Early Interferon Research Articles

Comparison of Immune Restoration in Early versus Late Alpha Interferon Therapy against Hepatitis C Virus

Early alpha interferon (IFN-alpha) therapy against hepatitis C virus (HCV) rescues polyfunctional, virus-specific memory CD8(+) T cells, but whether immune restoration is possible during late therapy remains controversial. We compared immune restoration of HCV-specific memory T cells in patients who cleared HCV infection spontaneously and following early or late IFN therapy. Multifunctional CD4(+) and CD8(+) memory T cells were detected in spontaneous resolvers and in individuals treated early following an acute infection. In contrast, limited responses were detected in patients treated during chronic infection, and the phenotype of HCV-specific cells was influenced by autologous viral sequences. Our data suggest that irreversible damage to the HCV-specific memory T-cell response is associated with chronic HCV infection.

The Early Interferon Alpha Subtype Response in Infant Macaques Infected Orally With SIV

The Early Interferon Alpha Subtype Response in Infant Macaques Infected Orally With SIV

Uncertain BENEFIT of early interferon beta-1b treatment

Uncertain BENEFIT of early interferon beta-1b treatment

The early interferon response of nasal-associated lymphoid tissue toStreptococcus pyogenesinfection

Streptococcus pyogenes is a major causative agent of tonsillitis or pharyngitis in children. Streptococcus pyogenes can persist in tonsils, and one-third of children treated with antibiotics continue to shed streptococci and have recurrent infections. Mouse nasal-associated lymphoid tissue (NALT) is functionally analogous to human oropharyngeal lymphoid tissues, and serves as a model for characterization of the mucosal innate immune response to S. pyogenes. Wild-type S. pyogenes induces transcription of both type I and interferon-gamma (IFN-gamma)-responsive genes, proinflammatory genes and acute-phase response proteins 24 h after intranasal infection. Invasion of NALT and the induction of the interferon response were not dependent on expression of antiphagocytic M protein. Intranasal infection induces a substantial influx of neutrophils into NALT at 24 h, which declines by 48 h after infection. Infection of IFN-gamma(-/-) [IFN-gamma knock-out mouse (GKO)] C57BL/6 mice with wild-type S. pyogenes resulted in local dissemination of bacteria to draining lymph nodes (LN), but did not lead to systemic infection by 48 h after infection. Infected GKO mice had an increased influx of neutrophils into NALT compared with immunocompetent mice. Thus, IFN-gamma-induced responses are required to prevent local dissemination of streptococci to the draining LN.

Early Interferon Beta Treatment in Multiple Sclerosis

Interferon beta (IFNbeta) is a first-line treatment for relapsing forms of multiple sclerosis (MS) that can reduce the rate of clinical attacks and limit disability progression. Recent trials have shown that initiating IFNbeta treatment at the time of the first clinical event suggesting MS can delay the onset of clinically definite MS and, in the case of IFNbeta-1 b, inhibit the progression of later disability. These findings have led to a trend toward earlier treatment initiation in clinical practice. While trials show good levels of adherence to therapy, there often is room for improvement in the clinical setting. Managing MS symptoms and treatment-related adverse events and providing patient education are vital to optimize adherence, and nurses can employ a number of strategies as part of the support program to ensure patients gain the most benefit from their treatment. In addition to providing a great deal of evidence supporting early MS treatment, the ongoing BEtaseron in Newly Emerging multiple sclerosis For Initial Treatment (BENEFIT) study has highlighted the fact that IFNbeta can be well tolerated, especially with correct management. This article summarizes the lessons learned from the BENEFIT study, and the ways in which nurses can incorporate this knowledge into clinical practice.

Function is the Key: Impact of Interferon on Hcv-Specific CD8 + t Cells During Acute Hcv Infection

Evaluation of: Badr G, Bédard N, Abdel-Hakeem MS et al.: Early interferon therapy for hepatitis C virus infection rescues polyfunctional, long-lived CD8+ memory T cells. J. Virol. 82(20), 10017–10031 (2008). Treatment of acute HCV infection with IFN-α is successful in the vast majority of patients. However, the mechanisms responsible for treatment success have remained unexplained. Specifically, the role of CD8+ T cells during treatment of acute HCV infection has been controversial since previous studies described a decline in HCV-specific CD8+ T-cell numbers during acute HCV infection and antiviral treatment irrespective of treatment outcome. Badr et al. demonstrate that successful viral clearance is associated with a polyfunctional HCV-specific CD8+ T-cell response. Importantly, IFN-α treatment was able to convert previously monofunctional HCV-specific CD8+ T cells to polyfunctionality, providing a potential explanation for the mechanisms of IFN-α-related treatment success during acute HCV infection.

Tick-borne flaviviruses: dissecting host immune responses and virus countermeasures

The tick-borne encephalitis (TBE) serocomplex of viruses, genus Flavivirus, includes a number of important human pathogens that cause serious neurological illnesses and hemorrhagic fevers. These viruses pose a significant public health problem due to high rates of morbidity and mortality, their emergence to new geographic areas, and the recent rise in the incidence of human infections. The most notable member of the TBE serocomplex is tick-borne encephalitis virus (TBEV), a neurotropic flavivirus that causes debilitating and sometimes fatal encephalitis. Although effective prophylactic anti-TBEV vaccines have been developed, there is currently no specific treatment for infection. To identify new targets for therapeutical intervention, it is imperative to understand interactions between TBEV and the host immune response to infection. Interferon (IFN) has a critical role in controlling flavivirus replication. Dendritic cells (DCs) represent an early target of TBEV infection and are major producers of IFN. Thus, interactions between DCs, IFN responses, and the virus are likely to substantially influence the outcome of infection. Early IFN and DC responses are modulated not only by the virus, but also by the tick vector and immunomodulatory compounds of tick saliva inoculated with virus into the skin. Our laboratory is examining interactions between the triad of virus, tick vector, and mammalian host that contribute to the pathogenesis of tick-borne flaviviruses. This work will provide a more detailed understanding of early events in virus infection and their impact on flavivirus pathogenesis.

Early interferon therapy for hepatitis C virus infection rescues polyfunctional, long-lived CD8+ memory T cells.

The majority of acute hepatitis C virus (HCV) infections progress to chronicity and progressive liver damage. Alpha interferon (IFN-alpha) antiviral therapy achieves the highest rate of success when IFN-alpha is administered early during the acute phase, but the underlying mechanisms are unknown. We used a panel of major histocompatibility complex class I tetramers to monitor the phenotypic and functional signatures of HCV-specific T cells during acute HCV infection with different infection outcomes and during early IFN therapy. We demonstrate that spontaneous resolution correlates with the early development of polyfunctional (IFN-gamma- and IL-2-producing and CD107a(+)) virus-specific CD8(+) T cells. These polyfunctional T cells are distinguished by the expression of CD127 and Bcl-2 and represent a transitional memory T-cell subset that exhibits the phenotypic and functional signatures of both central and effector memory T cells. In contrast, HCV-specific CD8(+) T cells in acute infections evolving to chronicity expressed low levels of CD127 and Bcl-2, exhibited diminished proliferation and cytokine production, and eventually disappeared from the periphery. Early therapeutic intervention with pegylated IFN-alpha rescued polyfunctional memory T cells expressing high levels of CD127 and Bcl-2. These cells were detectable for up to 1 year following discontinuation of therapy. Our results suggest that the polyfunctionality of HCV-specific T cells can be predictive of the outcome of acute HCV infection and that early therapeutic intervention can reconstitute the pool of long-lived polyfunctional memory T cells.

Therapy of Acute Hepatitis C: A Review of Literature

The goal of treatment for acute hepatitis C patients is to eradicate the virus in the early phase of infection, thus preventing progression to chronicity. Early interferon (IFN) monotherapy has been shown to significantly reduce this risk, and therefore it has been recommended by international guidelines. To date, there is no standard treatment for the acute form of hepatitis C because available studies refer to small patient series receiving a variety of treatment regimens administered at varying time-points after onset of acute infection. Nevertheless, on the basis of published data, pegylated IFN monotherapy seems to offer the best therapeutic option because it is as effective as standard IFN monotherapy, and more convenient for the patient. Delaying treatment for 3 months after disease onset does not appear to reduce treatment efficacy and allows the identification of subjects with spontaneous resolution. It remains to be defined if an immediate treatment is more effective in patients with asymptomatic disease or those with genotype 1b. The optimal duration of Peg-IFN monotherapy should be 6 months. The efficacy of a 3-month course is under evaluation, especially for patients with clearance of HCV viremia within the first 4 weeks of therapy. There is no evidence that Peg-IFN/ribavirin combination therapy is more effective than Peg-IFN monotherapy, thus combination therapy might represent an alternative for patients who do not respond to IFN monotherapy or for HIV/HCV co-infected patients. Ongoing randomized controlled clinical trials should focus on unresolved questions and definitely establish the optimal treatment for acute hepatitis C.

Association of early post-transplant interferon levels and CMV infection after HSCT

Association of early post-transplant interferon levels and CMV infection after HSCT

Effectiveness of early beta interferon on the first attack after confirmed multiple sclerosis: A comparative cohort study

Background In the absence of randomized controlled trials to support therapeutic decisions in pediatric MS (multiple sclerosis), comparative observational studies based on the real practice of physicians are important tools. Aim To assess the effectiveness of beta interferon (ßIFN) in preventing the first attack and severe disability after confirmed MS diagnosis in a pediatric cohort. Methods A cohort of 197 relapsing-remitting pediatric MS patients was studied (1990-2005). Patients were followed from MS diagnosis until the first subsequent attack or severe disability occurrence ( DSS score of ⩾4) or were censored. The Cox model, with time-dependent ßIFN exposure to account for the varying times of starting this treatment, was used to estimate the effect of ßIFN on the risk of this attack or severe disability, adjusting for potential confounding factors. Results During cohort follow-up (mean 5.5 years), 70.5% of the 197 children had a first attack (80% within the first 2 years) and 24 started ßIFN (mean delay 3.6 months; mean duration 17.1 months). The use of ßIFN was associated with a significant reduction in the rate of the first attack during the first year of treatment (hazard ratio: 0.31, 95% confidence interval: 0.13–0.72) as well as the first 2 years (0.40, 0.20–0.83). This effect was less significant over the entire follow-up of up to 4 years of treatment (0.57, 0.30–1.10). The use of ßIFN suggests a reduction on the occurrence of severe disability, although not statistically significant ( HR 0.78; 95% CI: 0.25–2.42). Conclusions The use of ßIFN, given after the diagnosis of MS, significantly reduces the risk of relapse during the first 2 years.

Mycobacterium tuberculosis-Induced Gamma Interferon Production by Natural Killer Cells Requires Cross Talk with Antigen-Presenting Cells Involving Toll-Like Receptors 2 and 4 and the Mannose Receptor in Tuberculous Pleurisy

Tuberculous pleurisy allows the study of human cells at the site of active Mycobacterium tuberculosis infection. In this study, we found that among pleural fluid (PF) lymphocytes, natural killer (NK) cells are a major source of early gamma interferon (IFN-gamma) upon M. tuberculosis stimulation, leading us to investigate the mechanisms and molecules involved in this process. We show that the whole bacterium is the best inducer of IFN-gamma, although a high-molecular-weight fraction of culture filtrate proteins from M. tuberculosis H37Rv and the whole-cell lysate also induce its expression. The mannose receptor seems to mediate the inhibitory effect of mannosylated lipoarabinomannan, and Toll-like receptor 2 and 4 agonists activate NK cells but do not induce IFN-gamma like M. tuberculosis does. Antigen-presenting cells (APC) and NK cells bind M. tuberculosis, and although interleukin-12 is required, it is not sufficient to induce IFN-gamma expression, indicating that NK cell-APC contact takes place. Indeed, major histocompatibility complex class I, adhesion, and costimulatory molecules as well as NK receptors regulate IFN-gamma induction. The signaling pathway is partially inhibited by dexamethasone and sensitive to Ca2+ flux and cyclosporine. Inhibition of p38 and extracellular-regulated kinase mitogen-activated protein kinase pathways reduces the number of IFN-gamma+ NK cells. Phosphorylated p38 (p-p38) is detected in ex vivo PF-NK cells, and M. tuberculosis triggers p-p38 in PF-NK cells at the same time that binding between NK and M. tuberculosis reaches its maximum value. Thus, interplay between M. tuberculosis and NK cells/APC triggering IFN-gamma would be expected to play a beneficial role in tuberculous pleurisy by helping to maintain a type 1 profile.

Early interferon-??-1b of BENEFIT for MS?

Early interferon-??-1b of BENEFIT for MS?

Effect of early versus delayed interferon beta-1b treatment on disability after a first clinical event suggestive of multiple sclerosis: a 3-year follow-up analysis of the BENEFIT study

Several controlled studies provide evidence that treatment with interferon beta in patients with a first event suggestive of multiple sclerosis (MS) delays conversion to clinically definite MS (CDMS). Our aim was to determine whether early initiation of treatment with interferon beta prevents development of confirmed disability in MS. In the initial placebo-controlled phase of the double-blinded BENEFIT study, patients with a first event suggestive of MS and a minimum of two clinically silent lesions in MRI were randomised to receive either interferon beta-1b 250 microg (n=292) or placebo (n=176) subcutaneously every other day for 2 years, or until diagnosis of CDMS. Patients were then eligible to enter the follow-up phase with open-label interferon beta-1b. In the current prospectively planned analysis 3 years after randomisation, the effects of early interferon beta-1b treatment were compared with those of delayed treatment initiated after diagnosis of CDMS or after 2 years on the study. The primary outcomes of this ITT analysis were time to diagnosis of CDMS, time to confirmed expanded disability status scale (EDSS) progression, and score on a patient-reported functional assessment scale (FAMS-TOI). This trial is registered with ClinicalTrials.gov, number NCT00185211. Of the 468 patients originally randomised, 418 (89%) entered the follow-up phase; 392 (84%) completed 3 years' post-randomisation follow-up. After 3 years, 99 (37%) patients in the early group developed CDMS compared with 85 (51%) patients in the delayed treatment group. Early treatment reduced the risk of CDMS by 41% (hazard ratio 0.59, 95% CI 0.44-0.80; p=0.0011; absolute risk reduction 14%) compared with delayed treatment. Over 3 years, 42 (16%) patients in the early group and 40 (24%) in the delayed group had confirmed EDSS progression; early treatment reduced the risk for progression of disability by 40% compared with delayed treatment (0.60, 0.39-0.92; p=0.022; absolute risk reduction 8%). The FAMS-TOI score was high and stable in both groups over the 3-year period (p=0.31). Our data suggest that early initiation of treatment with interferon beta-1b prevents the development of confirmed disability, supporting its use after the first manifestation of relapsing-remitting MS.

Effect of early interferon beta-1a therapy on conversion to multiple sclerosis in Iranian patients with a first demyelinating event

A new treatment approach to multiple sclerosis (MS) is the initiation of interferon therapy in the early phase of the disease when a patient presents with clinically isolated syndrome. The goal of this study was to assess the effect of early treatment on the risk of conversion to clinically definite MS in Iranian patients. Eligible patients had presented with a first episode of neurological dysfunction suggesting MS within the previous 3 months and had abnormal brain magnetic resonance imaging (MRI). Patients were randomly assigned to receive intramuscular interferon beta 1a 30 mug or placebo once a week for 3 years. Of the 217 patients randomized, 202 patients completed the study; 104 received Avonex and 98 received placebo. Fewer patients converted to clinically definite multiple sclerosis in the treated group than in the placebo group during the study (36.6% vs 58.2%, P < 0.003). The number of active T2-weighted MRI lesions was significantly lower in the treated group. The results of our study, which are consistent with those from western studies, show that treatment at an early stage of MS delays conversion to definite MS and has positive effects on MRI outcomes.

Group 2 coronaviruses prevent immediate early interferon induction by protection of viral RNA from host cell recognition

Many viruses encode antagonists to prevent interferon (IFN) induction. Infection of fibroblasts with the murine hepatitis coronavirus (MHV) and SARS-coronavirus (SARS-CoV) did not result in nuclear translocation of interferon-regulatory factor 3 (IRF3), a key transcription factor involved in IFN induction, and induction of IFN mRNA transcription. Furthermore, MHV and SARS-CoV infection could not prevent IFN induction by poly (I:C) or Sendai virus, suggesting that these CoVs do not inactivate IRF3-mediated transcription regulation, but apparently prevent detection of replicative RNA by cellular sensory molecules. Our data indicate that shielding of viral RNA to host cell sensors might be the main general mechanism for coronaviruses to prevent IFN induction.

Characterization of Early Gamma Interferon (IFN-γ) Expression during Murine Listeriosis: Identification of NK1.1+CD11c+Cells as the Primary IFN-γ-Expressing Cells

Though it is well established that gamma interferon (IFN-gamma) is crucial to the early innate defense of murine listeriosis, its sources remain controversial. In this study, intracellular cytokine staining of IFN-gamma-expressing splenocytes early after Listeria monocytogenes infection revealed that NK1.1(+), CD11c(+), CD8(+) T, and CD4(+) T cells expressed IFN-gamma 24 h after infection. Contrary to the previous report, most IFN-gamma(+) dendritic cells (DC) were CD8alpha(-) DC. Unexpectedly, almost all CD11c(+) IFN-gamma-expressing cells also expressed NK1.1. These NK1.1(+) CD11c(+) cells represented primary IFN-gamma-expressing cells after infection. In situ studies showed these NK1.1(+) CD11c(+) cells were recruited to the borders of infectious foci and expressed IFN-gamma. A significant NK1.1(+) CD11c(+) population was found in uninfected spleen, lymph node, blood, and bone marrow cells. And its number increased significantly in spleen, lymph node, and bone marrow after L. monocytogenes infection. Using interleukin-12 (IL-12) p40(-/-) mice, IFN-gamma expression was found to be largely IL-12 p40 dependent, and the number of IFN-gamma-expressing cells was only about one-third of that of wild-type mice. Moreover, the IFN-gamma expression was absolutely dependent on live L. monocytogenes infection, as no IFN-gamma was detected after inoculation of heat-killed L. monocytogenes. Our findings not only provide an insight into IFN-gamma expression after in vivo infection but may also change the current perceptions of DC and natural killer cells.

Retinoic Acid-Inducible Gene I Mediates Early Antiviral Response and Toll-Like Receptor 3 Expression in Respiratory Syncytial Virus-Infected Airway Epithelial Cells

Respiratory syncytial virus (RSV) is one of the most common viral pathogens causing severe lower respiratory tract infections in infants and young children. Infected host cells detect and respond to RNA viruses using different mechanisms in a cell-type-specific manner, including retinoic acid-inducible gene I (RIG-I)-dependent and Toll-like receptor (TLR)-dependent pathways. Because the relative contributions of these two pathways in the recognition of RSV infection are unknown, we examined their roles in this study. We found that RIG-I helicase binds RSV transcripts within 12 h of infection. Short interfering RNA (siRNA)-mediated RIG-I "knockdown" significantly inhibited early nuclear factor-kappaB (NF-kappaB) and interferon response factor 3 (IRF3) activation 9 h postinfection (p.i.). Consistent with this finding, RSV-induced beta interferon (IFN-beta), interferon-inducible protein 10 (IP-10), chemokine ligand 5 (CCL-5), and IFN-stimulated gene 15 (ISG15) expression levels were decreased in RIG-I-silenced cells during the early phase of infection but not at later times (18 h p.i.). In contrast, siRNA-mediated TLR3 knockdown did not affect RSV-induced NF-kappaB binding but did inhibit IFN-beta, IP-10, CCL-5, and ISG15 expression at late times of infection. Further studies revealed that TLR3 knockdown significantly reduced NF-kappaB/RelA transcription by its ability to block the activating phosphorylation of NF-kappaB/RelA at serine residue 276. We further found that TLR3 induction following RSV infection was regulated by RIG-I-dependent IFN-beta secreted from infected airway epithelial cells and was mediated by both IFN response-stimulated element (ISRE) and signal transducer and activator of transcription (STAT) sites in its proximal promoter. Together these findings indicate distinct temporal roles of RIG-I and TLR3 in mediating RSV-induced innate immune responses, which are coupled to distinct pathways controlling NF-kappaB activation.

Long-term subcutaneous interferon beta-1a therapy in patients with relapsing-remitting MS

To conduct systematic long-term follow-up (LTFU) of patients in the Prevention of Relapses and Disability by Interferon beta-1a Subcutaneously in Multiple Sclerosis (PRISMS) study to provide up to 8 years of safety, clinical and MRI outcomes on subcutaneous (s.c.) interferon (IFN) beta-1a in relapsing-remitting multiple sclerosis (RRMS). The original cohort of 560 patients was randomized to IFNbeta-1a, 44 or 22 microg three times weekly (TIW) or to placebo; after 2 years, patients on placebo were rerandomized to active treatment and the blinded study continued for a further 4 years. The LTFU visit was scheduled 7 to 8 years after baseline. LTFU was attended by 68.2% of the original PRISMS study cohort (382/560 patients). 72.0% (275/382) were still receiving IFNbeta-1a s.c. TIW. Patients originally randomized to IFNbeta-1a 44 microg s.c. TIW showed lower Expanded Disability Status Scale progression, relapse rate and T2 burden of disease up to 8 years compared with those in the late treatment group. Brain parenchymal volume did not show differences by treatment group. Overall, 19.7% of patients progressed to secondary progressive MS between baseline and LTFU (75/381). No new safety concerns were identified and treatment was generally well tolerated. Despite the limitations inherent in any long-term study (for example, potential differences between returning and nonreturning patients), these results indicate that patients with relapsing-remitting multiple sclerosis can experience sustained benefit over many years from early interferon beta-1a subcutaneous therapy three times weekly compared with patients whose treatment is delayed. This effect was more apparent in the patients receiving the higher dose.

The Pathogenic NY-1 Hantavirus G1 Cytoplasmic Tail Inhibits RIG-I- and TBK-1-Directed Interferon Responses

Hantaviruses cause two diseases with prominent vascular permeability defects, hemorrhagic fever with renal syndrome and hantavirus pulmonary syndrome. All hantaviruses infect human endothelial cells, although it is unclear what differentiates pathogenic from nonpathogenic hantaviruses. We observed dramatic differences in interferon-specific transcriptional responses between pathogenic and nonpathogenic hantaviruses at 1 day postinfection, suggesting that hantavirus pathogenesis may in part be determined by viral regulation of cellular interferon responses. In contrast to pathogenic NY-1 virus (NY-1V) and Hantaan virus (HTNV), nonpathogenic Prospect Hill virus (PHV) elicits early interferon responses following infection of human endothelial cells. We determined that PHV replication is blocked in human endothelial cells and that RNA and protein synthesis by PHV, but not NY-1V or HTNV, is inhibited at 2 to 4 days postinfection. The addition of antibodies to beta interferon (IFN-beta) blocked interferon-directed MxA induction by >90% and demonstrated that hantavirus infection induces the secretion of IFN-beta from endothelial cells. Coinfecting endothelial cells with NY-1V and PHV resulted in a 60% decrease in the induction of interferon-responsive MxA transcripts by PHV and further suggested the potential for NY-1V to regulate early IFN responses. Expression of the NY-1V G1 cytoplasmic tail inhibited by >90% RIG-I- and downstream TBK-1-directed transcription from interferon-stimulated response elements or beta-interferon promoters in a dose-dependent manner. In contrast, expression of the NY-1V nucleocapsid or PHV G1 tail had no effect on RIG-I- or TBK-1-directed transcriptional responses. Further, neither the NY-1V nor PHV G1 tails inhibited transcriptional responses directed by a constitutively active form of interferon regulatory factor 3 (IRF-3 5D), and IRF-3 is a direct target of TBK-1 phosphorylation. These findings indicate that the pathogenic NY-1V G1 protein regulates cellular IFN responses upstream of IRF-3 phosphorylation at the level of the TBK-1 complex. These findings further suggest that the G1 cytoplasmic tail contains a virulence element which determines the ability of hantaviruses to bypass innate cellular immune responses and delineates a mechanism for pathogenic hantaviruses to successfully replicate within human endothelial cells.