scholarly journals Mathematical modelling of the within-host HIV quasispecies dynamics in response to antiviral treatment

2015 ◽  
Vol 30 (3) ◽  
Author(s):  
Gennady A. Bocharov ◽  
Ilya S. Telatnikov ◽  
Valery A. Chereshnev ◽  
Javier Martinez ◽  
Andreas Meyerhans
Keyword(s):  
Antiviral Treatment ◽  
Antiviral Drug ◽  
Point Mutations ◽  
Original Data ◽  
Population Diversity ◽  
Target Cells ◽  
Viral Genomes ◽  
Letter Alphabet ◽  
Immunodeficiency Virus ◽  
Selection Of

AbstractThe aim of this work is the construction, calibration, and comparative analysis of mathematical models of the evolution of the human immunodeficiency virus (HIV) in the course of infection when the models are based on deterministic principles of the quasispecies theory (Eigen-Schuster) and on stochastic approaches of genetic algorithms (Holland). The models take into account the replication of viral genomes and selection of descendants according to their fitness, point mutations, multi-infection of target cells and recombination of genomes at the stage of formation of proviral DNA. The processes of diversification of the virus population under the action of the antiviral drug azidothymidine (AZT) that blocks reverse transcription of the virus are simulated. A four-letter alphabet is used in the stochasticmodel for description of nucleotide sequences. The parameters of the model are estimated using original data on the degree of adaptation of the HIV mutants that are partly or completely resistant to this drug. The influence of parameters of infection on the characteristics of viral mutants population diversity is studied

scholarly journals The Phosphatidylserine Receptor TIM-1 Enhances Authentic Chikungunya Virus Cell Entry

Cells ◽  
2021 ◽  
Vol 10 (7) ◽  
pp. 1828
Author(s):  
Jared Kirui ◽  
Yara Abidine ◽  
Annasara Lenman ◽  
Koushikul Islam ◽  
Yong-Dae Gwon ◽  
...  
Keyword(s):  
Chikungunya Virus ◽  
Molecular Mechanisms ◽  
Rna Virus ◽  
Ectopic Expression ◽  
Point Mutations ◽  
Cell Entry ◽  
Target Cells ◽  
Human Hepatoma Cells ◽  
Chikv Infection ◽  
Phosphatidylserine Receptor

Chikungunya virus (CHIKV) is a re-emerging, mosquito-transmitted, enveloped positive stranded RNA virus. Chikungunya fever is characterized by acute and chronic debilitating arthritis. Although multiple host factors have been shown to enhance CHIKV infection, the molecular mechanisms of cell entry and entry factors remain poorly understood. The phosphatidylserine-dependent receptors, T-cell immunoglobulin and mucin domain 1 (TIM-1) and Axl receptor tyrosine kinase (Axl), are transmembrane proteins that can serve as entry factors for enveloped viruses. Previous studies used pseudoviruses to delineate the role of TIM-1 and Axl in CHIKV entry. Conversely, here, we use the authentic CHIKV and cells ectopically expressing TIM-1 or Axl and demonstrate a role for TIM-1 in CHIKV infection. To further characterize TIM-1-dependent CHIKV infection, we generated cells expressing domain mutants of TIM-1. We show that point mutations in the phosphatidylserine binding site of TIM-1 lead to reduced binding, entry, and infection of CHIKV. Ectopic expression of TIM-1 renders immortalized keratinocytes permissive to CHIKV, whereas silencing of endogenously expressed TIM-1 in human hepatoma cells reduces CHIKV infection. Altogether, our findings indicate that, unlike Axl, TIM-1 readily promotes the productive entry of authentic CHIKV into target cells.

scholarly journals Potential Virus Involvement in Alzheimer’s Disease: Results from a Phase IIa Trial Evaluating Apovir, an Antiviral Drug Combination

2021 ◽  
pp. 1-19
Author(s):  
Nina Lindblom ◽  
Lars Lindquist ◽  
Jacob Westman ◽  
Mikael Åström ◽  
Roger Bullock ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Cerebrospinal Fluid ◽  
Drug Combination ◽  
Antiviral Treatment ◽  
Antiviral Drug ◽  
Disease Process ◽  
Drop Out ◽  
Large Drop ◽  
Drop Out Rate

Background: Accumulating data suggest infectious agents are involved in Alzheimer’s disease (AD). The two primary aims of this trial were to assess safety and efficacy of an antiviral drug combination on AD progression. Objective: The trial evaluated whether Apovir, a combination of two antiviral agents, pleconaril (active on enteroviruses) and ribavirin (active on several viruses), could slow AD progression. Methods: Sixty-nine patients 60–85 years were treated with Apovir or placebo for 9 months and followed until 12 months after end of treatment. Cognitive tests, safety, biomarkers, drug plasma, and cerebrospinal fluid concentrations were assessed. Results: The tolerability of Apovir was compromised as demonstrated by the large drop-out rate and increased frequency and severity of adverse events. The primary endpoint, demonstrating a difference in change from baseline to 9 months between groups in ADAS-cog total score, was not met (p = 0.1809). However, there were observations indicating potential effects on both ADAS-cog and CDR-SB but these effects need to be verified. Also, there was a decrease in cerebrospinal fluid amyloid-β in Apovir at 9 months (p = 0.0330) but no change in placebo. Conclusion: This was the first randomized, placebo controlled clinical trial exploring antiviral treatment on AD progression. The trial is considered inconclusive due to the large drop-out rate. New trials are needed to verify if the indications of effect observed can be confirmed and which component(s) in Apovir contributed to such effects. Pleconaril alone may be studied to improve the tolerability and to verify if enterovirus is involved in the disease process.

scholarly journals TRIM22. A Multitasking Antiviral Factor

Cells ◽  
2021 ◽  
Vol 10 (8) ◽  
pp. 1864
Author(s):  
Isabel Pagani ◽  
Guido Poli ◽  
Elisa Vicenzi
Keyword(s):  
Protein Interactions ◽  
Influenza A ◽  
Direct Interaction ◽  
Type I Interferons ◽  
Viral Gene ◽  
Target Cells ◽  
Type I ◽  
Protein Protein Interactions ◽  
Viral Genomes ◽  
Dna And Rna

Viral invasion of target cells triggers an immediate intracellular host defense system aimed at preventing further propagation of the virus. Viral genomes or early products of viral replication are sensed by a number of pattern recognition receptors, leading to the synthesis and production of type I interferons (IFNs) that, in turn, activate a cascade of IFN-stimulated genes (ISGs) with antiviral functions. Among these, several members of the tripartite motif (TRIM) family are antiviral executors. This article will focus, in particular, on TRIM22 as an example of a multitarget antiviral member of the TRIM family. The antiviral activities of TRIM22 against different DNA and RNA viruses, particularly human immunodeficiency virus type 1 (HIV-1) and influenza A virus (IAV), will be discussed. TRIM22 restriction of virus replication can involve either direct interaction of TRIM22 E3 ubiquitin ligase activity with viral proteins, or indirect protein–protein interactions resulting in control of viral gene transcription, but also epigenetic effects exerted at the chromatin level.

scholarly journals Role of antigen, CD8, and cytotoxic T lymphocyte (CTL) avidity in high dose antigen induction of apoptosis of effector CTL.

1996 ◽  
Vol 184 (2) ◽  
pp. 485-492 ◽  
Author(s):  
M A Alexander-Miller ◽  
G R Leggatt ◽  
A Sarin ◽  
J A Berzofsky
Keyword(s):  
T Lymphocytes ◽  
Cytotoxic T Lymphocyte ◽  
Target Cells ◽  
High Dose ◽  
High Avidity ◽  
Apoptotic Pathway ◽  
Peptide Antigen ◽  
Kinetics Of ◽  
Selection Of

Experimental data suggest that negative selection of thymocytes can occur as a result of supraoptimal antigenic stimulation. It is unknown, however, whether such mechanisms are at work in mature CD8+ T lymphocytes. Here, we show that CD8+ effector cytotoxic T lymphocytes (CTL) are susceptible to proliferative inhibition by high dose peptide antigen, leading to apoptotic death mediated by TNF-alpha release. Such inhibition is not reflected in the cytolytic potential of the CTL, since concentrations of antigen that are inhibitory for proliferation promote efficient lysis of target cells. Thus, although CTL have committed to the apoptotic pathway, the kinetics of this process are such that CTL function can occur before death of the CTL. The concentration of antigen required for inhibition is a function of the CTL avidity, in that concentrations of antigen capable of completely inhibiting high avidity CTL maximally stimulate low avidity CTL. Importantly, the inhibition can be detected in both activated and resting CTL. Blocking studies demonstrate that the CD8 molecule contributes significantly to the inhibitory signal as the addition of anti-CD8 antibody restores the proliferative response. Thus, our data support the model that mature CD8+ CTL can accommodate an activation signal of restricted intensity, which, if surpassed, results in deletion of that cell.

scholarly journals Discovery and Characterization of Vicriviroc (SCH 417690), a CCR5 Antagonist with Potent Activity against Human Immunodeficiency Virus Type 1

2005 ◽  
Vol 49 (12) ◽  
pp. 4911-4919 ◽  
Author(s):  
Julie M. Strizki ◽  
Cecile Tremblay ◽  
Serena Xu ◽  
Lisa Wojcik ◽  
Nicole Wagner ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Calcium Flux ◽  
Ccr5 Antagonist ◽  
Target Cells ◽  
Gene Transcript ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Inhibiting human immunodeficiency virus type 1 (HIV-1) infection by blocking the host cell coreceptors CCR5 and CXCR4 is an emerging strategy for antiretroviral therapy. Currently, several novel coreceptor inhibitors are being developed in the clinic, and early results have proven promising. In this report, we describe a novel CCR5 antagonist, vicriviroc (formerly SCH-D or SCH 417690), with improved antiviral activity and pharmacokinetic properties compared to those of SCH-C, a previously described CCR5 antagonist. Like SCH-C, vicriviroc binds specifically to the CCR5 receptor and prevents infection of target cells by CCR5-tropic HIV-1 isolates. In antiviral assays, vicriviroc showed potent, broad-spectrum activity against genetically diverse and drug-resistant HIV-1 isolates and was consistently more active than SCH-C in inhibiting viral replication. This compound demonstrated synergistic anti-HIV activity in combination with drugs from all other classes of approved antiretrovirals. Competition binding assays revealed that vicriviroc binds with higher affinity to CCR5 than SCH-C. Functional assays, including inhibition of calcium flux, guanosine 5′-[35S]triphosphate exchange, and chemotaxis, confirmed that vicriviroc acts as a receptor antagonist by inhibiting signaling of CCR5 by chemokines. Finally, vicriviroc demonstrated diminished affinity for the human ether a-go-go related gene transcript ion channel compared to SCH-C, suggesting a reduced potential for cardiac effects. Vicriviroc represents a promising new candidate for the treatment of HIV-1 infection.

Screening of potential donors for immunoglobulins M and G to new coronavirus infection

2021 ◽  
Vol 23 (3) ◽  
pp. 49-54
Author(s):  
Yuliia E. Romashova ◽  
Vladimir N. Vilyaninov ◽  
Nikolay V. Belgesov ◽  
Sergey P. Kaleko
Keyword(s):  
Human Immunodeficiency Virus ◽  
Active Movement ◽  
Frequency Of Occurrence ◽  
Age Group ◽  
Spring Period ◽  
Immunodeficiency Virus ◽  
Coronavirus Infection ◽  
Human Immunodeficiency Virus 1 ◽  
Epidemiological Situation ◽  
Selection Of

This study presents the results of the examination of potential donors of blood and its components for immunoglobulins M and G to patients with coronavirus disease 2019 (COVID-19) living in St. Petersburg. A total of 6782 people aged 1824 years were evaluated, which accounted for 2.07% of the regions population (326 760 people) of this age group. The study was carried out in the spring and autumn of 2020. A negative result (absence of antibodies) was obtained in 93.5% of the participants. The rates of immunoglobulins M and M + G were 0.58% and 4.18%, respectively, in the spring and autumn. Moreover, the number of participants who had immunoglobulins M and G + M in the autumn period was four times higher than the indicators of the spring period, which indicated greater infection activities in the population during this period. This is most likely due to the active movement of the population in the summer. When comparing the rates of COVID-19 infection and the frequency of occurrence in donors of the same age, markers of human immunodeficiency virus 1 and 2 and hepatitis B and C in 2020 (0.024, 0.012 and 0.13%, respectively) indicate the urgency of the problem of donor selection during blood services, especially during a difficult epidemiological situation because of COVID-19. Along with organizational measures for the selection of donors (e.g., attracting individuals from organized groups in which there are no signs of an unfavorable epidemiological situation to donation), mandatory testing of potential donors for immunoglobulins M and G should be considered.

scholarly journals Mycoviral Population Dynamics in Spanish Isolates of the Entomopathogenic Fungus Beauveria bassiana

Viruses ◽  
2018 ◽  
Vol 10 (12) ◽  
pp. 665 ◽  
Author(s):  
Charalampos Filippou ◽  
Inmaculada Garrido-Jurado ◽  
Nicolai Meyling ◽  
Enrique Quesada-Moraga ◽  
Robert Coutts ◽  
...  
Keyword(s):  
Beauveria Bassiana ◽  
Entomopathogenic Fungi ◽  
Insect Pests ◽  
Fruit Fly ◽  
Population Diversity ◽  
Viral Genomes ◽  
Large Panels ◽  
High Virulence ◽  
Fungus Beauveria Bassiana ◽  
Rna Polymerase Gene

The use of mycoviruses to manipulate the virulence of entomopathogenic fungi employed as biocontrol agents may lead to the development of novel methods to control attacks by insect pests. Such approaches are urgently required, as existing agrochemicals are being withdrawn from the market due to environmental and health concerns. The aim of this work is to investigate the presence and diversity of mycoviruses in large panels of entomopathogenic fungi, mostly from Spain and Denmark. In total, 151 isolates belonging to the genera Beauveria, Metarhizium, Lecanicillium, Purpureocillium, Isaria, and Paecilomyces were screened for the presence of dsRNA elements and 12 Spanish B. bassiana isolates were found to harbor mycoviruses. All identified mycoviruses belong to three previously characterised species, the officially recognised Beauveria bassiana victorivirus 1 (BbVV-1) and the proposed Beauveria bassiana partitivirus 2 (BbPV-2) and Beauveria bassiana polymycovirus 1 (BbPmV-1); individual B. bassiana isolates may harbor up to three of these mycoviruses. Notably, these mycovirus species are under distinct selection pressures, while recombination of viral genomes increases population diversity. Phylogenetic analysis of the RNA-dependent RNA polymerase gene sequences revealed that the current population structure in Spain is potentially a result of both vertical and horizontal mycovirus transmission. Finally, pathogenicity experiments using the Mediterranean fruit fly Ceratitis capitata showed no direct correlation between the presence of any particular mycovirus and the virulence of the B. bassiana isolates, but illustrated potentially interesting isolates that exhibit relatively high virulence, which will be used in more detailed virulence experimentation in the future.

scholarly journals Comparison of Predicted Scaffold-Compatible Sequence Variation in the Triple-Hairpin Structure of Human Immunodeficiency Virus Type 1 gp41 with Patient Data

2002 ◽  
Vol 76 (15) ◽  
pp. 7595-7606 ◽  
Author(s):  
Nathalie Boutonnet ◽  
Wouter Janssens ◽  
Carlo Boutton ◽  
Jean-Luc Verschelde ◽  
Leo Heyndrickx ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Sequence Variation ◽  
Single Point ◽  
Point Mutations ◽  
Hairpin Structure ◽  
Single Amino Acid ◽  
Immunodeficiency Virus

ABSTRACT It has been proposed that the ectodomain of human immunodeficiency virus type 1 (HIV-1) gp41 (e-gp41), involved in HIV entry into the target cell, exists in at least two conformations, a pre-hairpin intermediate and a fusion-active hairpin structure. To obtain more information on the structure-sequence relationship in e-gp41, we performed in silico a full single-amino-acid substitution analysis, resulting in a Fold Compatible Database (FCD) for each conformation. The FCD contains for each residue position in a given protein a list of values assessing the energetic compatibility (ECO) of each of the 20 natural amino acids at that position. Our results suggest that FCD predictions are in good agreement with the sequence variation observed for well-validated e-gp41 sequences. The data show that at a minECO threshold value of 5 kcal/mol, about 90% of the observed patient sequence variation is encompassed by the FCD predictions. Some inconsistent FCD predictions at N-helix positions packing against residues of the C helix suggest that packing of both peptides may involve some flexibility and may be attributed to an altered orientation of the C-helical domain versus the N-helical region. The permissiveness of sequence variation in the C helices is in agreement with FCD predictions. Comparison of N-core and triple-hairpin FCDs suggests that the N helices may impose more constraints on sequence variation than the C helices. Although the observed sequences of e-gp41 contain many multiple mutations, our method, which is based on single-point mutations, can predict the natural sequence variability of e-gp41 very well.

scholarly journals Compensatory Link between Fusion and Endocytosis of Human Immunodeficiency Virus Type 1 in Human CD4 T Lymphocytes

2004 ◽  
Vol 78 (3) ◽  
pp. 1375-1383 ◽  
Author(s):  
Evelyne Schaeffer ◽  
Vanessa B. Soros ◽  
Warner C. Greene
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Fluorescent Protein ◽  
Reciprocal Relationship ◽  
Endocytic Pathway ◽  
Productive Infection ◽  
Target Cells ◽  
Concanamycin A ◽  
Immunodeficiency Virus

ABSTRACT Virions of the type 1 human immunodeficiency virus (HIV-1) can enter target cells by fusion or endocytosis, with sharply different functional consequences. Fusion promotes productive infection of the target cell, while endocytosis generally leads to virion inactivation in acidified endosomes or degradation in lysosomes. Virion fusion and endocytosis occur equally in T cells, but these pathways have been regarded as independent because endocytosis of HIV virions requires neither CD4 nor CCR5/CXCR4 engagement in HeLa-CD4 cells. Using flow cytometric techniques to assess the binding and entry of green fluorescent protein (GFP)-Vpr-labeled HIV virions into primary peripheral blood mononuclear cells, we have found that HIV fusion and endocytosis are restricted to the CD4-expressing subset of cells and that both pathways commonly require the initial binding of HIV virions to surface CD4 receptors. Blockade of CXCR4-tropic HIV virion fusion with AMD3100, a CXCR4-specific entry inhibitor, increased virion entry via the endocytic pathway. Similarly, inhibition of endosome acidification with bafilomycin A1, concanamycin A, or NH4Cl enhanced entry via the fusion pathway. Although fusion remained dependent on CD4 and chemokine receptor binding, the endosome inhibitors did not alter surface expression of CD4 and CXCR4. These results suggest that fusion in the presence of the endosome inhibitors likely occurs within nonacidified endosomes. However, the ability of these inhibitors to impair vesicle trafficking from early to late endosomes in some cells could also increase the recycling of these virion-containing endosomes to the cell surface, where fusion occurs. In summary, our results reveal an unexpected, CD4-mediated reciprocal relationship between the pathways governing HIV virion fusion and endocytosis.

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