scholarly journals Dynamics of recurrent viral infection

2006 ◽  
Vol 273 (1598) ◽  
pp. 2193-2199 ◽  
Author(s):  
W Yao ◽  
L Hertel ◽  
L.M Wahl
Keyword(s):  
Viral Infection ◽  
Particle Production ◽  
Viral Infections ◽  
T Cell Response ◽  
Chronic Viral Infection ◽  
Viral Production ◽  
Infectious Particle ◽  
Exogenous Factors ◽  
Low Levels ◽  
Exogenous Trigger

In chronic viral infection, low levels of viral replication and infectious particle production are maintained over long periods, punctuated by brief bursts of high viral production and release. We apply well-established principles of modelling virus dynamics to the study of chronic viral infection, demonstrating that a model which incorporates the distinct contributions of cytotoxic T lymphocytes (CTLs) and antibodies exhibits long periods of quiescence followed by brief bursts of viral production. This suggests that for recurrent viral infections, no special mechanism or exogenous trigger is necessary to provoke an episode of reactivation; rather, the system may naturally cycle through recurrent episodes at intervals which can be many years long. We also find that exogenous factors which cause small fluctuations in the natural course of the infection can trigger a recurrent episode. Our model predicts that longer periods between recurrences are associated with more severe viral episodes. Four factors move the system towards less frequent, more severe episodes: decreased viral infectivity, decreased CTL efficacy, decreased memory T cell response and increased antibody efficacy.

scholarly journals Activation Status Dictates the Function of Unlicensed Natural Killer Cells

2021 ◽  
Author(s):  
Ethan G Aguilar ◽  
Cordelia Dunai ◽  
Sean J. Judge ◽  
Anthony Elston Zamora ◽  
Lam T. Khuat ◽  
...  
Keyword(s):  
Viral Infection ◽  
Nk Cells ◽  
Natural Killer ◽  
Viral Infections ◽  
Nk Cell ◽  
T Cell Response ◽  
High Dose ◽  
Hematopoietic Stem ◽  
Innate Defense ◽  
Activation Status

Natural Killer (NK) cells are involved in innate defense against viral infection and cancer. NK cells can be divided into subsets based on the ability of different receptors to bind to major histocompatibility (MHC) class I molecules resulting in differential responses upon activation in a process called "licensing" or "arming". NK cells expressing receptors that bind self-MHC are considered licensed due to augmented effector lytic function capability compared to unlicensed subsets. However, we demonstrated unlicensed NK subsets instead positively regulate the adaptive T cell response during viral infections due to localization and cytokine production. We demonstrate here that the differential effects of the two types of NK subsets is contingent on the environment using viral infection and hematopoietic stem cell transplantation (HSCT) models. Infection of mice with high-dose (HD) MCMV leads to a loss of licensing-associated differences as compared to mice with low-dose infection, as the unlicensed NK subset no longer localized in lymph nodes (LN), but instead remained at the site of infection. Similarly, the patterns observed during HD infection paralleled with the phenotypes of both human and mouse NK cells in a HSCT setting where NK cells exhibit an activated phenotype. However, in contrast to effects of subset depletion in T-replete models, the licensed NK cell subsets still dominated anti-viral responses post-HSCT. Overall, our results highlight the intricate tuning of the NK cells and how it impacts overall immune responses with regard to licensing patterns, as it is dependent on the level of stimulation and their activation status.

scholarly journals Antioxidant Treatment Reduces Expansion and Contraction of Antigen-Specific CD8+ T Cells during Primary but Not Secondary Viral Infection

2004 ◽  
Vol 78 (20) ◽  
pp. 11246-11257 ◽  
Author(s):  
Nathan G. Laniewski ◽  
Jason M. Grayson
Keyword(s):  
T Cells ◽  
Viral Infection ◽  
Large Scale ◽  
Viral Infections ◽  
Lymphocytic Choriomeningitis ◽  
T Cell Response ◽  
Oxygen Intermediates ◽  
Mimetic Compound

ABSTRACT During many viral infections, antigen-specific CD8+ T cells undergo large-scale expansion. After viral clearance, the vast majority of effector CD8+ T cells undergo apoptosis. Previous studies have implicated reactive oxygen intermediates (ROI) in lymphocyte apoptosis. The purpose of the experiments presented here was to determine the role of ROI in the expansion and contraction of CD8+ T cells in vivo during a physiological response such as viral infection. Mice were infected with lymphocytic choriomeningitis virus (LCMV) and treated with Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), a metalloporphyrin-mimetic compound with superoxide dismutase activity, from days 0 to 8 postinfection. At the peak of CD8+-T-cell response, on day 8 postinfection, the numbers of antigen-specific cells were 10-fold lower in MnTBAP-treated mice than in control mice. From days 8 to 30, a contraction phase ensued where the numbers of antigen-specific CD8+ T cells declined 25-fold in vehicle-treated mice compared to a 3.5-fold decrease in MnTBAP-treated mice. Differences in contraction appeared to be due to greater proliferation in drug-treated mice. By day 38, the numbers of antigen-specific CD8+ memory T cells were equivalent for the two groups. The administration of MnTBAP during secondary viral infection had no effect on the expansion of antigen-specific CD8+ secondary effector T cells. These data suggest that ROI production is critical for the massive expansion and contraction of antigen-specific CD8+ T cells during primary, but not secondary, viral infection.

scholarly journals Single-Epitope DNA Vaccination Prevents Exhaustion and Facilitates a Broad Antiviral CD8+T Cell Response during Chronic Viral Infection

2004 ◽  
Vol 173 (10) ◽  
pp. 6284-6293 ◽  
Author(s):  
Christina Bartholdy ◽  
Anette Stryhn ◽  
Jan Pravsgaard Christensen ◽  
Allan Randrup Thomsen
Keyword(s):  
T Cell ◽  
Viral Infection ◽  
Cell Response ◽  
Cd8 T Cell ◽  
Dna Vaccination ◽  
T Cell Response ◽  
Chronic Viral Infection

scholarly journals Plasmacytoid dendritic cells control T-cell response to chronic viral infection

2012 ◽  
Vol 109 (8) ◽  
pp. 3012-3017 ◽  
Author(s):  
L. Cervantes-Barragan ◽  
K. L. Lewis ◽  
S. Firner ◽  
V. Thiel ◽  
S. Hugues ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
Viral Infection ◽  
Cell Response ◽  
Plasmacytoid Dendritic Cells ◽  
T Cell Response ◽  
Chronic Viral Infection

scholarly journals A Combination of Anti-PD-L1 Treatment and Therapeutic Vaccination Facilitates Improved Retroviral Clearance via Reactivation of Highly Exhausted T Cells

mBio ◽  
2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Torben Knuschke ◽  
Sebastian Kollenda ◽  
Christina Wenzek ◽  
Gennadiy Zelinskyy ◽  
Philine Steinbach ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Combination Therapy ◽  
Viral Infection ◽  
Viral Infections ◽  
T Cell Immunity ◽  
Chronic Viral Infection ◽  
Therapeutic Vaccination ◽  
Chronic Viral Infections ◽  
Cell Immunity

ABSTRACT PD-1-targeted therapies have shown modest antiviral effects in preclinical models of chronic viral infection. Thus, novel therapy protocols are necessary to enhance T cell immunity and viral control to overcome T cell dysfunction and immunosuppression. Here, we demonstrate that nanoparticle-based therapeutic vaccination improved PD-1-targeted therapy during chronic infection with Friend retrovirus (FV). Prevention of inhibitory signals by blocking PD-L1 in combination with therapeutic vaccination with nanoparticles containing the microbial compound CpG and a CD8+ T cell Gag epitope peptide synergistically enhanced functional virus-specific CD8+ T cell responses and improved viral clearance. We characterized the CD8+ T cell populations that were affected by this combination therapy, demonstrating that new effector cells were generated and that exhausted CD8+ T cells were reactivated at the same time. While CD8+ T cells with high PD-1 (PD-1hi) expression turned into a large population of granzyme B-expressing CD8+ T cells after combination therapy, CXCR5-expressing follicular cytotoxic CD8+ T cells also expanded to a high degree. Thus, our study describes a very efficient approach to enhance virus control and may help us to understand the mechanisms of combination immunotherapy reactivating CD8+ T cell immunity. A better understanding of CD8+ T cell immunity during combination therapy will be important for developing efficient checkpoint therapies against chronic viral infections and cancer. IMPORTANCE Despite significant efforts, vaccines are not yet available for every infectious pathogen, and the search for a protective approach to prevent the establishment of chronic infections, i.e., with HIV, continues. Immune checkpoint therapies targeting inhibitory receptors, such as PD-1, have shown impressive results against solid tumors. However, immune checkpoint therapies have not yet been licensed to treat chronic viral infections, since a blockade of inhibitory receptors alone provides only limited benefit, as demonstrated in preclinical models of chronic viral infection. Thus, there is a high interest in the development of potent combination immunotherapies. Here, we tested whether the combination of a PD-L1 blockade and therapeutic vaccination with functionalized nanoparticles is a potent therapy during chronic Friend retrovirus infection. We demonstrate that the combination therapy induced a synergistic reinvigoration of the exhausted virus-specific CD8+ T cell immunity. Taken together, our results provide further information on how to improve PD-1-targeted therapies during chronic viral infection and cancer.

scholarly journals Autophagy Promotes Infectious Particle Production of Mopeia and Lassa Viruses

Viruses ◽  
2019 ◽  
Vol 11 (3) ◽  
pp. 293 ◽  
Author(s):  
Nicolas Baillet ◽  
Sophie Krieger ◽  
Alexandra Journeaux ◽  
Valérie Caro ◽  
Frédéric Tangy ◽  
...  
Keyword(s):  
Matrix Protein ◽  
Particle Production ◽  
Defense Mechanism ◽  
Viral Infections ◽  
Hybrid Approach ◽  
Hemorrhagic Fever ◽  
Lassa Virus ◽  
Infectious Particle ◽  
Cellular Defense ◽  
Infected Cells

Lassa virus (LASV) and Mopeia virus (MOPV) are two closely related Old-World mammarenaviruses. LASV causes severe hemorrhagic fever with high mortality in humans, whereas no case of MOPV infection has been reported. Comparing MOPV and LASV is a powerful strategy to unravel pathogenic mechanisms that occur during the course of pathogenic arenavirus infection. We used a yeast two-hybrid approach to identify cell partners of MOPV and LASV Z matrix protein in which two autophagy adaptors were identified, NDP52 and TAX1BP1. Autophagy has emerged as an important cellular defense mechanism against viral infections but its role during arenavirus infection has not been shown. Here, we demonstrate that autophagy is transiently induced by MOPV, but not LASV, in infected cells two days after infection. Impairment of the early steps of autophagy significantly decreased the production of MOPV and LASV infectious particles, whereas a blockade of the degradative steps impaired only MOPV infectious particle production. Our study provides insights into the role played by autophagy during MOPV and LASV infection and suggests that this process could partially explain their different pathogenicity.

Real-world outcomes of treatment with immune checkpoint inhibitors in unique patient cohorts: Elderly, non-caucasian race, poor performance status, obese, chronic viral infections, and autoimmune diseases.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2641-2641
Author(s):  
Neil J. Shah ◽  
Shuo Wang ◽  
Aquino Williams ◽  
Melinda Weber ◽  
Brittany Sinclaire ◽  
...  
Keyword(s):  
Viral Infection ◽  
Real World ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Viral Infections ◽  
Checkpoint Inhibitors ◽  
Chronic Viral Infection ◽  
Poor Performance Status ◽  
Chronic Viral Infections ◽  
Ecog Ps

2641 Background: Immune Checkpoint Inhibitors (ICI) have revolutionized current cancer treatment. Nevertheless, outcomes data across various patient cohorts are lacking. To address this knowledge gap, we conducted a comprehensive analysis of real-world data (RWD) that included patient cohorts traditionally underrepresented in clinical trials. Methods: We identified patients (pts) treated with ICI (anti-CTLA-4, anti-PD(L)1 or their combination at 6 US academic and community hospitals from 1/2011 – 4/2018. Clinical data obtained from EHR and CTCAE V4.03 was used to define immune-related adverse events (irAEs). Results: A total of 1332 pts treated with 1443 unique ICI treatments were included in the cohort. The median age was 66 (21-87), Male 58% (827), Caucasian 70% (1004), African American (AA) 16% (232), other race 14% (207), ECOG PS 0,1 79% (1130), chronic viral infection 5% [hepatitis B (24), hepatitis C (32) and HIV (17)], with BMI > 30 22% (287) and autoimmune disease (AID) 15% (215). Lung cancer (NSCLC) 34% (423), and melanoma 27% (389) were top 2 tumor types and nivolumab 38% (544), pembrolizumab 23% (332), and ipilimumab plus nivolumab 12% (180) were the most common ICI treatments. Overall survival (OS) was worse for patients with ECOG ≥2 (0.34 - 0.63) vs. ECOG 0,1 (1.27 - 1.73, P <0.001), and better with AID (1.21 - 2.63) vs. no AID ( 0.90 - 1.24, P=0.01) and Caucasian (1.02 - 1.45) vs AA (0.72 - 1.30, P=0.02). No difference in OS was noted for sex, other races, h/o chronic viral infection or obesity. We performed an analysis of OS and irAEs restricted to NSCLC patients (n=423); (N=447 unique ICI treatments); age >75 27% (120), AA 28% (124), Female 50% (224), ECOG PS ≥2 23% (104), BMI >30 15% (62), chronic viral infections 10% (44), and AID 14% (62). The ICI therapies were nivolumab 55% (245), pembrolizumab 23% (102), and atezolizumab 6% (27) and 16% (others). Data is contained in the table. Conclusions: Overall, in our RWD, OS appeared to be similar across above cohorts except poor OS for pts with ECOG ≥2. irAEs also appeared to be similar across cohorts except less with ECOG ≥2. In NSCLC cohort, we noted similar findings except less irAEs in Male cohort. Prospective studies are needed to confirm the above findings.[Table: see text]

scholarly journals Prevention of CD8 T Cell Deletion during Chronic Viral Infection

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1189
Author(s):  
David G. Brooks ◽  
Antoinette Tishon ◽  
Michael B. A. Oldstone ◽  
Dorian B. McGavern
Keyword(s):  
T Cells ◽  
T Cell ◽  
Viral Replication ◽  
Viral Infection ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Chronic Viral Infection ◽  
Loss Of Function ◽  
Cell Deletion

During chronic viral infections, CD8 T cells rapidly lose antiviral and immune-stimulatory functions in a sustained program termed exhaustion. In addition to this loss of function, CD8 T cells with the highest affinity for viral antigen can be physically deleted. Consequently, treatments designed to restore function to exhausted cells and control chronic viral replication are limited from the onset by the decreased breadth of the antiviral T cell response. Yet, it remains unclear why certain populations of CD8 T cells are deleted while others are preserved in an exhausted state. We report that CD8 T cell deletion during chronic viral infection can be prevented by therapeutically lowering viral replication early after infection. The initial resistance to deletion enabled long-term maintenance of antiviral cytolytic activity of the otherwise deleted high-affinity CD8 T cells. In combination with decreased virus titers, CD4 T cell help and prolonged interactions with costimulatory molecules B7-1/B7-2 were required to prevent CD8 T cell deletion. Thus, therapeutic strategies to decrease early virus replication could enhance virus-specific CD8 T cell diversity and function during chronic infection.

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