Zika virus transmission 7 days after the second blood meal. Our data demonstrate heterologous arbovirus synergism within mosquitoes, by unknown mechanisms, leading to enhancement of transmission under certain conditions.

scholarly journals Cell-Fusing Agent Virus Reduces Arbovirus Dissemination in Aedes aegypti Mosquitoes In Vivo

2019 ◽  
Vol 93 (18) ◽  
Author(s):  
Artem Baidaliuk ◽  
Elliott F. Miot ◽  
Sebastian Lequime ◽  
Isabelle Moltini-Conclois ◽  
Fanny Delaigue ◽  
...  
Keyword(s):  
Aedes Aegypti ◽  
Dengue Virus ◽  
Cell Line ◽  
Content Type ◽  
Cells In Culture ◽  
Mosquito Cells ◽  
Wide Range ◽  
Natural Hosts

ABSTRACT Aedes aegypti mosquitoes are the main vectors of arthropod-borne viruses (arboviruses) of public health significance, such as the flaviviruses dengue virus (DENV) and Zika virus (ZIKV). Mosquitoes are also the natural hosts of a wide range of viruses that are insect specific, raising the question of their influence on arbovirus transmission in nature. Cell-fusing agent virus (CFAV) was the first described insect-specific flavivirus, initially discovered in an A. aegypti cell line and subsequently detected in natural A. aegypti populations. It was recently shown that DENV and the CFAV strain isolated from the A. aegypti cell line have mutually beneficial interactions in mosquito cells in culture. However, whether natural strains of CFAV and DENV interact in live mosquitoes is unknown. Using a wild-type CFAV isolate recently derived from Thai A. aegypti mosquitoes, we found that CFAV negatively interferes with both DENV type 1 and ZIKV in vitro and in vivo. For both arboviruses, prior infection by CFAV reduced the dissemination titer in mosquito head tissues. Our results indicate that the interactions observed between arboviruses and the CFAV strain derived from the cell line might not be a relevant model of the viral interference that we observed in vivo. Overall, our study supports the hypothesis that insect-specific flaviviruses may contribute to reduce the transmission of human-pathogenic flaviviruses. IMPORTANCE The mosquito Aedes aegypti carries several arthropod-borne viruses (arboviruses) that are pathogenic to humans, including dengue and Zika viruses. Interestingly, A. aegypti is also naturally infected with insect-only viruses, such as cell-fusing agent virus. Although interactions between cell-fusing agent virus and dengue virus have been documented in mosquito cells in culture, whether wild strains of cell-fusing agent virus interfere with arbovirus transmission by live mosquitoes was unknown. We used an experimental approach to demonstrate that cell-fusing agent virus infection reduces the propagation of dengue and Zika viruses in A. aegypti mosquitoes. These results support the idea that insect-only viruses in nature can modulate the ability of mosquitoes to carry arboviruses of medical significance and that they could possibly be manipulated to reduce arbovirus transmission.

scholarly journals Telmisartan restricts Chikungunya virus infection in vitro and in vivo through the AT1/PPAR-γ/MAPKs pathways

2021 ◽  
Author(s):  
Saikat De ◽  
Prabhudutta Mamidi ◽  
Soumyajit Ghosh ◽  
Supriya Suman Keshry ◽  
Chandan Mahish ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
At1 Receptor ◽  
Host Factors ◽  
Raw 264.7 Cells ◽  
Raw 264.7 ◽  
Global Public Health ◽  
Chikv Infection ◽  
Ppar Γ

Chikungunya virus (CHIKV) has re-emerged as a global public health threat. The inflammatory pathways of RAS and PPAR-γ are usually involved in viral infections. Thus, Telmisartan (TM) with known capacity to block AT1 receptor and activate PPAR-γ, was investigated against CHIKV. The anti-CHIKV effect of TM was investigated in vitro (Vero, RAW 264.7 cells and hPBMCs) and in vivo (C57BL/6 mice). TM was found to abrogate CHIKV infection efficiently (IC50 of 15.34-20.89μM in the Vero and RAW 264.7 cells respectively). Viral RNA and proteins were reduced remarkably. Additionally, TM interfered in the early and late stages of CHIKV life cycle with efficacy in both pre and post-treatment assay. Moreover, the agonist of AT1 receptor and antagonist of PPAR-γ increased CHIKV infection suggesting TM’s anti-viral potential by modulating host factors. Besides, reduced activation of all major MAPKs, NF-κB (p65) and cytokines by TM through the inflammatory axis supported the fact that the anti-CHIKV efficacy of TM is partly mediated through the AT1/PPAR-γ/MAPKs pathways. Interestingly, at the human equivalent dose, TM abrogated CHIKV infection and inflammation significantly leading to reduced clinical score and complete survival of C57BL/6 mice. Additionally, TM reduced infection in hPBMC derived monocyte-macrophage populations in vitro . Hence, TM was found to reduce CHIKV infection by targeting both viral and host factors. Considering its safety and in vivo efficacy, it can be a suitable candidate in future for repurposing against CHIKV.

scholarly journals MOXIDECTIN AND IVERMECTIN INHIBIT SARS-COV-2 REPLICATION IN VERO E6 CELLS BUT NOT IN HUMAN PRIMARY AIRWAY EPITHELIUM CELLS

2021 ◽  
Author(s):  
Nilima Dinesh Kumar ◽  
Bram M. ter Ellen ◽  
Ellen M. Bouma ◽  
Berit Troost ◽  
Denise P. I. van de Pol ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Antiviral Effect ◽  
Vero Cells ◽  
In Vitro Models ◽  
World Health ◽  
Current Evidence ◽  
High Dose ◽  
Health Organization

Antiviral therapies are urgently needed to treat and limit the development of severe COVID-19 disease. Ivermectin, a broad-spectrum anti-parasitic agent, has been shown to have anti-SARS-CoV-2 activity in Vero cells at a concentration of 5 μM. These limited in vitro results triggered the investigation of ivermectin as a treatment option to alleviate COVID-19 disease. In April 2021, the World Health Organization stated, however, the following: “the current evidence on the use of ivermectin to treat COVID-19 patients is inconclusive”. It is speculated that the in vivo concentration of ivermectin is too low to exert a strong antiviral effect. Here, we performed a head-to head comparison of the antiviral activity of ivermectin and the structurally related, but metabolically more stable, moxidectin in multiple in vitro models of SARS-CoV-2 infection, including physiologically relevant human respiratory epithelial cells. Both moxidectin and ivermectin exhibited antiviral activity in Vero E6 cells. Subsequent experiments revealed that the compounds predominantly act on a step after virus cell entry. Surprisingly, however, in human airway-derived cell models, moxidectin and ivermectin failed to inhibit SARS-CoV-2 infection, even at a concentration of 10 μM. These disappointing results call for a word of caution in the interpretation of anti-SARS-CoV-2 activity of drugs solely based on Vero cells. Altogether, these findings suggest that, even by using a high-dose regimen of ivermectin or switching to another drug in the same class are unlikely to be useful for treatment against SARS-CoV-2 in humans.

scholarly journals The native European Aedes geniculatus mosquito species can transmit Chikungunya virus

2019 ◽  
Author(s):  
Jorian Prudhomme ◽  
Albin Fontaine ◽  
Guillaume Lacour ◽  
Jean-Charles Gantier ◽  
Laure Diancourt ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
Vector Competence ◽  
Mosquito Species ◽  
Cumulative Distribution ◽  
Mosquito Vector ◽  
Indigenous Species ◽  
Chikv Infection ◽  
Invasive Mosquito ◽  
Virus Emergence

AbstractEurope is the world’s leading tourism destination and is receiving every year travelers from areas with active arbovirus transmission. There is thus a threat of mosquito-borne virus emergence in Europe due to the presence of the invasive mosquito vector Aedes albopictus. Little attention has been paid about the possible role of indigenous mosquito species as vectors of emerging arboviruses. Here, we assessed the vector competence dynamic of Ae. geniculatus, a European anthropophilic mosquito species, for chikungunya virus (CHIKV) in comparison with Ae. albopictus.We revealed that Ae. geniculatus was highly susceptible to CHIKV infection and could transmit the virus. By specifically exploring the vector competence dynamic in both mosquito species, we revealed that the cumulative distribution of CHIKV incubation period in Ae. geniculatus was delayed by several days as compared to Ae. albopictus.Our results strengthen the importance of considering indigenous species as potential vectors for emerging arboviruses. They also revealed the importance of considering variation in arbovirus dissemination or transmission dynamics in mosquitoes when performing vector competence assays. We will discuss the implications of our results on a CHIKV outbreak dynamic in a theoretical framework.Sentence summaryThe European mosquito Aedes geniculatus is highly susceptible to CHIKV infection but disseminate and transmit the virus several days later than Ae. albopictus.

Intra and inter-cellular modeling of dynamic interaction between Zika virus and its naturally occurring defective viral genomes

2021 ◽  
Author(s):  
Vadim Sharov ◽  
Veronica V. Rezelj ◽  
Vladimir V. Galatenko ◽  
Avi Titievsky ◽  
Julia Panov ◽  
...  
Keyword(s):  
Virus Titer ◽  
Vero Cells ◽  
Mosquito Vector ◽  
Ns1 Protein ◽  
Coding Region ◽  
Viral Genomes ◽  
Naturally Occurring ◽  
Mosquito Cells ◽  
Infection Dynamics ◽  
Development Processes

Here we examine in-silico the infection dynamics and interactions of two ZIKV genomes: one is the full-length ZIKV genome (WT) and the other is one of the naturally occurring defective viral genomes (DVG), which can replicate in the presence of WT genome, appears under high MOI passaging conditions and carries a deletion encompassing part of the structural and NS1 protein-coding region. Ordinary differential equations (ODE) were used to simulate the infection of cells by virus particles and intra-cellular replication of the WT and DVG genomes that produces these particles. For each virus passage in Vero and C6/36 cell cultures, rates of the simulated processes were fitted to two types of observations: virus titer data and the assembled haplotypes of the replicate passage samples. We studied the consistency of the model with the experimental data across all passages of infection in each cell type separately, as well as sensitivity of model’s parameters. We also determined which simulated processes of the virus evolution are most important for adaptation of the WT and DVG interplay in these two disparate cell culture environments. Our results demonstrate that in majority of passages, the rates of DVG-production are higher in the C6/36 cells compared to Vero cells, which might result in tolerance and therefore drive persistence of the mosquito vector in the context of ZIKV infection. Additionally, the model simulations showed slower accumulation of infected cells under higher activation of the DVG associated processes, which indicates potential role of DVGs in virus attenuation. Importance. One of ideas on lessening Zika pathogenicity is addition of its natural or engineered defective virus genomes (DVG: have no pathogenicity) to the infection pool: DVG is redirecting the wild type (WT) associated virus development resources to its own maturation. The presented here mathematical model, attuned to the data from interplays between Zika WT viruses and their natural DVG in mammalian and mosquito cells, provides evidence that loss of uninfected cells is attenuated by the DVG development processes. This model enabled us to estimate rates of the virus development processes in the WT/DVG interplay, determine the key processes, and show that the key processes are faster in mosquito cells than in mammalian ones. In general, the presented model and its detailed study suggest in what important virus development processes the therapeutically efficient DVG might compete with WT: this may help in assembling engineered DVGs for ZIKV and other flaviviruses.

ANTIVIRAL ACTIVITY OF HERBAL IMMUNOMODULATORY PREPARATIONS NCV I AND AC II – AND THEIR USEFULNESS IN HIV INFECTION

INDIAN DRUGS ◽  
2015 ◽  
Vol 52 (11) ◽  
pp. 50-55
Author(s):  
S. T Tharakan ◽  
◽  
P. P. Binitha ◽  
R. Kuttan ◽  
G. Kuttan
Keyword(s):  
Human Immunodeficiency Virus ◽  
Antiviral Activity ◽  
Vero Cells ◽  
Chick Embryos ◽  
The Past ◽  
Immunodeficiency Virus ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome

NCV I and AC II are the two herbal immunomodulatory preparations being used in our centre for the treatment of acquired immunodeficiency syndrome (AIDS) for the past 20 years. The objective of this study is to check whether these drugs possess any antiviral activity in vitro and in vivo. In vitro antiviral activity was determined using Vero cells against Poliovirus. In vivo antiviral activity was determined in chick and duck embryonated eggs using New Castle Disease Virus (NDV), Egg Drop Syndrome (EDS) virus and also in NDV vaccinated chicks. NCV I and AC II decreased growth of poliovirus in culture. When the virus-inoculated Vero cells were treated with NCV I, the viral growth was inhibited by 59.87% and with AC II it was inhibited by 70.06%. When the chick embryos were treated with these viruses, there was no immediate lethality for 5 days but the haemagglutination titre (HA) was found to be significantly increased indicating an increase in viral load. The haemagglutination titre for NDV alone was found to be 1024 against normal untreated value of 128. In EDS treated duck eggs HA titre was found to be 4096. These titres were reduced to 4 in NCV I and 8 in AC II treated duck embryos. NCV I and AC II were also found to decrease the HA titre in chicks treated with NDV. These studies indicated the effectiveness of NCV I and AC II in HIV could be partially due to its antiviral activity against human immunodeficiency virus.

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