Dynamic Changes in Pro- and Anti-Inflammatory Cytokine Profiles and Gamma Interferon Receptor Signaling Integrity Correlate with Tuberculosis Disease Activity and Response to Curative Treatment

ABSTRACT Pro- and anti-inflammatory cytokines and their signaling pathways play key roles in protection from and pathogenesis of mycobacterial infection, and their balance and dynamic changes may control or predict clinical outcome. Peripheral blood cells' capacity to produce proinflammatory (tumor necrosis factor alpha [TNF-α], interleukin-12/23p40 [IL-12/23p40], and gamma interferon [IFN-γ]) and anti-inflammatory (IL-10) cytokines in response to Mycobacterium tuberculosis or unrelated stimuli (lipopolysaccharide, phytohemagglutinin) was studied in 93 pulmonary tuberculosis (TB) patients and 127 healthy controls from Indonesia. Their cells' ability to respond to IFN-γ was examined to investigate whether M. tuberculosis infection can also inhibit IFN-γ receptor (IFN-γR) signaling. Although there was interindividual variability in the observed responses, the overall results revealed that M. tuberculosis-induced TNF-α and IFN-γ levels showed opposite trends. Whereas TNF-α production was higher in active-TB patients than in controls, IFN-γ production was strongly depressed during active TB, correlated inversely with TB disease severity, and increased during therapy. By contrast, mitogen-induced IFN-γ production, although lower in patients than in controls, did not change during treatment, suggesting an M. tuberculosis-specific and reversible component in the depression of IFN-γ. Depressed IFN-γ production was not due to decreased IL-12/IL-23 production. Importantly, IFN-γ-inducible responses were also significantly depressed during active TB and normalized during treatment, revealing disease activity-related and reversible impairment in IFN-γR signaling in TB. Finally, IFN-γ/IL-10 ratios significantly correlated with TB cure. Taken together, these results show that M. tuberculosis-specific stimulation of IFN-γ (but not TNF-α) production and IFN-γR signaling are significantly depressed in active TB, correlate with TB disease severity and activity, and normalize during microbiological TB cure. The depression of both IFN-γ production and IFN-γR signaling may synergize in contributing to defective host control in active TB.

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Interleukin-12 Promotes Gamma Interferon-Dependent Neutrophil Recruitment in the Lung and Improves Protection against Respiratory Streptococcus pneumoniae Infection

Infection and Immunity ◽

10.1128/iai.01403-06 ◽

2007 ◽

Vol 75 (3) ◽

pp. 1196-1202 ◽

Cited By ~ 105

Author(s):

Keer Sun ◽

Sharon L. Salmon ◽

Steven A. Lotz ◽

Dennis W. Metzger

Keyword(s):

Streptococcus Pneumoniae ◽

Survival Rates ◽

Gamma Interferon ◽

Neutrophil Recruitment ◽

Interleukin 12 ◽

Necrosis Factor Alpha ◽

Innate Defense ◽

Tnf Α ◽

Ifn Γ

ABSTRACT The ability of exogenous interleukin-12 (IL-12) to elicit protective innate immune responses against the extracellular pathogen Streptococcus pneumoniae was tested by infecting BALB/c mice intranasally (i.n.) with S. pneumoniae after i.n. administration of IL-12. It was found that administration of IL-12 resulted in lower bacterial burdens in the infected mice and significantly improved survival rates. All IL-12-treated mice contained higher levels of pulmonary gamma interferon (IFN-γ) after infection and significantly more neutrophils than infected mice not treated with IL-12. IFN-γ was found to be essential for IL-12-induced resistance and for neutrophil influx into the lungs, and the observed changes correlated with increased levels of the IL-8 homologue keratinocyte-derived chemokine (KC). In addition, in vitro tumor necrosis factor alpha (TNF-α) production by alveolar macrophages stimulated with heat-killed pneumococci was enhanced by IFN-γ, and TNF-α in turn could enhance production of KC by lung cells. Finally, IL-12-induced protection was dependent upon the presence of neutrophils and the KC receptor CXCR2. Taken together, the results indicate that exogenous IL-12 can improve innate defense in the lung against S. pneumoniae by inducing IFN-γ production, which in turn enhances chemokine expression, and promotes pulmonary neutrophil recruitment into the infected lung. The findings show that IL-12 and IFN-γ can mediate a protective effect against respiratory infection caused by extracellular bacterial pathogens.

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Gamma Interferon and Lipopolysaccharide Interact at the Level of Transcription To Induce Tumor Necrosis Factor Alpha Expression

Infection and Immunity ◽

10.1128/iai.69.5.2847-2852.2001 ◽

2001 ◽

Vol 69 (5) ◽

pp. 2847-2852 ◽

Cited By ~ 18

Author(s):

Julia Y. Lee ◽

Kathleen E. Sullivan

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Gamma Interferon ◽

Necrosis Factor Alpha ◽

Rnase Protection ◽

Tnf Α ◽

Factor Alpha ◽

Ifn Γ ◽

Necrosis Factor

ABSTRACT Lipopolysaccharide (LPS) is a very potent inducer of tumor necrosis factor alpha (TNF-α) expression from monocytes and macrophages. Another inflammatory cytokine, gamma interferon (IFN-γ), can potentiate the effects of LPS, but the mechanism is not thoroughly understood. Previous reports emphasized the ability of IFN-γ to upregulate CD14 expression (the receptor for LPS), and nearly all studies have utilized sequential stimulation with IFN-γ followed by LPS to exploit this phenomenon. This study demonstrates that IFN-γ can upregulate the effect of LPS at the level of transcription. Human monoblastic Mono-Mac-6 cells produced up to threefold-greater levels of TNF-α when simultaneously stimulated with LPS and IFN-γ compared to treatment with LPS alone. RNase protection studies showed a similar increase in RNA beginning as early as within 30 min. The synthesis of TNF-α mRNA in IFN-γ- and LPS-treated Mono-Mac-6 cells was also temporally prolonged even though the message turnover rate was identical to that seen in LPS stimulated cells. The modulatory effect of IFN-γ may be mediated by Jak2.

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INHIBITORY EFFECTS ON TUMOR NECROSIS FACTOR ALPHA AND INTERLEUKIN 12 USING CLOBETASOL PROPIONATE LOADED TEA TREE OIL NANOEMULSION GEL ON ANIMAL MODEL

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i6.24888 ◽

2018 ◽

Vol 11 (6) ◽

pp. 182

Author(s):

Md Sarfaraz Alam ◽

Mohamammad Daud Ali ◽

Md Salahuddin Ansari ◽

Pankaj Sharma

Keyword(s):

Clobetasol Propionate ◽

Interleukin 12 ◽

Tea Tree Oil ◽

Necrosis Factor Alpha ◽

Tea Tree ◽

Tnf Α ◽

Nanoemulsion Gel ◽

Factor Alpha ◽

Anti Inflammatory ◽

Necrosis Factor

Objective: The main objective of our study is to explore anti-inflammatory activity at its molecular level like tumor necrosis factor alpha (TNF-α), interleukin 12 (IL-12) expression, and histopathological study.Methods: As per solubility/miscibility of clobetasol propionate (CP) with tea tree oil (TTO), surfactant and cosurfactant (Smix), and water in a ratio of oil:Smix:water (15:35:50) taken in milliliter for the preparation of nanoemulsion. Induced allergic contact dermatitis (ACD) with dinitrofluorobenzene (DNFB) was used for the study. TNF-α and interleukin 12 (IL-12) were estimated with rabbit antimouse TNF-α and rat antimouse IL-12 antibodies in 1% of bovine serum albumin in phosphate buffer.Results: Topical application of CP loaded nanoemulsion gel inhibits ear inflammation and erythema in DNFB-induced ACD in mice and significantly reduces the intracellular edema and infiltration with inflammatory mediator cells involving of mononuclear cells and neutrophils. CP loaded nanoemulsion gel reduces expression of protein level of TNF-α and IL-12.Conclusion: CP loaded nanoemulsion gel confirmed that anti-inflammatory effects showed more rapidly than the placebo and marketed gel preparation. However, the animals treated with placebo nanoemulsion gel showed a somehow comparable reduction of their inflammation during treatment compared with the marketed gel. This effect may be due to anti-inflammatory effect of TTO. This result suggested that anti-inflammatory activity of placebo nanoemulsion gel may be due to TTO present in nanoemulsion as vehicle.

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Simultaneous Measurement of Antigen-Stimulated Interleukin-1β and Gamma Interferon Production Enhances Test Sensitivity for the Detection of Mycobacterium bovis Infection in Cattle

Clinical and Vaccine Immunology ◽

10.1128/cvi.00377-10 ◽

2010 ◽

Vol 17 (12) ◽

pp. 1946-1951 ◽

Cited By ~ 19

Author(s):

Gareth J. Jones ◽

Chris Pirson ◽

R. Glyn Hewinson ◽

H. Martin Vordermeier

Keyword(s):

Mycobacterium Bovis ◽

Gamma Interferon ◽

Interleukin 1Β ◽

Induced Responses ◽

Readout System ◽

Necrosis Factor Alpha ◽

Test Sensitivity ◽

Inflammatory Protein ◽

Tnf Α ◽

Ifn Γ

ABSTRACT In order to identify cytokines that may be useful as candidates for inclusion in diagnostic tests for Mycobacterium bovis infection in cattle, we compared the levels of gamma interferon (IFN-γ), interleukin 1β (IL-1β), IL-4, IL-10, IL-12, macrophage inflammatory protein 1β (MIP-1β), and tumor necrosis factor alpha (TNF-α) in whole-blood cultures from tuberculosis (TB) reactor animals or TB-free controls following stimulation with M. bovis-specific antigens (purified protein derivative from M. bovis [PPD-B] or ESAT-6/CFP-10). In addition to IFN-γ responses, the production of IL-1β and TNF-α was also statistically significantly elevated in TB reactor cattle over that in uninfected controls following stimulation with PPD-B or ESAT-6/CFP-10 peptides. Thus, we evaluated whether the use of these two additional readouts could disclose further animals not detected by measuring IFN-γ alone. To this end, receiver operating characteristic (ROC) analyses were performed to define diagnostic cutoffs for positivity for TNF-α and IL-1β. These results revealed that for ESAT-6/CFP-10-induced responses, the use of all three readouts (IFN-γ, TNF-α, and IL-1β) in parallel increased the sensitivity of detection of M. bovis-infected animals by 11% but also resulted in a specificity decrease of 14%. However, applying only IFN-γ and IL-1β in parallel resulted in a 5% increase in sensitivity without the corresponding loss of specificity. The results for PPD-B-induced responses were similar, although the loss of specificity was more pronounced, even when only IFN-γ and IL-1β were used as readout systems. In conclusion, we have demonstrated that the use of an additional readout system, such as IL-1β, can potentially complement IFN-γ by increasing overall test sensitivity for the detection of M. bovis infection in cattle.

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Clinical and Immunologic Features of an Atypical Intracranial Mycobacterium avium Complex (MAC) Infection Compared with Those of Pulmonary MAC Infections

Clinical and Vaccine Immunology ◽

10.1128/cvi.00173-08 ◽

2008 ◽

Vol 15 (10) ◽

pp. 1580-1589 ◽

Cited By ~ 5

Author(s):

Mouhannad Sadek ◽

Feng Yun Yue ◽

Erika Yue Lee ◽

Gabor Gyenes ◽

R. Brad Jones ◽

...

Keyword(s):

T Cell ◽

Mycobacterium Avium ◽

The Body ◽

Interleukin 12 ◽

Elderly Persons ◽

Necrosis Factor Alpha ◽

Healthy Elderly ◽

Tnf Α ◽

Ifn Γ ◽

The Individual

ABSTRACT Members of the Mycobacterium avium complex (MAC) may cause chronic pulmonary infections in otherwise healthy elderly persons but rarely invade parts of the body outside of the lungs in immunocompetent hosts. We present a case of an isolated intracranial MAC infection in an apparently immunocompetent individual and review previous reports. We studied the T-cell and monocyte responses in healthy volunteers, individuals with a pulmonary MAC infection, and one individual with an isolated intracranial MAC infection. Genomic DNA from the individual with the brain MAC infection was studied for gamma interferon (IFN-γ) receptor mutations. Individuals with localized pulmonary MAC infections showed increased activation of monocytes and enhanced monocyte and T-cell tumor necrosis factor alpha (TNF-α) production in response to lipopolysaccharide and MAC antigens but defects in T-cell IFN-γ secretion. The individual with an intracranial MAC infection showed a lack of monocyte activation and deficiencies in both monocyte and T-cell TNF-α production and monocyte interleukin-12 (IL-12) production but had preserved T-cell IFN-γ production. Mutations or deletions in the IFN-γ receptor were not detected in the individual with the intracranial MAC infection. Our data suggest that distinct immune defects characterize two different manifestations of MAC infection. A relative defect in IFN-γ production in response to MAC may predispose an individual to localized but partially controlled lung disease, whereas defects leading to reduced IL-12 and TNF-α production may allow the dissemination of MAC. Further studies delineating the potential role of TNF-α in limiting the spread of MAC outside the lung are warranted.

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Respiratory Tract Infection with Mycoplasma pneumoniae in Interleukin-12 Knockout Mice Results in Improved Bacterial Clearance and Reduced Pulmonary Inflammation

Infection and Immunity ◽

10.1128/iai.01249-06 ◽

2006 ◽

Vol 75 (1) ◽

pp. 236-242 ◽

Cited By ~ 19

Author(s):

C. M. Salvatore ◽

M. Fonseca-Aten ◽

K. Katz-Gaynor ◽

A. M. Gomez ◽

A. Mejias ◽

...

Keyword(s):

Respiratory Disease ◽

Mycoplasma Pneumoniae ◽

Pulmonary Inflammation ◽

Airway Hyperreactivity ◽

Interleukin 12 ◽

Enzyme Linked Immunosorbent Assay ◽

Wild Type ◽

Necrosis Factor Alpha ◽

Tnf Α ◽

Ifn Γ

ABSTRACT Mycoplasma pneumoniae is a leading cause of pneumonia and is associated with asthma. Evidence links M. pneumoniae respiratory disease severity with interleukin-12 (IL-12) concentration in respiratory secretions. We evaluated the microbiologic, inflammatory, and pulmonary function indices of M. pneumoniae pneumonia in IL-12 (p35) knockout (KO) mice and wild-type (WT) mice to determine the role of IL-12 in M. pneumoniae respiratory disease. Eight-week-old wild-type BALB/c mice and 8-week-old IL-12 (p35) KO BALB/c mice were inoculated once intranasally with 107 CFU of M. pneumoniae. Mice were evaluated at days 2, 4, and 7 after inoculation. Outcome variables included quantitative bronchoalveolar lavage (BAL) M. pneumoniae culture, lung histopathologic scores (HPS), BAL cytokine concentrations determined by enzyme-linked immunosorbent assay (tumor necrosis factor alpha [TNF-α], gamma interferon [IFN-γ], IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, and granulocyte-macrophage colony-stimulating factor) and plethysmography, before and after methacholine, to assess airway obstruction (AO) and airway hyperreactivity (AHR). IL-12 (p35) KO mice infected with M. pneumoniae were found to have significantly lower BAL M. pneumoniae concentrations compared with M. pneumoniae-infected WT mice. Lung HPS and the parenchymal pneumonia subscores (neutrophilic alveolar infiltrate), as well as AO, were significantly lower in infected KO mice. No difference was found for AHR. Infected KO mice had significantly lower BAL concentrations of IFN-γ than WT mice; a trend toward lower BAL concentrations was observed for IL-10 (P = 0.065) and TNF-α (P = 0.078). No differences were found for IL-1β, IL-2, IL-4, IL-5, or IL-6. The lack of IL-12 in experimental M. pneumoniae pneumonia was associated with less severe pulmonary disease and more rapid microbiologic and histologic resolution.

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Toll-Like Receptor 9 Is Required for Full Host Resistance toMycobacteriumaviumInfection but Plays No Role in Induction of Th1 Responses

Infection and Immunity ◽

10.1128/iai.01030-10 ◽

2011 ◽

Vol 79 (4) ◽

pp. 1638-1646 ◽

Cited By ~ 25

Author(s):

Natália B. Carvalho ◽

Fernanda S. Oliveira ◽

Fernanda V. Durães ◽

Leonardo A. de Almeida ◽

Manuela Flórido ◽

...

Keyword(s):

Interleukin 12 ◽

Toll Like Receptor ◽

Necrosis Factor Alpha ◽

Histocompatibility Complex ◽

Tnf Α ◽

Factor Alpha ◽

Ifn Γ ◽

Myd88 Signaling ◽

Necrosis Factor

ABSTRACTTo investigate the role of Toll-like receptor 9 (TLR9) in innate immunity toMycobacteriumavium, TLR9, TLR2, and MyD88 knockout (KO) mice were infected with this bacterium. Bacterial burdens were higher in the spleens, livers, and lungs of infected TLR9 KO mice than in those of C57BL/6 mice, indicating that TLR9 is required for efficient control ofM.aviuminfection. However, TLR9 KO or TLR2 KO spleen cells displayed normalM.avium-induced tumor necrosis factor alpha (TNF-α) and gamma interferon (IFN-γ) responses. This finding was confirmed by determining the number of splenic CD4+T cells producing IFN-γ by flow cytometry. Furthermore, TLR2 and MyD88, but not TLR9, played a major role in interleukin-12 and TNF-α production byM.avium-infected macrophages and dendritic cells (DCs). We also found that major histocompatibility complex class II molecule expression on DCs is regulated by TLR2 and MyD88 signaling but not by TLR9. Finally, lack of TLR9, TLR2, or MyD88 reduced the numbers of macrophages, epithelioid cells, and lymphocytes inM.avium-induced granulomas but only MyD88 deficiency affected the number of liver granulomas. In summary, our data demonstrated that the involvement of TLR9 in the control ofM.aviuminfection is not related to the induction of Th1 responses.

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In Vivo Regulation of Replicative Legionella pneumophila Lung Infection by Endogenous Interleukin-12

Infection and Immunity ◽

10.1128/iai.66.1.65-69.1998 ◽

1998 ◽

Vol 66 (1) ◽

pp. 65-69 ◽

Cited By ~ 52

Author(s):

J. K. Brieland ◽

D. G. Remick ◽

M. L. LeGendre ◽

N. C. Engleberg ◽

J. C. Fantone

Keyword(s):

Legionella Pneumophila ◽

Lung Infection ◽

Interleukin 12 ◽

Necrosis Factor Alpha ◽

Protein Levels ◽

Tnf Α ◽

Factor Alpha ◽

Ifn Γ

ABSTRACT The in vivo role of endogenous interleukin 12 (IL-12) in modulating intrapulmonary growth of Legionella pneumophila was assessed by using a murine model of replicative L. pneumophila lung infection. Intratracheal inoculation of A/J mice with virulent bacteria (106 L. pneumophilacells per mouse) resulted in induction of IL-12, which preceded clearance of the bacteria from the lung. Inhibition of endogenous IL-12 activity, via administration of IL-12 neutralizing antiserum, resulted in enhanced intrapulmonary growth of the bacteria within 5 days postinfection (compared to untreated L. pneumophila-infected mice). Because IL-12 has previously been shown to modulate the expression of cytokines, including gamma interferon (IFN-γ), tumor necrosis factor alpha (TNF-α), and IL-10, which regulate L. pneumophila growth, immunomodulatory effects of endogenous IL-12 on intrapulmonary levels of these cytokines during replicative L. pneumophila lung infection were subsequently assessed. Results of these experiments demonstrated that TNF-α activity was significantly lower, while protein levels of IFN-γ and IL-10 in the lung were similar, in L. pneumophila-infected mice administered IL-12 antiserum, compared to similarly infected untreated mice. Together, these results demonstrate that IL-12 is critical for resolution of replicativeL. pneumophila lung infection and suggest that regulation of intrapulmonary growth of L. pneumophila by endogenous IL-12 is mediated, at least in part, by TNF-α.

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Gamma Interferon (IFN-γ) and IFN-γ-Inducing Cytokines Interleukin-12 (IL-12) and IL-18 Do Not Augment Infection-Stimulated Bone Resorption In Vivo

Clinical and Diagnostic Laboratory Immunology ◽

10.1128/cdli.11.1.106-110.2004 ◽

2004 ◽

Vol 11 (1) ◽

pp. 106-110 ◽

Cited By ~ 36

Author(s):

Hajime Sasaki ◽

Khaled Balto ◽

Nobuyuki Kawashima ◽

Jean Eastcott ◽

Katsuaki Hoshino ◽

...

Keyword(s):

Bone Resorption ◽

Alveolar Bone ◽

Interleukin 1 ◽

Bone Destruction ◽

Gamma Interferon ◽

Interleukin 12 ◽

Wild Type ◽

Necrosis Factor Alpha ◽

Ifn Γ

ABSTRACT Periapical granulomas are induced by bacterial infection of the dental pulp and result in destruction of the surrounding alveolar bone. In previous studies we have reported that the bone resorption in this model is primarily mediated by macrophage-expressed interleukin-1 (IL-1). The expression and activity of IL-1 is in turn modulated by a network of Th1 and Th2 regulatory cytokines. In the present study, the functional roles of the Th1 cytokine gamma interferon (IFN-γ) and IFN-γ-inducing cytokines IL-12 and IL-18 were determined in a murine model of periapical bone destruction. IL-12−/−, IL-18−/−, and IFN-γ−/− mice were subjected to surgical pulp exposure and infection with a mixture of four endodontic pathogens, and bone destruction was determined by microcomputed tomography on day 21. The results indicated that all IL-12−/−, IL-18−/−, and IFN-γ−/− mice had similar infection-stimulated bone resorption in vivo as wild-type control mice. Mice infused with recombinant IL-12 also had resorption similar to controls. IFN-γ−/− mice exhibited significant elevations in IL-6, IL-10, IL-12, and tumor necrosis factor alpha in lesions compared to wild-type mice, but these modulations had no net effect on IL-1α levels. Recombinant IL-12, IL-18, and IFN-γ individually failed to consistently modulate macrophage IL-1α production in vitro. We conclude that, at least individually, endogenous IL-12, IL-18, and IFN-γ do not have a significant effect on the pathogenesis of infection-stimulated bone resorption in vivo, suggesting possible functional redundancy in proinflammatory pathways.

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Immunomodulatory Effects of Inactivated Parapoxvirus Ovis (Orf Virus) on Human Peripheral Immune Cells: Induction of Cytokine Secretion in Monocytes and Th1-Like Cells

Journal of Virology ◽

10.1128/jvi.78.17.9400-9411.2004 ◽

2004 ◽

Vol 78 (17) ◽

pp. 9400-9411 ◽

Cited By ~ 37

Author(s):

Astrid Friebe ◽

Angela Siegling ◽

Sonja Friederichs ◽

Hans-Dieter Volk ◽

Olaf Weber

Keyword(s):

Immune Cells ◽

Cytokine Secretion ◽

Orf Virus ◽

Proinflammatory Response ◽

Necrosis Factor Alpha ◽

Virus Particles ◽

Tnf Α ◽

Ifn Γ ◽

Anti Inflammatory ◽

Parapoxvirus Ovis

ABSTRACT Inactivated parapoxvirus ovis (Orf virus; PPVO) recently displayed strong immunostimulating and modulating capacities in several animal models for acute and chronic virus infections through the induction of gamma interferon (IFN-γ) as a key mediator of antiviral activity. The data presented in this work demonstrate that inactivated PPVO has strong effects on cytokine secretion by human immune cells, including the upregulation of inflammatory and Th1-related cytokines (IFN-γ, tumor necrosis factor alpha [TNF-α], interleukin 6 [IL-6], IL-8, IL-12, and IL-18) as well as anti-inflammatory and Th2-related cytokines (IL-4, IL-10, and IL-1 receptor antagonist [IL-1ra]). Studies on the mechanism of action revealed virus particles to be the effective components of the preparation. The virus particles activate monocytes or other antigen-presenting cells (APC), e.g., plasmacytoid dendritic cells, through signaling over CD14 and a Toll-like receptor and the intracellular presence of certain PPVO-specific components. The activation of monocytes or APC is followed by the release of early proinflammatory cytokines (TNF-α, IL-6, and IL-8) as well as the Th1-related cytokines IL-12 and IL-18. Both IL-18 and IL-12 are involved in PPVO-mediated IFN-γ release by T cells and/or NK cells. The proinflammatory response is accompanied by the induction of anti-inflammatory and Th2-related cytokines (IL-4, IL-10, and IL-1ra), which exert a limiting efffect on the inflammatory response induced by PPVO. We conclude that the induction of a natural immune response with physiologically significant amounts of different cytokines and with antiviral potential might provide advantages over existing antiviral immunotherapies.

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