scholarly journals Predicted success of prophylactic antiviral therapy to block or delay SARS-CoV-2 infection depends on the targeted mechanism

2020 ◽  
Author(s):  
Peter Czuppon ◽  
Florence Débarre ◽  
Antonio Gonçalves ◽  
Olivier Tenaillon ◽  
Alan S. Perelson ◽  
...  
Keyword(s):  
Viral Infection ◽  
Viral Entry ◽  
Viral Infections ◽  
Drug Efficacy ◽  
Target Cells ◽  
High Exposure ◽  
Viral Loads ◽  
Repurposed Drugs ◽  
To Come ◽  
Prophylactic Antiviral Therapy

AbstractRepurposed drugs that are immediately available and have a good safety profile constitute a first line of defense against new viral infections. Despite a limited antiviral activity against SARS-CoV-2, several drugs serve as candidates for application, not only in infected individuals but also as prophylaxis to prevent infection establishment. Here we use a stochastic model to describe the early phase of a viral infection. We find that the critical efficacy needed to block viral establishment is typically above 80%. This value can be improved by combination therapy. Below the critical efficacy, establishment can still sometimes be prevented; for that purpose, drugs blocking viral entry into target cells (or equivalently enhancing viral clearance) are more effective than drugs reducing viral production or enhancing infected cell death. When a viral infection cannot be prevented because of high exposure or low drug efficacy, antivirals can still delay the time to reach detectable viral loads from 4 days when untreated to up to 30 days. This delay flattens the within-host viral dynamic curve, and possibly reduces transmission and symptom severity. These results suggest that antiviral prophylaxis, even with reduced efficacy, could be efficiently used to prevent or alleviate infection in people at high risk. It could thus be an important component of the strategy to combat the SARS-CoV-2 pandemic in the months or years to come.

scholarly journals Success of prophylactic antiviral therapy for SARS-CoV-2: Predicted critical efficacies and impact of different drug-specific mechanisms of action

2021 ◽  
Vol 17 (3) ◽  
pp. e1008752
Author(s):  
Peter Czuppon ◽  
Florence Débarre ◽  
Antonio Gonçalves ◽  
Olivier Tenaillon ◽  
Alan S. Perelson ◽  
...  
Keyword(s):  
Viral Infection ◽  
Viral Entry ◽  
Infectious Virus ◽  
Viral Infections ◽  
Viral Clearance ◽  
Risk Of Infection ◽  
Viral Production ◽  
Initial Inoculum ◽  
Infected Cells ◽  
Prophylactic Antiviral Therapy

Repurposed drugs that are safe and immediately available constitute a first line of defense against new viral infections. Despite limited antiviral activity against SARS-CoV-2, several drugs are being tested as medication or as prophylaxis to prevent infection. Using a stochastic model of early phase infection, we evaluate the success of prophylactic treatment with different drug types to prevent viral infection. We find that there exists a critical efficacy that a treatment must reach in order to block viral establishment. Treatment by a combination of drugs reduces the critical efficacy, most effectively by the combination of a drug blocking viral entry into cells and a drug increasing viral clearance. Below the critical efficacy, the risk of infection can nonetheless be reduced. Drugs blocking viral entry into cells or enhancing viral clearance reduce the risk of infection more than drugs that reduce viral production in infected cells. The larger the initial inoculum of infectious virus, the less likely is prevention of an infection. In our model, we find that as long as the viral inoculum is smaller than 10 infectious virus particles, viral infection can be prevented almost certainly with drugs of 90% efficacy (or more). Even when a viral infection cannot be prevented, antivirals delay the time to detectable viral loads. The largest delay of viral infection is achieved by drugs reducing viral production in infected cells. A delay of virus infection flattens the within-host viral dynamic curve, possibly reducing transmission and symptom severity. Thus, antiviral prophylaxis, even with reduced efficacy, could be efficiently used to prevent or alleviate infection in people at high risk.

scholarly journals Preinfection Treatment of Resistant Mice with CpG Oligodeoxynucleotides Renders Them Susceptible to Friend Retrovirus-Induced Leukemia

2003 ◽  
Vol 77 (19) ◽  
pp. 10658-10662 ◽  
Author(s):  
Anke R. M. Olbrich ◽  
Simone Schimmer ◽  
Ulf Dittmer
Keyword(s):  
Viral Infections ◽  
Critical Factor ◽  
Target Cells ◽  
Cpg Odn ◽  
Friend Virus ◽  
Erythroid Precursor ◽  
Viral Loads ◽  
Cpg Oligodeoxynucleotides ◽  
Friend Retrovirus ◽  
Immunostimulatory Oligodeoxynucleotides

ABSTRACT We recently reported that immunostimulatory oligodeoxynucleotides (CpG oligodeoxynucleotides [CpG-ODN]) were effective in postexposure treatment of retrovirus-induced disease (A. R. M. Olbrich et al., J. Virol. 76:11397-11404, 2002). We now show that the timing of treatment is a critical factor in treatment efficacy. In stark contrast to the success of postexposure treatments, we found that CpG treatment of susceptible mice prior to Friend retrovirus infection accelerated the development of virus-induced erythroleukemia. Furthermore, 70.8% of mice that were resistant to Friend virus-induced leukemia developed disease after inoculation of CpG-ODN before infection. The CpG pretreatment of these mice enhanced viral loads in their spleens and blood compared to controls that received ODN without CpG motifs. The main target cells of Friend virus, erythroid precursor cells and B cells, proliferated after CpG-ODN inoculation and provided an enlarged target cell population for viral infection. Our present findings together with our previous report demonstrate that CpG-ODN treatment of viral infections may be a double-edged sword that can result in an effective therapy but also in an acceleration of disease progression depending on the time point of treatment.

scholarly journals Viral Infection of Human Natural Killer Cells

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 243 ◽  
Author(s):  
Elisabeth van Erp ◽  
Mirjam van Kampen ◽  
Puck van Kasteren ◽  
Jelle de Wit
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Viral Entry ◽  
Viral Infections ◽  
Nk Cell ◽  
Cell Infection ◽  
Comprehensive Overview ◽  
Human Natural Killer Cells ◽  
Syncytial Virus

Natural killer (NK) cells are essential in the early immune response against viral infections, in particular through clearance of virus-infected cells. In return, viruses have evolved multiple mechanisms to evade NK cell-mediated viral clearance. Several unrelated viruses, including influenza virus, respiratory syncytial virus, and human immunodeficiency virus, can directly interfere with NK cell functioning through infection of these cells. Viral infection can lead to immune suppression, either by downregulation of the cytotoxic function or by triggering apoptosis, leading to depletion of NK cells. In contrast, some viruses induce proliferation or changes in the morphology of NK cells. In this review article, we provide a comprehensive overview of the viruses that have been reported to infect NK cells, we discuss their mechanisms of entry, and describe the interference with NK cell effector function and phenotype. Finally, we discuss the contribution of virus-infected NK cells to viral load. The development of specific therapeutics, such as viral entry inhibitors, could benefit from an enhanced understanding of viral infection of NK cells, opening up possibilities for the prevention of NK cell infection.

scholarly journals Role of KIR Receptor in NK Regulation during Viral Infections

Immuno ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 305-331
Author(s):  
Sabrina Rizzo ◽  
Giovanna Schiuma ◽  
Silvia Beltrami ◽  
Valentina Gentili ◽  
Roberta Rizzo ◽  
...  
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Cell Activation ◽  
Viral Infections ◽  
Nk Cell ◽  
Human Leukocyte ◽  
Target Cells ◽  
Inhibitory Receptors ◽  
Receptor Repertoire

Natural Killer (NK) cells are key effectors of the innate immune system which represent the first line of defense against viral infections. NK cell activation depends on the engagement of a complex receptor repertoire expressed on their surface, consisting of both activating and inhibitory receptors. Among the known NK cell receptors, the family of killer Ig-like receptors (KIRs) consists in activating/inhibitory receptors that interact with specific human leukocyte antigen (HLA) molecules expressed on target cells. In particular, the expression of peculiar KIRs have been reported to be associated to viral infection susceptibility. Interestingly, a significant association between the development and onset of different human pathologies, such as tumors, neurodegeneration and infertility, and a clonal KIRs expression on NK cells has been described in presence of viral infections, supporting the crucial role of KIRs in defining the effect of viral infections in different tissues and organs. This review aims to report the state of art about the role of KIRs receptors in NK cell activation and viral infection control.

scholarly journals Excessive Innate Immunity Steers Pathogenic Adaptive Immunity in the Development of Theiler’s Virus-Induced Demyelinating Disease

2021 ◽  
Vol 22 (10) ◽  
pp. 5254
Author(s):  
Byung S. Kim
Keyword(s):  
B Cells ◽  
Viral Infection ◽  
Cytokine Production ◽  
Viral Infections ◽  
Demyelinating Disease ◽  
Demyelinating Diseases ◽  
Viral Loads ◽  
Underlying Mechanisms ◽  
The Many ◽  
Antigen Presenting

Several virus-induced models were used to study the underlying mechanisms of multiple sclerosis (MS). The infection of susceptible mice with Theiler’s murine encephalomyelitis virus (TMEV) establishes persistent viral infections and induces chronic inflammatory demyelinating disease. In this review, the innate and adaptive immune responses to TMEV are discussed to better understand the pathogenic mechanisms of viral infections. Professional (dendritic cells (DCs), macrophages, and B cells) and non-professional (microglia, astrocytes, and oligodendrocytes) antigen-presenting cells (APCs) are the major cell populations permissive to viral infection and involved in cytokine production. The levels of viral loads and cytokine production in the APCs correspond to the degrees of susceptibility of the mice to the TMEV-induced demyelinating diseases. TMEV infection leads to the activation of cytokine production via TLRs and MDA-5 coupled with NF-κB activation, which is required for TMEV replication. These activation signals further amplify the cytokine production and viral loads, promote the differentiation of pathogenic Th17 responses, and prevent cellular apoptosis, enabling viral persistence. Among the many chemokines and cytokines induced after viral infection, IFN α/β plays an essential role in the downstream expression of costimulatory molecules in APCs. The excessive levels of cytokine production after viral infection facilitate the pathogenesis of TMEV-induced demyelinating disease. In particular, IL-6 and IL-1β play critical roles in the development of pathogenic Th17 responses to viral antigens and autoantigens. These cytokines, together with TLR2, may preferentially generate deficient FoxP3+CD25- regulatory cells converting to Th17. These cytokines also inhibit the apoptosis of TMEV-infected cells and cytolytic function of CD8+ T lymphocytes (CTLs) and prolong the survival of B cells reactive to viral and self-antigens, which preferentially stimulate Th17 responses.

scholarly journals Enterocytes, fibroblasts and myeloid cells synergize in anti-bacterial and anti-viral pathways with IL22 as the central cytokine

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Jean Paul ten Klooster ◽  
Marianne Bol-Schoenmakers ◽  
Kitty van Summeren ◽  
Arno L. W. van Vliet ◽  
Cornelis A. M. de Haan ◽  
...  
Keyword(s):  
T Cells ◽  
Viral Infection ◽  
Viral Entry ◽  
Defense Mechanisms ◽  
Viral Infections ◽  
Myeloid Cells ◽  
Viral Proteins ◽  
Intestinal Cells ◽  
Important Cytokine ◽  
Bacterial Products

AbstractIL22 is an important cytokine involved in the intestinal defense mechanisms against microbiome. By using ileum-derived organoids, we show that the expression of anti-microbial peptides (AMPs) and anti-viral peptides (AVPs) can be induced by IL22. In addition, we identified a bacterial and a viral route, both leading to IL22 production by T cells, but via different pathways. Bacterial products, such as LPS, induce enterocyte-secreted SAA1, which triggers the secretion of IL6 in fibroblasts, and subsequently IL22 in T cells. This IL22 induction can then be enhanced by macrophage-derived TNFα in two ways: by enhancing the responsiveness of T cells to IL6 and by increasing the expression of IL6 by fibroblasts. Viral infections of intestinal cells induce IFNβ1 and subsequently IL7. IFNβ1 can induce the expression of IL6 in fibroblasts and the combined activity of IL6 and IL7 can then induce IL22 expression in T cells. We also show that IL22 reduces the expression of viral entry receptors (e.g. ACE2, TMPRSS2, DPP4, CD46 and TNFRSF14), increases the expression of anti-viral proteins (e.g. RSAD2, AOS, ISG20 and Mx1) and, consequently, reduces the viral infection of neighboring cells. Overall, our data indicates that IL22 contributes to the innate responses against both bacteria and viruses.

scholarly journals Transcriptome and Coronavirus: New Hope and Therapy

2020 ◽  
Vol 11 (2) ◽  
pp. 9541-9552
Keyword(s):  
Viral Infection ◽  
Host Cell ◽  
Genome Size ◽  
Viral Entry ◽  
Viral Infections ◽  
Cell Transformation ◽  
In Vitro Study ◽  
Cell Protein ◽  
Transformation Mechanism

Transcriptome refers to all RNA particles occur inside one cell or inside numerous cells in one organ. Coronaviruses are a family of correlated viruses that induce viral infection. In humans, coronaviruses induce respiratory viral infections that may be mild or dangerous. The coronavirus shape is large circular elements that have round tip outbreaks - the virus diameter particles=120 nm. The RNA viral genome occurs in coronavirus. The coronavirus genome size = 27-34 kilobases, and this size is the largest RNA genome size. The Life cycle of coronavirus includes viral entry, replication, and release. Coronavirus transmission was done through the connection of its protein with host cell receptors in a specific process. There are 4 types of coronavirus genus: (1) Alphacoronavirus, (2) Betacoronavirus, (3) Gammacoronavirus, and (4) Deltacoronavirus. Viral replication, immune evasion, and virion biogenesis correlated with host cell transformation mechanism. Viral molecular mechanism hijacks the host cell protein production mechanism. There is an important host factor (CPSF6) that connects with nuclear protein (NP1). The CPSF6 increases the nuclear production of NP1 in the same time, CPSF6 possesses an important role in the progress of capsid mRNAs inside the nucleus. In a viral infection, there is an increase in mRNA, myeloid differentiation 2-related lipid recognition protein (ML), and Niemann Pick-type C1 (NPC1) genes. Coronavirus is capable of replicating in in vitro study and causes lower transcriptomic variations before 12 h after viral infection. As infection progress, coronavirus causes a significant dysregulation of the host transcriptome greater than the SARS virus. In conclusion, future transcriptome studies are the basis for detecting coronavirus in the human host and for developing a specific preventive and therapeutic method for the virus.

scholarly journals Viral Infection in Renal Transplant Recipients

2012 ◽  
Vol 2012 ◽  
pp. 1-18 ◽  
Author(s):  
Jovana Cukuranovic ◽  
Sladjana Ugrenovic ◽  
Ivan Jovanovic ◽  
Milan Visnjic ◽  
Vladisav Stefanovic
Keyword(s):  
Viral Infection ◽  
Antiviral Therapy ◽  
Viral Infections ◽  
Opportunistic Pathogen ◽  
Renal Transplant Recipients ◽  
Transplant Recipients ◽  
Cellular Effects ◽  
Improved Outcomes ◽  
Prophylactic Antiviral Therapy ◽  
The Impact

Viruses are among the most common causes of opportunistic infection after transplantation. The risk for viral infection is a function of the specific virus encountered, the intensity of immune suppression used to prevent graft rejection, and other host factors governing susceptibility. Although cytomegalovirus is the most common opportunistic pathogen seen in transplant recipients, numerous other viruses have also affected outcomes. In some cases, preventive measures such as pretransplant screening, prophylactic antiviral therapy, or posttransplant viral monitoring may limit the impact of these infections. Recent advances in laboratory monitoring and antiviral therapy have improved outcomes. Studies of viral latency, reactivation, and the cellular effects of viral infection will provide clues for future strategies in prevention and treatment of viral infections. This paper will summarize the major viral infections seen following transplant and discuss strategies for prevention and management of these potential pathogens.

scholarly journals Modeling the dynamics of within-host viral infection and evolution predicts quasispecies distributions and phase boundaries separating distinct classes of infections

2021 ◽  
Author(s):  
Greyson R Lewis ◽  
Wallace F Marshall ◽  
Barbara A Jones
Keyword(s):  
Viral Infection ◽  
Viral Entry ◽  
Viral Infections ◽  
Viral Disease ◽  
Significant Inhibition ◽  
High Rate ◽  
Variable Binding ◽  
Wide Range ◽  
Viral Responses ◽  
Physical Phenomena

We use computational modeling to study within-host viral infection and evolution. In our model, viruses exhibit variable binding to cells, with better infection and replication countered by a stronger immune response and a high rate of mutation. By varying host conditions (permissivity to viral entry T and immune clearance intensity A) for large numbers of cells and viruses, we study the dynamics of how viral populations evolve from initial infection to steady state and obtain a phase diagram of the range of cell and viral responses. We find three distinct replicative strategies corresponding to three physiological classes of viral infections: acute, chronic, and opportunistic. We show similarities between our findings and the behavior of real viral infections such as common flu, hepatitis, and SARS-CoV-2019. The phases associated with the three strategies are separated by a phase transition of primarily first order, in addition to a crossover region. Our simulations also reveal a wide range of physical phenomena, including metastable states, periodicity, and glassy dynamics. Lastly, our results suggest that the resolution of acute viral disease in patients whose immunity cannot be boosted can only be achieved by significant inhibition of viral infection and replication.

The diagnosis of hepatitis C viral infection

2014 ◽  
Vol 155 (26) ◽  
pp. 1019-1023
Author(s):  
Judit Gervain
Keyword(s):  
Hepatitis C ◽  
Nucleic Acid ◽  
Viral Infection ◽  
Structural Changes ◽  
Viral Infections ◽  
Transient Elastography ◽  
Viral Nucleic Acid ◽  
Length Of Treatment ◽  
Subtype B

The successful therapy of hepatitis C viral infection requires that the illness is diagnosed before the development of structural changes of the liver. Testing is stepwise consisting of screening, diagnosis, and anti-viral therapy follow-up. For these steps there are different biochemical, serological, histological and molecular biological methods available. For screening, alanine aminotransferase and anti-HCV tests are used. The diagnosis of infection is confirmed using real-time polymerase chain reaction of the viral nucleic acid. Before initiation of the therapy liver biopsy is recommended to determine the level of structural changes in the liver. Alternatively, transient elastography or blood biomarkers may be also used for this purpose. Differential diagnosis should exclude the co-existence of other viral infections and chronic hepatitis due to other origin, with special attention to the presence of autoantibodies. The outcome of the antiviral therapy and the length of treatment are mainly determined by the viral genotype. In Hungary, most patients are infected with genotype 1, subtype b. The polymorphism type that occurs in the single nucleotide located next to the interleukin 28B region in chromosome 19 and the viral polymorphism type Q80K for infection with HCV 1a serve as predictive therapeutic markers. The follow-up of therapy is based on the quantitative determination of viral nucleic acid according to national and international protocols and should use the same method and laboratory throughout the treatment of an individual patient. Orv. Hetil., 2014, 155(26), 1019–1023.

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