Viral Reduction Research Articles

Antiviral activity of ciclesonide acetal derivatives blocking SARS-CoV-2 RNA replication

Ciclesonide (Cic) is approved as an inhalant for asthma and was clinically tested as a candidate therapy for coronavirus disease 2019 (COVID-19). Its active metabolite Cic2 was recently reported to suppress genomic RNA replication of severe acute respiratory syndrome coronavirus 2. In this study, we designed and synthesized a set of ciclesonide-acetal (Cic-acetal) derivatives. Among designated compounds, some Cic-acetal derivatives with a linear alkyl chain exhibited strong viral copy-number reduction activities compared with Cic2. These compounds might serve as lead compounds for developing novel anti-COVID-19 agents.

The pathophysiological mechanisms of COVID-19 and host immunity, with emphasis on the dysbiosis of the lung and gut microbiomes and pregnancy

The coronavirus 2019 (COVID-19) pandemic is a health and economic crisis. It has also highlighted human relational problems, such as racism and conflicts between nations. Although vaccination programs against the severe respiratory syndrome coronavirus 2 (SARS-CoV-2) have started worldwide, the pandemic is ongoing, and people are struggling. The mechanism of disease severity in COVID-19 is multifactorial, complicated, and affected by viral pathogenesis. For example, monocyte dysfunction due to aging and respiratory and gut dysbiosis influence the host's immunity against SARS-CoV-2 including helper T-cell imbalance and viral clearance reduction, leading to accelerated disease progression in older patients or those with underlying diseases. The different immune responses against SARS-CoV-2 also contribute to various radiological findings, including that of acute respiratory distress syndrome, which is associated with high mortality, especially in patients susceptible to disease progression. We aimed to review the pathophysiological mechanisms involved in COVID-19, with emphasis on the altered microbiome in the lung and gut, and the different radiological findings in different patient groups, such as younger adults and pregnant women.

Anti-Zika Virus Activity of Plant Extracts Containing Polyphenols and Triterpenes on Vero CCL-81 and Human Neuroblastoma SH-SY5Y Cells.

Zika virus (ZIKV) infection is a global threat associated to neurological disorders in adults and microcephaly in children born to infected mothers. No vaccine or drug is available against ZIKV. We herein report the anti-ZIKV activity of 36 plant extracts containing polyphenols and/or triterpenes. ZIKV-infected Vero CCL-81 cells were treated with samples at non-cytotoxic concentrations, determined by MTT and LDH assays. One third of the extracts elicited concentration-dependent anti-ZIKV effect, with viral loads reduction from 0.4 to 3.8 log units. The 12 active extracts were tested on ZIKV-infected SH-SY5Y cells and significant reductions of viral loads (in log units) were induced by Maytenus ilicifolia (4.5 log), Terminalia phaeocarpa (3.7 log), Maytenus rigida (1.7 log) and Echinodorus grandiflorus (1.7 log) extracts. Median cytotoxic concentration (CC50 ) of these extracts in Vero cells were higher than in SH-SY5Y lineage. M. ilicifolia (IC50 =16.8±10.3 μg/mL, SI=3.4) and T. phaeocarpa (IC50 =22.0±6.8 μg/mL, SI=4.8) were the most active extracts. UPLC-ESI-MS/MS analysis of M. ilicifolia extract led to the identification of 7 triterpenes, of which lupeol and a mixture of friedelin/friedelinol showed no activity against ZIKV. The composition of T. phaeocarpa extract comprises phenolic acids, ellagitannins and flavonoids, as recently reported by us. In conclusion, the anti-ZIKV activity of 12 plant extracts is here described for the first time and polyphenols and triterpenes were identified as the probable bioactive constituents of T. phaeocarpa and M. ilicifolia, respectively.

Searching for plant-derived antivirals against dengue virus and Zika virus

BackgroundThe worldwide epidemics of diseases as dengue and Zika have triggered an intense effort to repurpose drugs and search for novel antivirals to treat patients as no approved drugs for these diseases are currently available. Our aim was to screen plant-derived extracts to identify and isolate compounds with antiviral properties against dengue virus (DENV) and Zika virus (ZIKV).MethodsSeven thousand plant extracts were screened in vitro for their antiviral properties against DENV-2 and ZIKV by their viral cytopathic effect reduction followed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method, previously validated for this purpose. Selected extracts were submitted to bioactivity-guided fractionation using high- and ultrahigh-pressure liquid chromatography. In parallel, high-resolution mass spectrometric data (MSn) were collected from each fraction, allowing compounds into the active fractions to be tracked in subsequent fractionation procedures. The virucidal activity of extracts and compounds was assessed by using the plaque reduction assay. EC50 and CC50 were determined by dose response experiments, and the ratio (EC50/CC50) was used as a selectivity index (SI) to measure the antiviral vs. cytotoxic activity. Purified compounds were used in nuclear magnetic resonance spectroscopy to identify their chemical structures. Two compounds were associated in different proportions and submitted to bioassays against both viruses to investigate possible synergy. In silico prediction of the pharmacokinetic and toxicity (ADMET) properties of the antiviral compounds were calculated using the pkCSM platform.ResultsWe detected antiviral activity against DENV-2 and ZIKV in 21 extracts obtained from 15 plant species. Hippeastrum (Amaryllidaceae) was the most represented genus, affording seven active extracts. Bioactivity-guided fractionation of several extracts led to the purification of lycorine, pretazettine, narciclasine, and narciclasine-4-O-β-D-xylopyranoside (NXP). Another 16 compounds were identified in active fractions. Association of lycorine and pretazettine did not improve their antiviral activity against DENV-2 and neither to ZIKV. ADMET prediction suggested that these four compounds may have a good metabolism and no mutagenic toxicity. Predicted oral absorption, distribution, and excretion parameters of lycorine and pretazettine indicate them as candidates to be tested in animal models.ConclusionsOur results showed that plant extracts, especially those from the Hippeastrum genus, can be a valuable source of antiviral compounds against ZIKV and DENV-2. The majority of compounds identified have never been previously described for their activity against ZIKV and other viruses.

Intestinal Colonization With Bifidobacterium longum Subspecies Is Associated With Length at Birth, Exclusive Breastfeeding, and Decreased Risk of Enteric Virus Infections, but Not With Histo-Blood Group Antigens, Oral Vaccine Response or Later Growth in Three Birth Cohorts.

Bifidobacterium longum subspecies detected in infant stool have been associated with numerous subsequent health outcomes and are potential early markers of deviation from healthy developmental trajectories. This analysis derived indicators of carriage and early colonization with B. infantis and B. longum and quantified their associations with a panel of early-life exposures and outcomes. In a sub-study nested within a multi-site birth cohort, extant stool samples from infants in Bangladesh, Pakistan and Tanzania were tested for presence and quantity of two Bifidobacterium longum subspecies. The results were matched to indicators of nutritional status, enteropathogen infection, histo-blood group antigens, vaccine response and feeding status and regression models were fitted to test for associations while adjusting for covariates. B. infantis was associated with lower quantity of and decreased odds of colonization with B. longum, and vice versa. Length at birth was associated with a 0.36 increase in log10 B. infantis and a 0.28 decrease in B. longum quantity at 1 month of age. B. infantis colonization was associated with fewer viral infections and small reductions in the risk of rotavirus and sapovirus infections, but not reduced overall diarrheal disease risk. No associations with vaccine responses, HBGAs or later nutritional status were identified. Suboptimal intrauterine growth and a shorter duration of exclusive breastfeeding may predispose infants to early intestinal colonization with the B. longum subspecies at the expense of B. infantis, thus denying them potential benefits of reduced enteric virus episodes.

Design and Realization of a UV-C Based Disinfection Tools Monitored by Mobile Application

In many outbreaks, patients and healthcare workers are particularly at risk from nosocomial infections as a result of non-effective disinfection methods. With increasing incidence of viral infections such as severe acute respiratory syndrome, in one hand, and the increase in the rate of antibiotic resistant bacteria associated with nosocomial infections in other hand, there is a need to design novel engineering tools for inactivation of nosocomial pathogens. Ultraviolet germicidal irradiation (UVGI) is considered as a promising method to inactivate bacteria and viruses. This paper presents UV-C Based disinfection tools monitored by mobile application, designed for hospital and Epidemic Treatment Center. The evolution of the irradiation intensity over time was evaluated, and the theorical disinfection duration for several nosocomial pathogens was determined. In the case of SARS-CoV2, less than 12 minutes were needed to achieve 99.99% viral reduction in a room of 36 sqm.

Prevalence of the Human Immunodeficiency Virus and associated factors in pregnant women in the state of Pará.

to analyze the prevalence of the Human Immunodeficiency Virus and the associated factors in pregnant women in the state of Pará. retrospective, analytical, quantitative study with a sample of 332 medical records of HIV-positive pregnant women hospitalized at the Referral Maternity Hospital in the state of Pará between 2010 and 2019. Bivariate and multivariate statistical analysis were performed with the variables collected. the average prevalence in the period was 2.39% and the Metropolitan Region concentrated 66.87% of cases. There was a strong relationship between the number of antenatal consultations and lack of knowledge of serological status (p value equal to 0.01E-17) variables, and a correlation between the education and number of antenatal consultations variables. the increase in the infection rate during the study period revealed the need to intensify health actions, early diagnosis and strategies to improve adherence to antiretroviral treatment for maternal viral suppression and reduction of the risk of vertical transmission, contributing to improve public policies.

Treatment Effect of Various Concentration of Plant Extracts on Murine Norovirus

Noroviruses are positive-sense, single-stranded, non-enveloped RNA virus that measures approximately 27 - 35 nm in diameter. It affects humans of all ages and races causing most cases of viral gastroenteritis worldwide. Infection results from ingestion of contaminated food or water as well as causing diarrhea and vomiting in humans. Extracts from plants are known to have antioxidant, anti-inflammatory, and adhesive properties which are associated with barrier functions. The aim of this study was to elucidate whether plaque reduction was due to an effect of methanolic plant extract directly on the virus, whether the extract affects viral replication, and lastly, whether the extract disrupts the cell surface binding with the virus. The plant extracts of interest were the calyces of Hibiscus sabdariffa (HS) and the seeds of Zanthoxylum armatum (ZA). Antiviral activities of these extracts were determined against murine norovirus. The logarithmic viral reduction per plaque-forming unit was (22 log10) PFU/ml (control), (15 log10) PFU/ml (treated HS), and (12 log10) PFU/ml (treated ZA) with a significant reduction (68% and 55% respectively) when compared with the control for the direct effect on the virus. The role of extracts on virus replication showed (25 log10) PFU/ml (control) as against the HS treated-virus-infected cells (9 log10) PFU/ml and ZA treated-virus-infected cells (5 log10) PFU/ml (36% and 20% respectively). Finally, effect of the extract on the viral attachment showed (31 log10) PFU/ml (control), (12 log10) (HS-treated) and (9 log10) PFU/ml (ZA-treated), (39% and 29% respectively. Extract treatment with HS and ZA has shown evidence of a reduced number of plaques formation with the latter having fewer plaques. Both extracts have proven potential to reduce the viral multiplication process by interfering with the replication process. This study shows that Hibiscus sabdariffa (calyces) and Zanthoxylum armatum (seed) extracts disrupt murine norovirus from consistent viral replication.

An overview of solutions for airborne viral transmission reduction related to HVAC systems including liquid desiccant air-scrubbing

The spread of the coronavirus SARS-CoV-2 affects the health of people and the economy worldwide. As air transmits the virus, heating, ventilation and air-conditioning (HVAC) systems in buildings, enclosed spaces and public transport play a significant role in limiting the transmission of airborne pathogens at the expenses of increased energy consumption and possibly reduced thermal comfort. On the other hand, liquid desiccant technology could be adopted as an air scrubber to increase indoor air quality and inactivate pathogens through temperature and humidity control, making them less favourable to the growth, proliferation and infectivity of microorganisms. The objectives of this study are to review the role of HVAC in airborne viral transmission, estimate its energy penalty associated with the adoption of HVAC for transmission reduction and understand the potential of liquid desiccant technology. Factors affecting the inactivation of pathogens by liquid desiccant solutions and possible modifications to increase their heat and mass transfer and sanitising characteristics are also described, followed by an economic evaluation. It is concluded that the liquid desiccant technology could be beneficial in buildings (requiring humidity control or moisture removal in particular when viruses are likely to present) or in high-footfall enclosed spaces (during virus outbreaks).

Exploiting the antiviral potential of intermetallic nanoparticles

Viral pandemic outbreaks cause a significant burden on global health as well as healthcare expenditure. The use of antiviral agents not only reduces the spread of viral pathogens but also diminishes the likelihood of them causing infection. The antiviral properties of novel copper-silver and copper-zinc intermetallic nanoparticles against Escherichia coli bacteriophage MS2 (RNA virus) and Escherichia coli bacteriophage T4 (DNA virus) are presented. The intermetallic nanoparticles were spherical in shape and were between 90 and 120 nm. Antiviral activity was assessed at concentrations ranging from 0.05 to 2.0 wt/v% for 3 and 24 h using DNA and RNA virus model organisms. Both types of nanoparticles demonstrated strong potency towards RNA viruses (> 89% viral reduction), whilst copper-silver nanoparticles were slightly more toxic towards DNA viruses when compared to copper-zinc nanoparticles. Both nanoparticles were then incorporated into polymeric fibres (carrier) to investigate their antiviral effectiveness when composited into polymeric matrices. Fibres containing copper-silver nanoparticles exhibited favourable antiviral properties, with a viral reduction of 75% after 3 h of exposure. The excellent antiviral properties of the intermetallic nanoparticles reported in this study against both types of viruses together with their unique material properties can make them significant alternatives to conventional antiviral therapies and decontamination agents.

Antimicrobial silver nanoparticle-photodeposited fabrics for SARS-CoV-2 destruction

Surfaces containing antiviral nanoparticles could play a crucial role in minimizing the virus spread further, specifically for COVID-19. Here in, we have developed a facile and durable antiviral and antimicrobial fabric containing photodeposited silver nanoparticles. Scanning and transmission electron microscopy, UV-VIS spectroscopy, and XPS are used to characterize the silver nanoparticles deposited cloth. It is evident that Ag0/Ag+ redox couple is formed during fabrication, which acts as an active agent. Antiviral testing results show that silver nanoparticles deposited fabric exhibits 97% viral reduction specific to SARS-CoV-2. Besides its excellent antiviral property, the modified fabric also offers antimicrobial efficiency when tested with the airborne human pathogenic bacteria Escherichia coli and fungi Aspergillus Niger. The direct photodeposition provides Ag-O-C interaction leads to firmly grafted nanoparticles on fabric allow the modified fabric to sustain the laundry durability test. The straightforward strategy to prepare an efficient antimicrobial cloth can attract rapid large-scale industrial production.

An emerging innovative UV disinfection technology: virucide activity on SARS-CoV-2

Abstract Background Surface sanitation is one of the key points to reduce the risk of transmission both in healthcare and other public spaces. UV-C is already used in hospital and laboratory's disinfection procedure furthermore some recent studies show effectiveness on SARS-CoV-2. UV-C may be generated by Lamps and Light Emitting Diode, but novel sources are emerging. The aim of the study was to test a device having UV chips for inactivating SARS-CoV2. Methods The descriptive study was conducted in the period between June and July 2019, in laboratories of the University of Siena and of the scientific park of Toscana life sciences. The device, shaped in a rectangular box, contained six UV chips (10 mW each, with a peak at 264nm nm ranging from 260 to 350 nm) placed in the bottom. Central and short side long positions were tested expecting different dose levels. Each experiment was conducted in triplicate, with and without the device lid, at 3, 6 and 10 minutes. All repetitions were tested for SARS-CoV-2 having a virus suspension of 10^7.2. Results The zones with the higher value of irradiance (max 187.9 µW/cm2) were near the corners of the box, while the lowest (min 61.9 µW/cm2) near one of the long sides. The light distribution was almost symmetrical. The tests revealed a viral charge reduction from an initial concentration of virus suspension of 10^7.2 TCID50/mL, of more than 99.9% after 3 minutes of UV exposure; at 6 minutes, the minimum Log10 attenuation value was over 5 Log10(99,999%); the maximum detectable attenuation value of Log10 = 5.7 was measured at 10 minutes. Conclusions This device is the first one which introduces this novel UV chip source, similarly it is the first time it was tested against the SARS-CoV-2. Objects that need to be disinfected may benefit of such devices according a proper exposition time for homogeneous disinfections of the surfaces. Key messages Implementation of cleaning and disinfection devices has been shown to reduce Sars-cov-2 infection incidence. In the hospital sanitation field, but also in public places and homes, using viable alternatives as UV-C can contribute to the reduction of pandemic spread.

Effectiveness of Disinfection with Chlorine Dioxide on Respiratory Transmitted, Enteric, and Bloodborne Viruses: A Narrative Synthesis.

A viral spread occurrence such as the SARS-CoV-2 pandemic has prompted the evaluation of different disinfectants suitable for a wide range of environmental matrices. Chlorine dioxide (ClO2) represents one of the most-used virucidal agents in different settings effective against both enveloped and nonenveloped viruses. This narrative synthesis is focused on the effectiveness of ClO2 applied in healthcare and community settings in order to eliminate respiratory transmitted, enteric, and bloodborne viruses. Influenza viruses were reduced by 99.9% by 0.5–1.0 mg/L of ClO2 in less than 5 min. Higher concentration (20 mg/L) eliminated SARS-CoV-2 from sewage. ClO2 concentrations from 0.2 to 1.0 mg/L ensured at least a 99% viral reduction of AD40, HAV, Coxsackie B5 virus, and other enteric viruses in less than 30 min. Considering bloodborne viruses, 30 mg/L of ClO2 can eliminate them in 5 min. Bloodborne viruses (HIV-1, HCV, and HBV) may be completely eliminated from medical devices and human fluids after a treatment with 30 mg/L of ClO2 for 30 min. In conclusion, ClO2 is a versatile virucidal agent suitable for different environmental matrices.

Inactivation of Murine Norovirus Suspended in Organic Matter Simulating Actual Conditions of Viral Contamination.

Foodborne viral illnesses are frequent worldwide and costly for the society. Human norovirus is one of the most common causal agents. Although some norovirus genotypes can now be cultured, surrogates are still used for inactivation studies. The aim of this study was to evaluate the effects of different organic loads individually (artificial feces, real fecal matter, ASTM tripartite organic load, fetal bovine serum) on the efficacy of three highly used sanitization treatments (thermal inactivation, peracetic acid and sodium hypochlorite treatment) using murine norovirus 3 in solutions and surfaces. Based on plaque-forming units, we show that organic matter protects murine norovirus 3 against thermal inactivation (viral reduction of ~ 1 log compared to 2.67 with PBS). However, there was a low-level but significant protection against peracetic acid (viral reduction of ~ 2 log compared to 2.85 with PBS) and none in the presence of sodium hypochlorite. Our study showed that the tested organic matters do not behave similarly depending on the treatments, especially with heat treatments, which showed a higher protection. Furthermore, Feclone ™ artificial feces mimicked some aspect of real fecal matter and may be used instead. Our results will be helpful to researchers undertaking viral inactivation studies in which an organic matrix is used to simulate actual conditions of human norovirus environment.

Physical and Biological Performance Evaluation of Disinfection Systems for Transportation Vehicles against AI Virus.

To prevent the outbreak of infectious diseases that inflict huge economic and social losses, domestic livestock farms and related facilities have introduced automatic and semiautomatic disinfectant solution-spraying systems for vehicles. However, the facility standards and specifications vary by manufacturer, and no scientific performance evaluation has been conducted. The puropose of this study is to develop physical and biological evaluation methods. Physical and biological appraisals were conducted using two types of disinfection facilities (tunnel- and U-type) and two types of vehicles (passenger car, truck). Water-sensitive paper was used to evaluate the physical performance values for the disinfection facilities. In addition, to assess their biological performance, carriers containing low-pathogenic avian influenza virus were attached to vehicles, and the viral reduction was measured after the vehicles moved through the facility. The tunnel-type had rates of coverage in the range of 70-90% for the passenger car and 60-90% for the truck. At least 4-log virus reduction after spraying for 1-5 min was shown for both vehicles. For the U-type facility evaluation, the coverage rates were in the range of 60-90% for the passenger car and at least 90% for the truck. More than 4-log viral reduction was estimated within a spraying time of 5 min. To reduce viruses on the surface of vehicles by at least 4 log within a short period, the disinfectant solution should cover at least 71% of the pathogens. In conclusion, we were able to assess the physical and biological performance criteria for disinfection facilities aboard transportation vehicles.

Removal of minute virus of mice-mock virus particles by nanofiltration of culture growth medium supplemented with 10% human platelet lysate

Background aimsPlatelet concentrates (PCs) are pooled to prepare human platelet lysate (HPL) supplements of growth media to expand primary human cells for transplantation; this increases the risk of contamination by known, emerging, and unknown viruses. This possibility should be of concern because viral contamination of cell cultures is difficult to detect and may have detrimental consequences for recipients of cell therapies. Viral reduction treatments of chemically defined growth media have been proposed, but they are not applicable when media contain protein supplements currently needed to expand primary cell cultures. Recently, we successfully developed a Planova 35NPlanova 20N nanofiltration sequence of growth media supplemented with two types of HPL. The nanofiltered medium was found to be suitable for mesenchymal Stromal cell (MSC) expansion. MethodsHerein, we report viral clearance achieved by this nanofiltration process used for assessing a new experimental model using non-infectious minute virus of mice-mock virus particle (MVM-MVP) and its quantification by an immunoqPCR. Then, high doses of MVM-MVP (1012 MVPs/mL) were spiked to obtain a final concentration of 1010 MVPs/mL in Planova 35N-nanofiltered growth medium supplemented with both types of HPLs [serum converted platelet lysate SCPL) and intercept human platelet lysate (I-HPL)] at 10% (v/v) and then filtering through Planova 20N. ResultsNo substantial interference of growth medium matrices by the immune-qPCR assay was first verified. Log reduction values (LRVs) were ≥ 5.43 and ≥ 5.36 respectively, SCPL and I-HPL media. MVM-MVPs were also undetectable by dynamic light scattering and transmission electron microscopy. ConclusionsThe nanofiltration of growth media supplemented with 10% HPL provides robust removal of small nonenveloped viruses, and is an option to improve the safety of therapeutic cells expanded using HPL supplements.

Synergistic effect of remdesivir and pegylated interferon alfa 1 beta in treatment of Covid 19

Background: Pharmacological therapies of proven efficacy in corona virus disease 2019 are still lacking with no proven antiviral treatment. Impaired type I interferon activity may be responsible for severe disease in COVID-19 patient. We performed prospective, observational, open-label study to evaluate the efficacy and safety of a single dose of Pegylated IFN-α2b in addition to Remdesivir with moderate to severe COVID-19 cases. Aim: The aim of this study is to assess the role of synergistic effect of Remdesivir and Pegylated Interferon alfa 2 Beta in moderate to severe COIVID-19 disease. Materials and Methods: 24 subjects with moderate to severe covid disease are included. Subjects were given PEG IFN-α2b (1 μg/kg subcutaneous [SC] injection, single dose) plus Remdesivir and other standard treatment protocol (MoHFW).We observed oxygen saturation and respiratory rate at discharge and duration of hospital stay and the impact of comorbidities on the same. Results: In the study at admission mean SpO2 was 90.25 ± 2.454% and at discharge was 95.13 ± 1.872%.At admission mean RR was 23.00 ± 2.670 bpm and at discharge was 18.71 ± 1.546 bpm. Mean duration of illness was 7.88 ± 2.112 days. Mean HRCT score was 12.21 ± 2.889.Mean days of recovery was 7.29 ± 3.329 days. There was no significant change in o2 saturation respiratory rate and duration of illness with respect to co morbidities. Conclusions: This study provides evidence for the potential use of a single dose of 1 μg/kg PEG IFN-α2b in the treatment of moderate COVID-19 disease. The significant improvement in clinical status is likely due to faster viral reduction. Further confirmatory studies are required to support the data observed in this study.

The synthesis and antiviral activity against yellow fewer virus of 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides

Aim. To synthesize 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides and study their antiviral activity against yellow fever virus (YFV). Results and discussion. The target 2-(4,6-di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides were obtained in three-step format from cyanuric chloride in good to high yields. The carbothioamides synthesized were estimated to possess the antiviral activity against YFV. The results obtained indicate that most of the compounds studied show the inhibitory activity against YFV in concentrations ≤10 μg/mL. For the most active substances, EC90 was in the range of 0.06 – 2.2 μg/mL. Good effective concentration values were accompanied by low levels of cytotoxicity resulting in excellent selectivity index values. The data obtained also indicate that the presence of an alkyl substituent in ortho-position of the N-aryl fragment is crucial for an effective inhibition of YFV growth. Experimental part. 2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides were synthesized starting from cyanuric chloride in three steps by its successive interaction with two equivalents of pyrrolidine, hydrazine and a series of alkyl-/arylisothiocyanates. The antiviral and cytotoxic activities of the target carbothioamides were studied in the Southern Research Institute (SRI, Birmingham, Alabama) by the viral cytopathic effect reduction assay and the virus yield reduction assay. Conclusions. 2-(4,6-Di(pyrrolidin-1-yl)-1,3,5-triazin-2-yl)-N-(alkyl, aryl)hydrazine-1-carbothioamides synthesized have been proven to be a promising class of compounds for treating such a severe viral disease as yellow fever.

Gut germinal center regeneration and enhanced antiviral immunity by mesenchymal stem/stromal cells in SIV infection.

Although antiretroviral therapy suppresses HIV replication, it does not eliminate viral reservoirs or restore damaged lymphoid tissue, posing obstacles to HIV eradication. Using the SIV model of AIDS, we investigated the effect of mesenchymal stem/stromal cell (MSC) infusions on gut mucosal recovery, antiviral immunity, and viral suppression and determined associated molecular/metabolic signatures. MSC administration to SIV-infected macaques resulted in viral reduction and heightened virus-specific responses. Marked clearance of SIV-positive cells from gut mucosal effector sites was correlated with robust regeneration of germinal centers, restoration of follicular B cells and T follicular helper (Tfh) cells, and enhanced antigen presentation by viral trapping within the follicular DC network. Gut transcriptomic analyses showed increased antiviral response mediated by pathways of type I/II IFN signaling, viral restriction factors, innate immunity, and B cell proliferation and provided the molecular signature underlying enhanced host immunity. Metabolic analysis revealed strong correlations between B and Tfh cell activation, anti-SIV antibodies, and IL-7 expression with enriched retinol metabolism, which facilitates gut homing of antigen-activated lymphocytes. We identified potentially new MSC functions in modulating antiviral immunity for enhanced viral clearance predominantly through type I/II IFN signaling and B cell signature, providing a road map for multipronged HIV eradication strategies.

Viral reduction of human blood by ultraviolet A-photosensitized vitamin K5.

Blood product transfusion can transmit viral pathogens. Pathogen reduction methods for blood products have been developed but, so far, are not available for whole blood. We evaluated if vitamin K5 (VK5) and ultraviolet A (UVA) irradiation could be used for virus inactivation in plasma and whole blood. Undiluted human plasma and whole blood diluted to 20% were spiked with high levels of vaccinia or Zika viruses. Infectious titers were measured by standard TCID50 assay before and after VK5/UVA treatments. Up to 3.6 log of vaccinia and 3.2 log of Zika were reduced in plasma by the combination of 500 μM VK5 and 3 J/cm2 UVA, and 3.1 log of vaccinia and 2.9 log of Zika were reduced in diluted human blood (20%) by the combination of 500 μM VK5 and 70 J/cm2 UVA. At end of whole blood treatment, hemolysis increased from 0.18% to 0.41% but remained below 1% hemolysis, which is acceptable to the Food and Drug Administration for red cell transfusion products. No significant alteration of biochemical parameters of red blood cells occurred with treatment. Our results provide proof of theconcept that a viral pathogen reduction method based on VK5/UVA may be developed for whole blood.