Immune Responses Associated to Viral Control

Key PointsHIV-2 viral control is associated with a polyfunctional Gag-specific CD8+ T-cell response but not with perforin upregulation. Our findings provide insight into cellular immune responses associated with a naturally contained human retroviral infection.

Download Full-text

Acute-Phase CD4+T Cell Responses Targeting Invariant Viral Regions Are Associated with Control of Live Attenuated Simian Immunodeficiency Virus

Journal of Virology ◽

10.1128/jvi.00830-18 ◽

2018 ◽

Vol 92 (21) ◽

Cited By ~ 5

Author(s):

Matthew S. Sutton ◽

Amy Ellis-Connell ◽

Ryan V. Moriarty ◽

Alexis J. Balgeman ◽

Dane Gellerup ◽

...

Keyword(s):

T Cell ◽

Immune Responses ◽

Virus Replication ◽

T Cell Responses ◽

Viral Control ◽

Variable Regions ◽

Cell Responses ◽

Immunodeficiency Virus ◽

Invariant Regions ◽

Mhc Alleles

ABSTRACTWe manipulated SIVmac239Δnef, a model of major histocompatibility complex (MHC)-independent viral control, to evaluate characteristics of effective cellular responses mounted by Mauritian cynomolgus macaques (MCMs) that express the M3 MHC haplotype, which has been associated with poor control of pathogenic simian immunodeficiency virus (SIV). We created SIVΔnef-8x to test the hypothesis that effective SIV-specific T cell responses targeting invariant viral regions can emerge in the absence of immunodominant CD8+T cell responses targeting variable epitopes and that control is achievable in individuals lacking known “protective” MHC alleles. Full-proteome gamma interferon (IFN-γ) enzyme-linked immunospot (ELISPOT) assays identified six newly targeted immunogenic regions following SIVΔnef-8x infection of M3/M3 MCMs. We deep sequenced circulating virus and found that four of the six newly targeted regions rarely accumulated mutations. Six animals infected with SIVΔnef-8x had T cell responses that targeted at least one of the four invariant regions and had a lower set point viral load than two animals that did not have T cell responses that targeted any invariant regions. We found that MHC class II molecules restricted all four of the invariant peptide regions, while the two variable regions were restricted by MHC class I molecules. Therefore, in the absence of immunodominant CD8+T cell responses that target variable regions during SIVmac239Δnef infection, individuals without protective MHC alleles developed predominantly CD4+T cell responses specific for invariant regions that may improve control of virus replication. Our results provide some evidence that antiviral CD4+T cells during acute SIV infection can contribute to effective viral control and should be considered in strategies to combat HIV infection.IMPORTANCEStudies defining effective cellular immune responses to human immunodeficiency virus (HIV) and SIV have largely focused on a rare population that express specific MHC class I alleles and control virus replication in the absence of antiretroviral treatment. This leaves in question whether similar effective immune responses can be achieved in the larger population. The majority of HIV-infected individuals mount CD8+T cell responses that target variable viral regions that accumulate high-frequency escape mutations. Limiting T cell responses to these variable regions and targeting invariant viral regions, similar to observations in rare “elite controllers,” may provide an ideal strategy for the development of effective T cell responses in individuals with diverse MHC genetics. Therefore, it is of paramount importance to determine whether T cell responses can be redirected toward invariant viral regions in individuals without protective MHC alleles and if these responses improve control of virus replication.

Download Full-text

The influence of the gut microbiota on influenza vaccine-induced immunity

10.26686/wgtn.17131847 ◽

2021 ◽

Author(s):

◽

Anna Mooney

Keyword(s):

Immune Response ◽

Gut Microbiota ◽

Immune Responses ◽

Influenza Vaccine ◽

Influenza Vaccination ◽

Antibody Production ◽

Host Immune System ◽

Viral Control ◽

Nutritional Interventions ◽

The Impact

<p>Currently, annual vaccination is widely considered the most effective method for preventing and controlling influenza virus infection. However, many individuals mount suboptimal immune responses to vaccination and the factors leading to poor immune responses are yet to be elucidated. Interestingly, it has been proposed that microorganisms that inhabit the intestinal tract, the gut microbiota, can profoundly influence many facets of the host immune system, including the strength of the immune response to influenza vaccination. In line with these observations, we observed that short-term administration of antibiotics drastically reduced influenza vaccine-specific antibody production. In particular, antibiotic treatment diminished the frequency and activation status of multiple myeloid cell subsets in the draining lymph nodes at steady-state and following vaccination, with associated impairments in B and TFH cell responses. Composition and function of gut microbiota communities can be rapidly altered through dietary changes. Therefore, the impact of potential prebiotic and probiotic nutritional interventions on the immune response to influenza vaccination and subsequent infection was assessed. No improvement in antibody responses to influenza vaccination was observed following the nutritional interventions studies. However, oral administration of a propolis formulation led to some improvement in viral control following infection. Collectively, this investigation indicates that alterations in microbial-associated signals leads to severe impairments in cellular responses crucial to humoral immunity and subsequent vaccine-induced antibody production. Furthermore, by altering the gut microbiota through dietary interventions, there is potential to improve immune responses to vaccination.</p>

Download Full-text

The influence of the gut microbiota on influenza vaccine-induced immunity

10.26686/wgtn.17131847.v1 ◽

2021 ◽

Author(s):

◽

Anna Mooney

Keyword(s):

Immune Response ◽

Gut Microbiota ◽

Immune Responses ◽

Influenza Vaccine ◽

Influenza Vaccination ◽

Antibody Production ◽

Host Immune System ◽

Viral Control ◽

Nutritional Interventions ◽

The Impact

<p>Currently, annual vaccination is widely considered the most effective method for preventing and controlling influenza virus infection. However, many individuals mount suboptimal immune responses to vaccination and the factors leading to poor immune responses are yet to be elucidated. Interestingly, it has been proposed that microorganisms that inhabit the intestinal tract, the gut microbiota, can profoundly influence many facets of the host immune system, including the strength of the immune response to influenza vaccination. In line with these observations, we observed that short-term administration of antibiotics drastically reduced influenza vaccine-specific antibody production. In particular, antibiotic treatment diminished the frequency and activation status of multiple myeloid cell subsets in the draining lymph nodes at steady-state and following vaccination, with associated impairments in B and TFH cell responses. Composition and function of gut microbiota communities can be rapidly altered through dietary changes. Therefore, the impact of potential prebiotic and probiotic nutritional interventions on the immune response to influenza vaccination and subsequent infection was assessed. No improvement in antibody responses to influenza vaccination was observed following the nutritional interventions studies. However, oral administration of a propolis formulation led to some improvement in viral control following infection. Collectively, this investigation indicates that alterations in microbial-associated signals leads to severe impairments in cellular responses crucial to humoral immunity and subsequent vaccine-induced antibody production. Furthermore, by altering the gut microbiota through dietary interventions, there is potential to improve immune responses to vaccination.</p>

Download Full-text

Magnitude and Quality of Vaccine-Elicited T-Cell Responses in the Control of Immunodeficiency Virus Replication in Rhesus Monkeys

Journal of Virology ◽

10.1128/jvi.00204-08 ◽

2008 ◽

Vol 82 (17) ◽

pp. 8812-8819 ◽

Cited By ~ 32

Author(s):

Yue Sun ◽

Sampa Santra ◽

Jörn E. Schmitz ◽

Mario Roederer ◽

Norman L. Letvin

Keyword(s):

T Cell ◽

Immune Responses ◽

Rhesus Monkeys ◽

T Cell Responses ◽

Viral Control ◽

Cell Responses ◽

Cellular Immune Responses ◽

Immunodeficiency Virus ◽

Cellular Immune ◽

Functional Profiles

ABSTRACT While a diversity of immunogens that elicit qualitatively different cellular immune responses are being assessed in clinical human immunodeficiency virus vaccine trials, the consequences of those varied responses for viral control remain poorly understood. In the present study, we evaluated the induction of virus-specific T-cell responses in rhesus monkeys using a series of diverse vaccine vectors. We assessed both the magnitude and the functional profile of the virus-specific CD8+ T cells by measuring gamma interferon, interleukin-2, and tumor necrosis factor alpha production. We found that the different vectors generated virus-specific T-cell responses of different magnitudes and with different functional profiles. Heterologous prime-boost vaccine regimens induced particularly high-frequency virus-specific T-cell responses with polyfunctional repertoires. Yet, immediately after a pathogenic simian-human immunodeficiency virus (SHIV) challenge, no significant differences were observed between these cohorts of vaccinated monkeys in the magnitudes or the functional profiles of their virus-specific CD8+ T cells. This finding suggests that the high viral load shapes the functional repertoire of the cellular immune response during primary infection. Nevertheless, in all vaccination regimens, higher frequency and more polyfunctional vaccine-elicited virus-specific CD8+ T-cell responses were associated with better viral control after SHIV challenge. These observations highlight the contributions of both the quality and the magnitude of vaccine-elicited cellular immune responses in the control of immunodeficiency virus replication.

Download Full-text

Restoration of HCV-Specific Immune Responses with Antiviral Therapy: A Case for DAA Treatment in Acute HCV Infection

Cells ◽

10.3390/cells8040317 ◽

2019 ◽

Vol 8 (4) ◽

pp. 317 ◽

Cited By ~ 1

Author(s):

Julia L. Casey ◽

Jordan J. Feld ◽

Sonya A. MacParland

Keyword(s):

T Cells ◽

Immune Responses ◽

Viral Infection ◽

Antiviral Therapy ◽

Hcv Infection ◽

Immune Restoration ◽

Viral Control ◽

Acute Hcv ◽

Ifn Treatment ◽

Acute Hcv Infection

Worldwide, 71 million individuals are chronically infected with Hepatitis C Virus (HCV). Chronic HCV infection can lead to potentially fatal outcomes including liver cirrhosis and hepatocellular carcinoma. HCV-specific immune responses play a major role in viral control and may explain why approximately 20% of infections are spontaneously cleared before the establishment of chronicity. Chronic infection, associated with prolonged antigen exposure, leads to immune exhaustion of HCV-specific T cells. These exhausted T cells are unable to control the viral infection. Before the introduction of direct acting antivirals (DAAs), interferon (IFN)-based therapies demonstrated successful clearance of viral infection in approximately 50% of treated patients. New effective and well-tolerated DAAs lead to a sustained virological response (SVR) in more than 95% of patients regardless of viral genotype. Researchers have investigated whether treatment, and the subsequent elimination of HCV antigen, can reverse this HCV-induced exhausted phenotype. Here we review literature exploring the restoration of HCV-specific immune responses following antiviral therapy, both IFN and DAA-based regimens. IFN treatment during acute HCV infection results in greater immune restoration than IFN treatment of chronically infected patients. Immune restoration data following DAA treatment in chronically HCV infected patients shows varied results but suggests that DAA treatment may lead to partial restoration that could be improved with earlier administration. Future research should investigate immune restoration following DAA therapies administered during acute HCV infection.

Download Full-text

Viral adaptation to immune selection pressure by HLA class I–restricted CTL responses targeting epitopes in HIV frameshift sequences

Journal of Experimental Medicine ◽

10.1084/jem.20091808 ◽

2010 ◽

Vol 207 (1) ◽

pp. 61-75 ◽

Cited By ~ 39

Author(s):

Christoph T. Berger ◽

Jonathan M. Carlson ◽

Chanson J. Brumme ◽

Kari L. Hartman ◽

Zabrina L. Brumme ◽

...

Keyword(s):

Immune Responses ◽

Viral Replication ◽

Ex Vivo ◽

Natural Infection ◽

Human Leukocyte ◽

Population Level ◽

Sequence Information ◽

Viral Control

CD8+ cytotoxic T lymphocyte (CTL)–mediated immune responses to HIV contribute to viral control in vivo. Epitopes encoded by alternative reading frame (ARF) peptides may be targeted by CTLs as well, but their frequency and in vivo relevance are unknown. Using host genetic (human leukocyte antigen [HLA]) and plasma viral sequence information from 765 HIV-infected subjects, we identified 64 statistically significant (q < 0.2) associations between specific HLA alleles and sequence polymorphisms in alternate reading frames of gag, pol, and nef that did not affect the regular frame protein sequence. Peptides spanning the top 20 HLA-associated imprints were used to test for ex vivo immune responses in 85 HIV-infected subjects and showed responses to 10 of these ARF peptides. The most frequent response recognized an HLA-A*03–restricted +2 frame–encoded epitope containing a unique A*03-associated polymorphism at position 6. Epitope-specific CTLs efficiently inhibited viral replication in vitro when viruses containing the wild-type sequence but not the observed polymorphism were tested. Mutating alternative internal start codons abrogated the CTL-mediated inhibition of viral replication. These data indicate that responses to ARF-encoded HIV epitopes are induced during natural infection, can contribute to viral control in vivo, and drive viral evolution on a population level.

Download Full-text

Daily viral kinetics and innate and adaptive immune responses assessment in COVID-19: a case series

10.1101/2020.07.02.20143271 ◽

2020 ◽

Cited By ~ 2

Author(s):

Pauline Vetter ◽

Christiane Eberhardt ◽

Benjamin Meyer ◽

Paola Andrea Martinez Murillo ◽

Giulia Torriani ◽

...

Keyword(s):

Immune Responses ◽

Respiratory Tract ◽

Infectious Virus ◽

Upper Respiratory Tract ◽

Innate Response ◽

Viral Control ◽

Adaptive Immune Responses ◽

Viral Loads ◽

Viral Shedding ◽

Adaptive Immune

AbstractBackgroundViral shedding patterns and its correlation with the immune responses of mildly symptomatic COVID-19 patients are still poorly characterized.MethodsWe enrolled the first five COVID-19 patients quarantined in our institution; none received immunomodulatory treatment. We monitored shedding of viral RNA and infectious virus by RT-PCR and cell culture from the upper respiratory tract, and characterized the kinetics of systemic innate and adaptive immune responses.ResultsDespite mild clinical disease, high viral loads and shedding of infectious virus were observed from the respiratory tract, with isolation of infectious virus and prolonged positivity by PCR up to day 7 and 19 post onset of symptoms, respectively. Robust innate responses characterized by an increase in activated CD14+CD16+ monocytes and cytokine responses were observed as early as 2 days after symptoms onset. Cellular and humoral SARS-CoV-2 specific adaptive responses were detectable in all patients.ConclusionInfectious virus shedding was limited to the first week of symptom onset in mild cases. A strong innate response, characterized by the mobilization of activated monocytes during the first days of infection, as well as SARS-CoV-2 specific antibodies were detectable, even in patients with mild disease.SummaryWe describe viral and immune profiles of the first five SARS-CoV-2 patients in our institution, showing high viral loads and infectious viral shedding in early acute disease. Mild patients mount an innate response sufficient for viral control and specific immunity.

Download Full-text

Hantaan Virus Infection Induces Both Th1 and ThGranzyme B+ Cell Immune Responses That Associated with Viral Control and Clinical Outcome in Humans

PLoS Pathogens ◽

10.1371/journal.ppat.1004788 ◽

2015 ◽

Vol 11 (4) ◽

pp. e1004788 ◽

Cited By ~ 17

Author(s):

Ying Ma ◽

Bin Yuan ◽

Ran Zhuang ◽

Yusi Zhang ◽

Bei Liu ◽

...

Keyword(s):

Virus Infection ◽

Clinical Outcome ◽

Immune Responses ◽

B Cell ◽

Hantaan Virus ◽

Viral Control

Download Full-text

Role of Immunomodulators in Functional Cure Strategies for HBV

Current Hepatology Reports ◽

10.1007/s11901-020-00538-6 ◽

2020 ◽

Vol 19 (4) ◽

pp. 337-344

Author(s):

Benedikt Binder ◽

Maike Hofmann ◽

Robert Thimme

Keyword(s):

Immune Responses ◽

Innate Immune ◽

Hbv Infection ◽

Viral Control ◽

Curative Therapy ◽

Chronic Hepatitis B Virus ◽

B Virus ◽

Chronic Hbv ◽

Immunomodulatory Therapies

Abstract Purpose of Review Chronic Hepatitis B Virus (HBV) Infection is a major global health burden. Currently, a curative therapy does not exist; thus, there is an urgent need for new therapeutical options. Viral elimination in the natural course of infection results from a robust and multispecific T and B cell response that, however, is dysfunctional in chronically infected patients. Therefore, immunomodulatory therapies that strengthen the immune responses are an obvious approach trying to control HBV infection. In this review, we summarize the rationale and current options of immunological cure of chronic HBV infection. Recent Findings Recently, among others, drugs that stimulate the innate immune system or overcome CD8+ T cell exhaustion by checkpoint blockade, and transfer of HBV-specific engineered CD8+ T cells emerged as promising approaches. Summary HBV-specific immunity is responsible for viral control, but also for immunopathogenesis. Thus, the development of immunomodulatory therapies is a difficult process on a thin line between viral control and excessive immunopathology. Some promising agents are under investigation. Nevertheless, further research is indispensable in order to optimally orchestrate immunostimulation.

Download Full-text