BISTABILITY ANALYSIS OF AN HIV MODEL WITH IMMUNE RESPONSE

2017 ◽  
Vol 25 (04) ◽  
pp. 677-695 ◽  
Author(s):  
SHAOLI WANG ◽  
FEI XU ◽  
LIBIN RONG
Keyword(s):  
Immune Response ◽  
Steady State ◽  
Viral Load ◽  
Immune Cell ◽  
Post Treatment ◽  
Proliferation Rate ◽  
Virus Dynamics ◽  
Elite Controllers ◽  
Viral Control ◽  
Hiv Model

Some HIV-infected patients (the so-called post-treatment controllers) can control the virus after cessation of antiretroviral therapy. A small fraction of patients can even naturally maintain undetectable viral load without therapy (they are called elite controllers). The immune response may play an important role in viral control in these patients. In this paper, we analyze a within-host model including immune response to study the virus dynamics in HIV-infected patients. We derived two threshold values for the immune cell proliferation parameter. Below the lower immune proliferation rate, the model has a stable immune-free steady state, which predicts that patients have a high viral load. Above the higher immune proliferation rate, the model has a stable low infected steady state, which indicates that patients are under elite control. Between the two immune thresholds, the model exhibits the dynamic behavior of bistability, which suggests that patients either undergo viral rebound after treatment termination or achieve the post-treatment control. These results may explain the different virus dynamics in HIV-infected patients.

TLR2-mediated innate immune priming boosts lung anti-viral immunity

2020 ◽  
pp. 2001584
Author(s):  
Jason Girkin ◽  
Su-Ling Loo ◽  
Camille Esneau ◽  
Steven Maltby ◽  
Francesca Mercuri ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Innate Immunity ◽  
Viral Load ◽  
Epithelial Cell ◽  
Epithelial Cells ◽  
Immune Cell ◽  
Innate Immune ◽  
Immune Priming ◽  
Tlr2 Activation

Research questionAssessment of whether TLR2 activation boosts the innate immune response to rhinovirus infection, as a treatment strategy for virus-induced respiratory diseases.MethodsWe employed treatment with a novel TLR2 agonist (INNA-X) prior to rhinovirus infection in mice, and INNA-X treatment in differentiated human bronchial epithelial cells derived from asthmatic-donors. We assessed viral load, immune cell recruitment, cytokines, type I and III IFN production, as well as the lung tissue and epithelial cell immune transcriptome.ResultsWe show in vivo, that a single INNA-X treatment induced innate immune priming characterised by low-level IFN-λ, Fas ligand, chemokine expression and airway lymphocyte recruitment. Treatment 7-days before infection significantly reduced lung viral load, increased IFN-β/λ expression and inhibited neutrophilic inflammation. Corticosteroid treatment enhanced the anti-inflammatory effects of INNA-X. Treatment 1-day before infection increased expression of 190 lung tissue immune genes. This tissue gene expression signature was absent with INNA-X treatment 7-days before infection, suggesting an alternate mechanism, potentially via establishment of immune cell-mediated mucosal innate immunity. In vitro, INNA-X treatment induced a priming response defined by upregulated IFN-λ, chemokine and anti-microbial gene expression that preceded an accelerated response to infection enriched for NF-κB-regulated genes and reduced viral loads, even in epithelial cells derived from asthmatic donors with intrinsic delayed anti-viral immune response.ConclusionAirway epithelial cell TLR2 activation induces prolonged innate immune priming, defined by early NF-κB activation, IFN-λ expression and lymphocyte recruitment. This response enhanced anti-viral innate immunity and reduced virus-induced airway inflammation.

Mathematical modeling and analysis of innate and humoral immune responses to dengue infections

2019 ◽  
Vol 12 (07) ◽  
pp. 1950077 ◽  
Author(s):  
Sulanie Perera ◽  
S. S. N. Perera
Keyword(s):  
Immune Response ◽  
Innate Immunity ◽  
Steady State ◽  
Immune Responses ◽  
Dengue Virus ◽  
Innate Immune ◽  
Virus Dynamics ◽  
Quasi Steady State ◽  
Humoral Immune ◽  
Humoral Immune Responses

Dengue is an acute arthropode-borne virus, belonging to the family Flaviviridae. Currently, there are no vaccines or treatments available against dengue. Thus it is important to understand the dynamics of dengue in order to control the infection. In this paper, we study the long-term dynamics of the model that is presented in [S. D. Perera and S. S. N. Perera, Simulation model for dynamics of dengue with innate and humoral immune responses, Comput. Math. Methods Med. 2018 (2018) 8798057, 18 pp. https://doi.org/10.1155/2018/8798057 ] which describes the interaction of virus with infected and uninfected cells in the presence of innate and humoral immune responses. It was found the model has three equilibria, namely: infection free equilibrium, no immune equilibrium and endemic equilibrium, then analyzed its stability analytically. The analytical findings of each model have been exemplified by numerical simulations. Given the fact that intensity of dengue virus replication at early times of infection could determine clinical outcomes, it is important to understand the impact of innate immunity, which is believed to be the first line of defense against an invading pathogen. For this we carry out a simulation case study to investigate the importance of innate immune response on dengue virus dynamics. A comparison was done assuming that innate immunity was active; innate immunity was in quasi-steady state and innate immunity was inactive during the virus replication process. By a further analysis of the qualitative behavior of the quasi-steady state, it was observed that innate immune response plays a pivotal role in dengue virus dynamics. It can change the dynamical behavior of the system and is essential for the virus clearance.

scholarly journals CD8lowCD100−T Cells Identify a Novel CD8 T Cell Subset Associated with Viral Control during Human Hantaan Virus Infection

2015 ◽  
Vol 89 (23) ◽  
pp. 11834-11844 ◽  
Author(s):  
Bei Liu ◽  
Ying Ma ◽  
Yusi Zhang ◽  
Chunmei Zhang ◽  
Jing Yi ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Viral Load ◽  
T Cell ◽  
Early Phase ◽  
Late Phase ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Hantaan Virus ◽  
Viral Control

ABSTRACTHantaan virus (HTNV) infection can cause a severe lethal hemorrhagic fever with renal syndrome (HFRS) in humans. CD8+T cells play a critical role in combating HTNV infections. However, the contributions of different CD8+T cell subsets to the immune response against viral infection are poorly understood. Here, we identified a novel subset of CD8+T cells characterized by the CD8lowCD100−phenotype in HFRS patients. The CD8lowCD100−subset accounted for a median of 14.3% of the total CD8+T cells in early phase of HFRS, and this percentage subsequently declined in the late phase of infection, whereas this subset was absent in healthy controls. Furthermore, the CD8lowCD100−cells were associated with high activation and expressed high levels of cytolytic effector molecules and exhibited a distinct expression profile of effector CD8+T cells (CCR7+/−CD45RA−CD127highCD27intCD28lowCD62L−). When stimulated with specific HTNV nucleocapsid protein-derived peptide pools, most responding CD8+cells (gamma interferon [IFN-γ] positive and/or tumor necrosis factor alpha [TNF-α] positive) were CD8lowCD100−cells. The frequency of CD8lowCD100−cells among HTNV-specific CD8+T cells was higher in milder cases than in more severe cases. Importantly, the proportion of the CD8lowCD100−subset among CD8+T cells in early phase of HFRS was negatively correlated with the HTNV viral load, suggesting that CD8lowCD100−cells may be associated with viral clearance. The contraction of the CD8lowCD100−subset in late phase of infection may be related to the consistently high expression levels of PD-1. These results may provide new insights into our understanding of CD8+T cell-mediated protective immunity as well as immune homeostasis after HTNV infection in humans.IMPORTANCECD8+T cells play important roles in the antiviral immune response. We found that the proportion of CD8lowCD100−cells among CD8+T cells from HFRS patients was negatively correlated with the HTNV viral load, and the frequency of CD8lowCD100−cells among virus-specific CD8+T cells was higher in milder HFRS cases than in more severe cases. These results imply a beneficial role for the CD8lowCD100−cell subset in viral control during human HTNV infection.

scholarly journals CTIM-25. ONCOLYTIC VIRUS FOR DIPG: THE CLINICAL EXPERIENCE WITH DNX-2401

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii38-ii38
Author(s):  
Marta M Alonso ◽  
Ignacio Iñigo-Marco ◽  
Marc Garcia-Moure ◽  
Marisol González-Huarriz ◽  
Chris Jones ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Combined Treatment ◽  
Intratumoral Injection ◽  
Peripheral Blood Lymphocytes ◽  
Post Treatment ◽  
Virus Infectivity ◽  
Tumor Biopsy

Abstract Despite our increased understanding of Diffuse Intrinsic Pontine Glioma (DIPG) the outcome remains dismal. Recently we showed that the virus Delta-24-RGD (DNX-2401 in the clinic) was effective in preclinical models of DIPG and had the ability to trigger an antitumor immune response. These data allowed us to propel a phase I clinical trial for newly diagnosed DIPGs (NCT03178032) where the patients received an intratumoral viral injection followed by standard radiotherapy. The main objective is to determine the safety, tolerability, and toxicity of DNX-2401. Secondary endpoints are overall survival at 12 months, percentage of responses and induced immune response against tumor. Tumor biopsy was performed through the cerebellar peduncle, followed by intratumoral injection of DNX-2401 (N=12). Three patients were treated with the D1=1x1010vp and because the lack of toxicity we escalated to the D2= 5x1010vp. The procedure was well tolerated and safe. All patients displayed a reduced tumor volume after combined treatment. We performed molecular studies in 9 out of the 12 patients. The immune cell composition of the biopsies was assessed using multiplexed quantitative immunofluorescence. T cells were hardly noticeable in these tumors while macrophages were abundant. We detected increased clonal T cell diversity following treatment with virus in peripheral blood lymphocytes when compared paired pre- and post-treatment samples from the trial. In addition, we measure pre and post treatment neutralizing antibodies and its relationship with survival. Finally, we performed functional studies using 2 cell lines isolated from patients included in this trial to assess the response to the virus (infectivity, viability, T-cell recognition). Overall, the administration of DNX2401 was safe, feasible and therapeutically beneficial in a subgroup of patients. This trial constitutes a proof of principle that aids to understand the response of DIPGs to viral therapies allowing to set the bases to improve this strategy for DIPG.

scholarly journals PDCT-18 (LTBK-03). PHASE I CLINICAL TRIAL WITH ONCOLYTIC VIRUS DNX-2401 FOR DIPGS

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi283-vi284
Author(s):  
Ignacio Iñigo-Marco ◽  
Ricardo Díez-Valle ◽  
Marc Garcia-Moure ◽  
Ana Patiño-García ◽  
Marisol González Huarriz ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
T Cells ◽  
Phase I ◽  
Neutralizing Antibodies ◽  
Immune Cell ◽  
Combined Treatment ◽  
Post Treatment ◽  
Phase I Clinical Trial ◽  
Tumor Biopsy

Abstract Delta-24-RGD (DNX-2401 in the clinic) has been tested for adult glioblastoma presenting a safe profile and promising efficacy. Our group has showed that the virus is safe and effective in preclinical models of pHGG and DIPG. Moreover, we showed that the virus is able to trigger an antitumor immune response. These results allowed us to propel a phase I clinical trial for newly diagnosed DIPGs (NCT03178032) where the patients received an intratumoral injection of DNX-2401 (N=12). Tumor biopsy is performed through the cerebellar peduncle, followed by virus injection using a cannula that prevents the reflux. The trial is uncontrolled, unicentric with a 3 + 3 design. The objective of this trial is to determine the safety, tolerability, and toxicity of DNX-2401 in subjects with DIPG. Secondary endpoints are overall survival at 12 months (OS12), percentage of responses and induced immune response against tumor. To date 9 patients have been treated within the trial. Three patients were treated with the D1=1x1010vp and because the lack of toxicity we escalated to the D2= 5x1010vp. The procedure was well tolerated and safe. Patients were home 3–4 days after the injection. All the patients displayed a reduced tumor volume after combined treatment. We performed molecular studies in 8 out of the 9 patients (RNAseq and a thermofisher pediatric panel). Subsequently we evaluated the immune cell composition in the tumor using multiplexed quantitative immunofluorescence on the biopsies pre-virus injection. T cells were hardly noticeable in these tumors while macrophages were abundant. Using a multiplexed TCR-sequencing mRNA-based assay to analyze 18 available paired pre- and post-treatment samples from the trial, we detected increased clonal T cell diversity following treatment with virus. In addition, we are assessing the existence of pre and post treatment neutralizing antibodies and its relationship with survival. Finally, we have performed functional studies using 2 cell lines isolated from patients included in this trials and confronting them with T-cells isolated from peripheral blood of the same patients before and after the treatment with the virus. Information acquired within this clinical study would aid to understand the response of DIPGs to viral therapies and therefore to better tailor this strategy to improve the survival of pediatric brain tumors.

scholarly journals Killer immunoglobulin-like receptor (KIR) genes are associated with the risk of episodes of high-level and detectable viremia among HIV controllers

F1000Research ◽  
2021 ◽  
Vol 10 ◽  
pp. 546
Author(s):  
Nathalia Beatriz Ramos De Sá ◽  
Karina dos S. Silva ◽  
Marcelo Ribeiro-Alves ◽  
Diogo Gama Caetano ◽  
Fernanda Heloise Côrtes ◽  
...  
Keyword(s):  
Viral Load ◽  
Viral Replication ◽  
Human Leukocyte ◽  
Nucleotide Polymorphisms ◽  
Elite Controllers ◽  
Viral Control ◽  
Kir Genes ◽  
Specific Amplification ◽  
Hiv Controllers ◽  
High Level

Background: HIV controllers (HICs) constitute a heterogeneous group of HIV-1 individuals able to suppress plasma viremia to low or undetectable levels in the absence of antiretroviral therapy. Host genetic factors may be involved in the sustained control of viral replication observed. We investigated the distribution and the potential impact of human leukocyte antigens (HLA)-B and -C alleles, killer immunoglobulin-like receptor (KIR) genes, single nucleotide polymorphisms (SNPs) of the NLRP3, CARD8 and IL-1β inflammasome genes, and CCR5Δ32 mutation on the viral control among HICs. Methods: In total, 28 HICs were categorized as persistent elite controllers (PECs, n = 7), ebbing elite controllers (EECs, n = 7), and viremic controllers (VCs, n = 14) according to the level of natural suppression of viremia. HLA alleles were assigned by sequencing-based typing, KIR alleles by polymerase chain reaction (PCR) sequence-specific amplification, SNPs by real-time PCR, and the CCR5Δ32 mutation by PCR. Results: Significant differences were observed in the pairwise comparisons of protective HLA-B alleles, KIR Bx genotype, KIR2DL3 + C1 pair, KIR2DL5, and KIR2DS5 allelic carrier frequencies among the HIC groups. Multivariate models showed that HICs without the KIR2DL3 allele or without KIR2DL3 + C1/C2 pair, with the HLA-C*08 allele or with the NLRP3 rs10754558-G SNP had a higher mean hazard of a viral load above 2,000 copies/mL, while a lower mean hazard of this event was observed for HICs with KIR2DL5, KIR2DS1, KIR2DS5, and KIR3DS1 alleles. Moreover, HICs with the KIR2DS5 allele had less risk of undergoing viral load (VL) blips within the same normalized period than those participants without this allele, while HICs without the KIR2DL3 allele had a mean higher risk of experiencing VL blips. Conclusions: These results indicate that innate immune mechanisms may play an essential role in modulating the sustained control of viral replication in HICs.

scholarly journals Analysis of an HIV model with post-treatment control

2018 ◽  
Author(s):  
Shaoli Wang ◽  
Fei Xu
Keyword(s):  
Hiv Infection ◽  
Mathematical Analysis ◽  
Post Treatment ◽  
Proliferation Rate ◽  
Latent Reservoir ◽  
Immune Control ◽  
Treatment Control ◽  
Hiv Model ◽  
Control Threshold ◽  
Immune Impairment

AbstractRecent investigation indicated that latent reservoir and immune impairment are responsible for the post-treatment control of HIV infection. In this paper, we simplify the disease model with latent reservoir and immune impairment and perform a series of mathematical analysis. We obtain the basic infection reproductive number R0 to characterize the viral dynamics. We prove that when R0 < 1, the uninfected equilibrium of the proposed model is globally asymptotically stable. When R0 > 1, we obtain two thresholds, the post-treatment immune control threshold and the elite control threshold. The model has bistable behaviors in the interval between the two thresholds. If the proliferation rate of CTLs is less than the post-treatment immune control threshold, the model does not have positive equilibria. In this case, the immune free equilibrium is stable and the system will have virus rebound. On the other hand, when the proliferation rate of CTLs is greater than the elite control threshold, the system has stable positive immune equilibrium and unstable immune free equilibrium. Thus, the system is under elite control.Author summaryIn this article, we use mathematical model to investigate the combined effect of latent reservoir and immune impairment on the post-treatment control of HIV infection. By simplifying an HIV model with latent reservoir and immune impairment, and performing mathematical analysis, we obtain the post-treatment immune control threshold and the elite control threshold for the HIV dynamics when R0 > 1. The HIV model displays bistable behaviors in the interval between the two thresholds. We illustrate our results using both mathematical analysis and numerical simulation. Our result is consistent with recent medical experiment. We show that patient with low proliferation rate of CTLs may undergo virus rebound, and patient with high proliferation rate of CTLs may obtain elite control of HIV infection. We perform bifurcation analysis to illustrate the infection status of patient with the variation of proliferation rate of CTLs, which potentially explain the reason behind different outcomes among HIV patients.

scholarly journals Mechanistic basis of post-treatment control of SIV after anti-α4β7 antibody therapy

2021 ◽  
Vol 17 (6) ◽  
pp. e1009031
Author(s):  
Chad R. Wells ◽  
Youfang Cao ◽  
David P. Durham ◽  
Siddappa N. Byrareddy ◽  
Aftab A. Ansari ◽  
...  
Keyword(s):  
Viral Load ◽  
Antibody Therapy ◽  
Post Treatment ◽  
Treatment Control ◽  
Antibody Treatment ◽  
Viral Control ◽  
Viral Kinetics ◽  
Immune Effector ◽  
Set Point ◽  
Host Interaction

Treating macaques with an anti-α4β7 antibody under the umbrella of combination antiretroviral therapy (cART) during early SIV infection can lead to viral remission, with viral loads maintained at < 50 SIV RNA copies/ml after removal of all treatment in a subset of animals. Depletion of CD8+ lymphocytes in controllers resulted in transient recrudescence of viremia, suggesting that the combination of cART and anti-α4β7 antibody treatment led to a state where ongoing immune responses kept the virus undetectable in the absence of treatment. A previous mathematical model of HIV infection and cART incorporates immune effector cell responses and exhibits the property of two different viral load set-points. While the lower set-point could correspond to the attainment of long-term viral remission, attaining the higher set-point may be the result of viral rebound. Here we expand that model to include possible mechanisms of action of an anti-α4β7 antibody operating in these treated animals. We show that the model can fit the longitudinal viral load data from both IgG control and anti-α4β7 antibody treated macaques, suggesting explanations for the viral control associated with cART and an anti-α4β7 antibody treatment. This effective perturbation to the virus-host interaction can also explain observations in other nonhuman primate experiments in which cART and immunotherapy have led to post-treatment control or resetting of the viral load set-point. Interestingly, because the viral kinetics in the various treated animals differed—some animals exhibited large fluctuations in viral load after cART cessation—the model suggests that anti-α4β7 treatment could act by different primary mechanisms in different animals and still lead to post-treatment viral control. This outcome is nonetheless in accordance with a model with two stable viral load set-points, in which therapy can perturb the system from one set-point to a lower one through different biological mechanisms.

scholarly journals Mathematical Analysis and Clinical Implications of an HIV Model with Adaptive Immunity

2019 ◽  
Vol 2019 ◽  
pp. 1-19
Author(s):  
Jaouad Danane ◽  
Karam Allali
Keyword(s):  
Mathematical Model ◽  
Immune Response ◽  
Steady State ◽  
Adaptive Immunity ◽  
Reproduction Number ◽  
Adaptive Immune Response ◽  
Hiv Model ◽  
Adaptive Immune ◽  
The Impact ◽  
Ctl Immune Response

In this paper, a mathematical model describing the human immunodeficiency virus (HIV) pathogenesis with adaptive immune response is presented and studied. The mathematical model includes six nonlinear differential equations describing the interaction between the uninfected cells, the exposed cells, the actively infected cells, the free viruses, and the adaptive immune response. The considered adaptive immunity will be represented by cytotoxic T-lymphocytes cells (CTLs) and antibodies. First, the global stability of the disease-free steady state and the endemic steady states is established depending on the basic reproduction number R0, the CTL immune response reproduction number R1z, the antibody immune response reproduction number R1w, the antibody immune competition reproduction number R2w, and the CTL immune response competition reproduction number R3z. On the other hand, different numerical simulations are performed in order to confirm numerically the stability for each steady state. Moreover, a comparison with some clinical data is conducted and analyzed. Finally, a sensitivity analysis for R0 is performed in order to check the impact of different input parameters.

scholarly journals Profiles of Peripheral Immune Cells of Uncomplicated COVID-19 Cases with Distinct Viral RNA Shedding Periods

Viruses ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 514
Author(s):  
Denise Utami Putri ◽  
Cheng-Hui Wang ◽  
Po-Chun Tseng ◽  
Wen-Sen Lee ◽  
Fu-Lun Chen ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Cells ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Severe Disease ◽  
Viral Rna ◽  
Disease Course ◽  
Peripheral Blood Mononuclear ◽  
Peripheral Immune Cells ◽  
Cell Profile

The heterogeneity of immune response to COVID-19 has been reported to correlate with disease severity and prognosis. While so, how the immune response progress along the period of viral RNA-shedding (VRS), which determines the infectiousness of disease, is yet to be elucidated. We aim to exhaustively evaluate the peripheral immune cells to expose the interplay of the immune system in uncomplicated COVID-19 cases with different VRS periods and dynamic changes of the immune cell profile in the prolonged cases. We prospectively recruited four uncomplicated COVID-19 patients and four healthy controls (HCs) and evaluated the immune cell profile throughout the disease course. Peripheral blood mononuclear cells (PBMCs) were collected and submitted to a multi-panel flowcytometric assay. CD19+-B cells were upregulated, while CD4, CD8, and NK cells were downregulated in prolonged VRS patients. Additionally, the pro-inflammatory-Th1 population showed downregulation, followed by improvement along the disease course, while the immunoregulatory cells showed upregulation with subsequent decline. COVID-19 patients with longer VRS expressed an immune profile comparable to those with severe disease, although they remained clinically stable. Further studies of immune signature in a larger cohort are warranted.

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