Advances in Antiviral Therapies Targeting Toll-like Receptors

ABSTRACT Introduction: Organisms have evolved a rapid and non-specific way to defend themselves via Toll-like receptors (TLRs), which recognize specific signatures present on invading microbes and viruses. Once detected, these receptors flood the cell with cytokines and IFNs that not only help to eradicate the invading viruses but also activate the adaptive immune response. Owing to difficulties in viral detection, a whole class of TLRs is dedicated to sensing viral nucleic acids, while other TLRs detect viral coat proteins and aid in establishing antiviral immunity. To protect humans better, TLRs and their downstream mediators can be used as potential drug targets, which can be either activated or inhibited, to counter viral infections. Areas covered: The current review focuses on TLR-targeting investigational drugs developed to treat viral diseases and virus-induced complications. Expert opinion: TLRs are a good choice for eradicating viral infections because they can fine-tune the immune response. However, TLRs should be exploited carefully, as there have been instances where their activation has led to unwanted responses in terms of both immune and viral activation. Therefore, more focus should be placed on novel drugs that can induce significant and long-term immunity, while concomitantly alleviating side effects.

[1]  H. Yin,et al.  Pyrimidine Triazole Thioether Derivatives as Toll‐Like Receptor 5 (TLR5)/Flagellin Complex Inhibitors , 2016, ChemMedChem.

[2]  A. Gruber,et al.  Pulmonary Immunostimulation with MALP-2 in Influenza Virus-Infected Mice Increases Survival after Pneumococcal Superinfection , 2015, Infection and Immunity.

[3]  Sangdun Choi,et al.  In silico mechanistic analysis of IRF3 inactivation and high-risk HPV E6 species-dependent drug response , 2015, Scientific Reports.

[4]  Z. Pan,et al.  A porcine reproductive and respiratory syndrome virus (PRRSV) vaccine candidate based on the fusion protein of PRRSV glycoprotein 5 and the Toll-like Receptor-5 agonist Salmonella Typhimurium FljB , 2015, BMC Veterinary Research.

[5]  H. Yin,et al.  Specific activation of the TLR1-TLR2 heterodimer by small-molecule agonists , 2015, Science Advances.

[6]  M. Boukhvalova,et al.  Novel drugs targeting Toll-like receptors for antiviral therapy. , 2014, Future virology.

[7]  A. Rubartelli,et al.  TLR Costimulation Causes Oxidative Stress with Unbalance of Proinflammatory and Anti-Inflammatory Cytokine Production , 2014, The Journal of Immunology.

[8]  A. Gewirtz,et al.  Recombinant TLR5 Agonist CBLB502 Promotes NK Cell-Mediated Anti-CMV Immunity in Mice , 2014, PloS one.

[9]  Sangdun Choi,et al.  Multiple Roles of Toll-Like Receptor 4 in Colorectal Cancer , 2014, Front. Immunol..

[10]  P. Massari,et al.  Immune Adjuvant Effect of Molecularly-defined Toll-Like Receptor Ligands , 2014, Vaccines.

[11]  M. Boukhvalova,et al.  A recombinant anchorless respiratory syncytial virus (RSV) fusion (F) protein/monophosphoryl lipid A (MPL) vaccine protects against RSV-induced replication and lung pathology. , 2014, Vaccine.

[12]  Melvin J. Yu,et al.  Novel Small Molecule Inhibitors of TLR7 and TLR9: Mechanism of Action and Efficacy In Vivo , 2014, Molecular Pharmacology.

[13]  A. Mesecar,et al.  MERS-CoV papain-like protease has deISGylating and deubiquitinating activities , 2013, Virology.

[14]  Kui Li,et al.  Toll-Like Receptors in Antiviral Innate Immunity , 2013, Journal of Molecular Biology.

[15]  S. Kosanke,et al.  A TLR4-interacting SPA4 peptide inhibits LPS-induced lung inflammation , 2013, Innate immunity.

[16]  Yang Yang,et al.  The structural and accessory proteins M, ORF 4a, ORF 4b, and ORF 5 of Middle East respiratory syndrome coronavirus (MERS-CoV) are potent interferon antagonists , 2013, Protein & Cell.

[17]  F. Weber,et al.  Middle East Respiratory Syndrome Coronavirus Accessory Protein 4a Is a Type I Interferon Antagonist , 2013, Journal of Virology.

[18]  John A. Taylor,et al.  Rotavirus NSP4 Triggers Secretion of Proinflammatory Cytokines from Macrophages via Toll-Like Receptor 2 , 2013, Journal of Virology.

[19]  H. Ren,et al.  Vaccinia virus protein K7 is a virulence factor that alters the acute immune response to infection , 2013, The Journal of general virology.

[20]  A. J. da Silva Duarte,et al.  TLR7/TLR8 Activation Restores Defective Cytokine Secretion by Myeloid Dendritic Cells but Not by Plasmacytoid Dendritic Cells in HIV-Infected Pregnant Women and Newborns , 2013, PloS one.

[21]  R. Lanford,et al.  GS-9620, an oral agonist of Toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. , 2013, Gastroenterology.

[22]  J. Wilschut,et al.  Efficacy and safety of an intranasal virosomal respiratory syncytial virus vaccine adjuvanted with monophosphoryl lipid A in mice and cotton rats. , 2013, Vaccine.

[23]  B. Kearney,et al.  Safety, Pharmacokinetics and Pharmacodynamics of Gs-9620, An Oral Toll-Like Receptor 7 Agonist , 2013, Antiviral therapy.

[24]  J. Vincent,et al.  Effect of eritoran, an antagonist of MD2-TLR4, on mortality in patients with severe sepsis: the ACCESS randomized trial. , 2013, JAMA.

[25]  Dong Yu,et al.  Design, synthesis and biological evaluation of novel antagonist compounds of Toll-like receptors 7, 8 and 9 , 2013, Nucleic acids research.

[26]  Sangdun Choi,et al.  Negative regulatory approaches to the attenuation of Toll-like receptor signaling , 2013, Experimental & Molecular Medicine.

[27]  A. Bowie,et al.  Poxvirus Targeting of E3 Ligase β-TrCP by Molecular Mimicry: A Mechanism to Inhibit NF-κB Activation and Promote Immune Evasion and Virulence , 2013, PLoS pathogens.

[28]  M. Selsted,et al.  Rhesus Macaque Theta Defensins Suppress Inflammatory Cytokines and Enhance Survival in Mouse Models of Bacteremic Sepsis , 2012, PloS one.

[29]  Xiaohui Wang,et al.  Discovery of small-molecule inhibitors of the TLR1/TLR2 complex. , 2012, Angewandte Chemie.

[30]  Q. Jin,et al.  Cleavage of Interferon Regulatory Factor 7 by Enterovirus 71 3C Suppresses Cellular Responses , 2012, Journal of Virology.

[31]  Y. Li,et al.  Hantaan virus triggers TLR4-dependent innate immune responses. , 2012, Viral immunology.

[32]  Jincun Zhao,et al.  Intranasal Treatment with Poly(I·C) Protects Aged Mice from Lethal Respiratory Virus Infections , 2012, Journal of Virology.

[33]  J. McVernon,et al.  Intranasal administration of the TLR2 agonist Pam2Cys provides rapid protection against influenza in mice. , 2012, Molecular pharmaceutics.

[34]  A. Spetz,et al.  Single-stranded DNA oligonucleotides inhibit TLR3-mediated responses in human monocyte-derived dendritic cells and in vivo in cynomolgus macaques. , 2012, Blood.

[35]  S. Xiao,et al.  Foot-and-Mouth Disease Virus 3C Protease Cleaves NEMO To Impair Innate Immune Signaling , 2012, Journal of Virology.

[36]  M. Selsted,et al.  θ-Defensins: Cyclic Peptides with Endless Potential* , 2012, The Journal of Biological Chemistry.

[37]  F. Bäckhed,et al.  Age-Dependent TLR3 Expression of the Intestinal Epithelium Contributes to Rotavirus Susceptibility , 2012, PLoS pathogens.

[38]  R. D. de Knegt,et al.  Potent Immune Activation in Chronic Hepatitis C Patients upon Administration of An Oral Inducer of Endogenous Interferons that Acts via Toll-Like Receptor 7 , 2012, Antiviral therapy.

[39]  S. Navas-Martín,et al.  Protective Role of Toll-like Receptor 3-Induced Type I Interferon in Murine Coronavirus Infection of Macrophages , 2012, Viruses.

[40]  S. Salvioli,et al.  Herpes Simplex Virus Glycoproteins gH/gL and gB Bind Toll-Like Receptor 2, and Soluble gH/gL Is Sufficient To Activate NF-κB , 2012, Journal of Virology.

[41]  J. Nyengaard,et al.  TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice. , 2012, The Journal of clinical investigation.

[42]  Kui Li,et al.  Coronavirus Papain-like Proteases Negatively Regulate Antiviral Innate Immune Response through Disruption of STING-Mediated Signaling , 2012, PloS one.

[43]  B. Gilbert,et al.  Synergistic TLR2/6 and TLR9 Activation Protects Mice against Lethal Influenza Pneumonia , 2012, PloS one.

[44]  M. Zhang,et al.  R-848 triggers the expression of TLR7/8 and suppresses HIV replication in monocytes , 2012, BMC Infectious Diseases.

[45]  Wei Hu,et al.  Role for B-cell adapter for PI3K (BCAP) as a signaling adapter linking Toll-like receptors (TLRs) to serine/threonine kinases PI3K/Akt , 2011, Proceedings of the National Academy of Sciences.

[46]  R. Steinman,et al.  Synthetic double-stranded RNA induces innate immune responses similar to a live viral vaccine in humans , 2011, The Journal of experimental medicine.

[47]  F. Granucci,et al.  CD14 Controls the LPS-Induced Endocytosis of Toll-like Receptor 4 , 2011, Cell.

[48]  S. Akira,et al.  The Toll-Like Receptor 3-Mediated Antiviral Response Is Important for Protection against Poliovirus Infection in Poliovirus Receptor Transgenic Mice , 2011, Journal of Virology.

[49]  C. Mandl,et al.  Vaccines for the twenty-first century society , 2011, Nature Reviews Immunology.

[50]  M. Chew,et al.  FimH, a TLR4 ligand, induces innate antiviral responses in the lung leading to protection against lethal influenza infection in mice. , 2011, Antiviral research.

[51]  S. Locarnini,et al.  The hepatitis B e antigen (HBeAg) targets and suppresses activation of the toll-like receptor signaling pathway. , 2011, Journal of hepatology.

[52]  Yuqiong Liang,et al.  Disruption of TLR3 Signaling Due to Cleavage of TRIF by the Hepatitis A Virus Protease-Polymerase Processing Intermediate, 3CD , 2011, PLoS pathogens.

[53]  Kui Li,et al.  A novel mechanism for the inhibition of interferon regulatory factor-3-dependent gene expression by human respiratory syncytial virus NS1 protein. , 2011, The Journal of general virology.

[54]  D. Stuart,et al.  How vaccinia virus has evolved to subvert the host immune response , 2011, Journal of structural biology.

[55]  R. D. de Knegt,et al.  Randomised clinical trial: anti‐viral activity of ANA773, an oral inducer of endogenous interferons acting via TLR7, in chronic HCV , 2011, Alimentary pharmacology & therapeutics.

[56]  J. Treanor,et al.  Induction of a potent immune response in the elderly using the TLR-5 agonist, flagellin, with a recombinant hemagglutinin influenza-flagellin fusion vaccine (VAX125, STF2.HA1 SI). , 2011, Vaccine.

[57]  B. Walker,et al.  Antiviral Activity of ANA773, an Oral Inducer of Endogenous Interferons that Acts Via TLR7, in Chronic Hepatitis C Patients , 2011 .

[58]  Q. Jin,et al.  Cleavage of the Adaptor Protein TRIF by Enterovirus 71 3C Inhibits Antiviral Responses Mediated by Toll-Like Receptor 3 , 2011, Journal of Virology.

[59]  M. Fidock,et al.  The Innate Immune Response, Clinical Outcomes, and Ex Vivo HCV Antiviral Efficacy of a TLR7 Agonist (PF‐4878691) , 2011, Clinical pharmacology and therapeutics.

[60]  E. Kurt-Jones,et al.  Pattern Recognition Receptors and the Innate Immune Response to Viral Infection , 2011, Viruses.

[61]  S. Akira,et al.  Plasmacytoid Dendritic Cells Promote Host Defense against Acute Pneumovirus Infection via the TLR7–MyD88-Dependent Signaling Pathway , 2011, The Journal of Immunology.

[62]  C. Bode,et al.  TLR-based immune adjuvants. , 2011, Vaccine.

[63]  N. Garçon,et al.  Recent clinical experience with vaccines using MPL- and QS-21-containing Adjuvant Systems , 2011, Expert review of vaccines.

[64]  H. M. Nielsen,et al.  Immunity by formulation design: induction of high CD8+ T-cell responses by poly(I:C) incorporated into the CAF01 adjuvant via a double emulsion method. , 2011, Journal of controlled release : official journal of the Controlled Release Society.

[65]  Xiaohui Wang,et al.  Small-molecule inhibitors of the TLR3/dsRNA complex. , 2011, Journal of the American Chemical Society.

[66]  Hong Zhou,et al.  A novel antagonist of TLR9 blocking all classes of immunostimulatory CpG-ODNs. , 2011, Vaccine.

[67]  Hailing Lu,et al.  The pharmacokinetics of Toll-like receptor agonists and the impact on the immune system , 2011, Expert review of clinical pharmacology.

[68]  R. Lin,et al.  Kaposi Sarcoma-associated Herpesvirus Degrades Cellular Toll-Interleukin-1 Receptor Domain-containing Adaptor-inducing β-Interferon (TRIF)* , 2011, The Journal of Biological Chemistry.

[69]  C. O’Farrelly,et al.  Interferon‐α suppressed granulocyte colony stimulating factor production is reversed by CL097, a TLR7/8 agonist , 2010, Journal of gastroenterology and hepatology.

[70]  A. Bowie,et al.  Recent insights into the role of Toll‐like receptors in viral infection , 2010, Clinical and experimental immunology.

[71]  D. Knipe,et al.  Discovery of a novel TLR2 signaling inhibitor with anti-viral activity. , 2010, Antiviral research.

[72]  M. Severa,et al.  Herpes Simplex Virus Immediate-Early ICP0 Protein Inhibits Toll-Like Receptor 2-Dependent Inflammatory Responses and NF-κB Signaling , 2010, Journal of Virology.

[73]  W. Ryu,et al.  Hepatitis B Virus Polymerase Blocks Pattern Recognition Receptor Signaling via Interaction with DDX3: Implications for Immune Evasion , 2010, PLoS pathogens.

[74]  G. Prince,et al.  New insights for development of a safe and protective RSV vaccine , 2010, Human vaccines.

[75]  G. Prince,et al.  Activation of interferon response through toll-like receptor 3 impacts viral pathogenesis and pulmonary toll-like receptor expression during respiratory syncytial virus and influenza infections in the cotton rat Sigmodon hispidus model. , 2010, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[76]  A. Fasano,et al.  Novel signaling interactions between proteinase-activated receptor 2 and Toll-like receptors in vitro and in vivo , 2010, Mucosal Immunology.

[77]  M. Colonna,et al.  Cutting Edge: Polyinosinic:Polycytidylic Acid Boosts the Generation of Memory CD8 T Cells through Melanoma Differentiation-Associated Protein 5 Expressed in Stromal Cells , 2010, The Journal of Immunology.

[78]  R. Pyles,et al.  FSL-1, a bacterial-derived toll-like receptor 2/6 agonist, enhances resistance to experimental HSV-2 infection , 2009, Virology Journal.

[79]  G. Chang,et al.  Toll-like receptor 7-induced immune response to cutaneous West Nile virus infection. , 2009, The Journal of general virology.

[80]  Atsushi Okumura,et al.  Interaction between Ebola Virus Glycoprotein and Host Toll-Like Receptor 4 Leads to Induction of Proinflammatory Cytokines and SOCS1 , 2009, Journal of Virology.

[81]  K. Kawa,et al.  Epstein-Barr virus (EBV)–encoded small RNA is released from EBV-infected cells and activates signaling from toll-like receptor 3 , 2009, The Journal of experimental medicine.

[82]  P. Andersen,et al.  A Novel Liposome-Based Adjuvant CAF01 for Induction of CD8+ Cytotoxic T-Lymphocytes (CTL) to HIV-1 Minimal CTL Peptides in HLA-A*0201 Transgenic Mice , 2009, PloS one.

[83]  Jae U. Jung,et al.  Viral interferon regulatory factors. , 2009, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[84]  Yuqiong Liang,et al.  Toll-Like Receptor 3 Mediates Establishment of an Antiviral State against Hepatitis C Virus in Hepatoma Cells , 2009, Journal of Virology.

[85]  M. Altfeld,et al.  Sex differences in the Toll-like receptor–mediated response of plasmacytoid dendritic cells to HIV-1 , 2009, Nature Medicine.

[86]  G. Barton,et al.  A cell biological view of Toll-like receptor function: regulation through compartmentalization , 2009, Nature Reviews Immunology.

[87]  S. Perlman,et al.  Coronaviruses post-SARS: update on replication and pathogenesis , 2009, Nature Reviews Microbiology.

[88]  Chun-Nan Lee,et al.  Human TLR3 recognizes dengue virus and modulates viral replication in vitro , 2009, Cellular microbiology.

[89]  A. Salazar,et al.  Antiviral role of toll-like receptor-3 agonists against seasonal and avian influenza viruses. , 2009, Current pharmaceutical design.

[90]  Ruth R. Montgomery,et al.  Toll-like receptor 7 mitigates lethal West Nile encephalitis via interleukin 23-dependent immune cell infiltration and homing. , 2009, Immunity.

[91]  E. Ooi,et al.  A TLR3 ligand that exhibits potent inhibition of influenza virus replication and has strong adjuvant activity has the potential for dual applications in an influenza pandemic , 2009, Vaccine.

[92]  R. Glaser,et al.  The EBV-Encoded dUTPase Activates NF-κB through the TLR2 and MyD88-Dependent Signaling Pathway1 , 2009, The Journal of Immunology.

[93]  M. Richer,et al.  Toll-Like Receptor 3 Signaling on Macrophages Is Required for Survival Following Coxsackievirus B4 Infection , 2009, PloS one.

[94]  S. Paludan,et al.  TLR2 and TLR9 Synergistically Control Herpes Simplex Virus Infection in the Brain1 , 2008, The Journal of Immunology.

[95]  A. Bowie,et al.  Viral evasion and subversion of pattern-recognition receptor signalling , 2008, Nature Reviews Immunology.

[96]  L. Anderson,et al.  Respiratory Syncytial Virus Activates Innate Immunity through Toll-Like Receptor 2 , 2008, Journal of Virology.

[97]  K. Conzelmann,et al.  Measles Virus V Protein Is a Decoy Substrate for IκB Kinase α and Prevents Toll-Like Receptor 7/9-Mediated Interferon Induction , 2008, Journal of Virology.

[98]  M. Muroi,et al.  A novel TLR4-binding peptide that inhibits LPS-induced activation of NF-kappaB and in vivo toxicity. , 2008, European journal of pharmacology.

[99]  Michael Gale,et al.  Toll-Like Receptor 3 Has a Protective Role against West Nile Virus Infection , 2008, Journal of Virology.

[100]  A. Fauci,et al.  CpG Oligonucleotides Enhance Proliferative and Effector Responses of B Cells in HIV-Infected Individuals1 , 2008, The Journal of Immunology.

[101]  S. Akira,et al.  Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid–inducible gene-I and melanoma differentiation–associated gene 5 , 2008, The Journal of experimental medicine.

[102]  C. Horvath,et al.  Select Paramyxoviral V Proteins Inhibit IRF3 Activation by Acting as Alternative Substrates for Inhibitor of κB Kinase ϵ (IKKe)/TBK1* , 2008, Journal of Biological Chemistry.

[103]  C. Kao,et al.  Single-Stranded Oligonucleotides Can Inhibit Cytokine Production Induced by Human Toll-Like Receptor 3 , 2008, Molecular and Cellular Biology.

[104]  S. Akira,et al.  Survival of lethal poxvirus infection in mice depends on TLR9, and therapeutic vaccination provides protection. , 2008, The Journal of clinical investigation.

[105]  T. Seya,et al.  TLR3: interferon induction by double-stranded RNA including poly(I:C). , 2008, Advanced drug delivery reviews.

[106]  Arthur S Slutsky,et al.  Identification of Oxidative Stress and Toll-like Receptor 4 Signaling as a Key Pathway of Acute Lung Injury , 2008, Cell.

[107]  H. Ezelle,et al.  HIV-1 accessory proteins VPR and Vif modulate antiviral response by targeting IRF-3 for degradation. , 2008, Virology.

[108]  Richard L. Miller,et al.  The antiviral activity of Toll-like receptor 7 and 7/8 agonists. , 2008, Drug news & perspectives.

[109]  R. Steinman,et al.  The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine , 2008, Proceedings of the National Academy of Sciences.

[110]  J. Curtis,et al.  TLR3 Increases Disease Morbidity and Mortality from Vaccinia Infection1 , 2008, The Journal of Immunology.

[111]  M. Moutschen,et al.  Recombinant gp350 vaccine for infectious mononucleosis: a phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. , 2007, The Journal of infectious diseases.

[112]  S. Fletcher,et al.  The pharmacology of endosomal TLR agonists in viral disease. , 2007, Biochemical Society transactions.

[113]  S. Webber,et al.  Discovery of ANA975: An Oral Prodrug of the TLR-7 Agonist Isatoribine , 2007, Nucleosides, nucleotides & nucleic acids.

[114]  Zhongbin Chen,et al.  Regulation of IRF-3-dependent Innate Immunity by the Papain-like Protease Domain of the Severe Acute Respiratory Syndrome Coronavirus , 2007, Journal of Biological Chemistry.

[115]  B. Bacon,et al.  Phase 1B, randomized, double‐blind, dose‐escalation trial of CPG 10101 in patients with chronic hepatitis C virus , 2007, Hepatology.

[116]  C. Rouzioux,et al.  Interruption of antiretroviral therapy initiated during primary HIV-1 infection: impact of a therapeutic vaccination strategy combined with interleukin (IL)-2 compared with IL-2 alone in the ANRS 095 Randomized Study. , 2007, AIDS research and human retroviruses.

[117]  S. Lemon,et al.  Ubiquitination and proteasomal degradation of interferon regulatory factor-3 induced by Npro from a cytopathic bovine viral diarrhea virus. , 2007, Virology.

[118]  A. Judge,et al.  2'-O-methyl-modified RNAs act as TLR7 antagonists. , 2007, Molecular therapy : the journal of the American Society of Gene Therapy.

[119]  T. Ichinohe,et al.  Intranasal immunization with H5N1 vaccine plus Poly I:Poly C12U, a Toll-like receptor agonist, protects mice against homologous and heterologous virus challenge. , 2007, Microbes and infection.

[120]  L. Cuzin,et al.  Cellular Immune Responses Induced with Dose-Sparing Intradermal Administration of HIV Vaccine to HIV-Uninfected Volunteers in the ANRS VAC16 Trial , 2007, PloS one.

[121]  Bao-zong Li,et al.  The membrane protein of SARS‐CoV suppresses NF‐κB activation , 2007, Journal of medical virology.

[122]  A. Vicari,et al.  Safety, Pharmacokinetics and Immune Effects in Normal Volunteers of CPG 10101 (ACTILON™), an Investigational Synthetic Toll-like Receptor 9 Agonist , 2007, Antiviral therapy.

[123]  S. Akira,et al.  Hepatitis C Virus Nonstructural Protein 5A Modulates the Toll-Like Receptor-MyD88-Dependent Signaling Pathway in Macrophage Cell Lines , 2007, Journal of Virology.

[124]  Zhengfan Jiang,et al.  Vesicular stomatitis virus glycoprotein G activates a specific antiviral Toll-like receptor 4-dependent pathway. , 2007, Virology.

[125]  R. Flavell,et al.  TLR3 Is Essential for the Induction of Protective Immunity against Punta Toro Virus Infection by the Double-Stranded RNA (dsRNA), Poly(I:C12U), but not Poly(I:C): Differential Recognition of Synthetic dsRNA Molecules1 , 2007, The Journal of Immunology.

[126]  P. Schaffer,et al.  Recruitment of activated IRF-3 and CBP/p300 to herpes simplex virus ICP0 nuclear foci: Potential role in blocking IFN-beta induction. , 2007, Virology.

[127]  Changyou Wu,et al.  PIKA as an adjuvant enhances specific humoral and cellular immune responses following the vaccination of mice with HBsAg plus PIKA. , 2007, Cellular & molecular immunology.

[128]  A. Sher,et al.  Cooperation of Toll-like receptor signals in innate immune defence , 2007, Nature Reviews Immunology.

[129]  A. Fauci,et al.  HIV-1 gp120 inhibits TLR9-mediated activation and IFN-α secretion in plasmacytoid dendritic cells , 2007, Proceedings of the National Academy of Sciences.

[130]  Xiaopei Huang,et al.  Innate Immune Response to Adenoviral Vectors Is Mediated by both Toll-Like Receptor-Dependent and -Independent Pathways , 2007, Journal of Virology.

[131]  J. Tratschin,et al.  Classical Swine Fever Virus Npro Interacts with Interferon Regulatory Factor 3 and Induces Its Proteasomal Degradation , 2007, Journal of Virology.

[132]  D. Jackson,et al.  Comparison of lipopeptide-based immunocontraceptive vaccines containing different lipid groups. , 2007, Vaccine.

[133]  Z. Janowicz,et al.  A controlled clinical trial comparing the safety and immunogenicity of a new adjuvanted hepatitis B vaccine with a standard hepatitis B vaccine. , 2006, Vaccine.

[134]  Gunther Hartmann,et al.  5'-Triphosphate RNA Is the Ligand for RIG-I , 2006, Science.

[135]  A. Pichlmair,et al.  RIG-I-Mediated Antiviral Responses to Single-Stranded RNA Bearing 5'-Phosphates , 2006, Science.

[136]  R. Flavell,et al.  TLR3 Deletion Limits Mortality and Disease Severity due to Phlebovirus Infection1 , 2006, The Journal of Immunology.

[137]  T. Kanda,et al.  EB virus‐encoded RNAs are recognized by RIG‐I and activate signaling to induce type I IFN , 2006, The EMBO journal.

[138]  S. Akira,et al.  Toll-like receptors and innate immunity , 2006, Journal of Molecular Medicine.

[139]  L. Kalish,et al.  Innate Immunity of the Human Newborn Is Polarized Toward a High Ratio of IL-6/TNF-α Production In Vitro and In Vivo , 2006, Pediatric Research.

[140]  G. Prince,et al.  The TLR4 agonist, monophosphoryl lipid A, attenuates the cytokine storm associated with respiratory syncytial virus vaccine-enhanced disease. , 2006, Vaccine.

[141]  Lena Alexopoulou,et al.  Detrimental Contribution of the Toll-Like Receptor (TLR)3 to Influenza A Virus–Induced Acute Pneumonia , 2006, PLoS pathogens.

[142]  Erica Ollmann Saphire,et al.  Ebola Virus VP35 Protein Binds Double-Stranded RNA and Inhibits Alpha/Beta Interferon Production Induced by RIG-I Signaling , 2006, Journal of Virology.

[143]  Richard A Flavell,et al.  Essential role of mda-5 in type I IFN responses to polyriboinosinic:polyribocytidylic acid and encephalomyocarditis picornavirus. , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[144]  K. Ishii,et al.  Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses , 2006, Nature.

[145]  Y. Lévy,et al.  Clinical safety of HIV lipopeptides used as vaccines in healthy volunteers and HIV-infected adults , 2006, AIDS.

[146]  B. Finlay,et al.  Anti-Immunology: Evasion of the Host Immune System by Bacterial and Viral Pathogens , 2006, Cell.

[147]  Tomoaki Nakamura,et al.  Synthesis and biological evaluation of novel 9-substituted-8-hydroxyadenine derivatives as potent interferon inducers. , 2006, Journal of medicinal chemistry.

[148]  R. Koup,et al.  HIV Gag protein conjugated to a Toll-like receptor 7/8 agonist improves the magnitude and quality of Th1 and CD8+ T cell responses in nonhuman primates. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[149]  A. Kaur,et al.  The evolution of vertebrate Toll-like receptors. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[150]  K. Kretschmer,et al.  The Mucosal Adjuvant Macrophage-Activating Lipopeptide-2 Directly Stimulates B Lymphocytes via the TLR2 without the Need of Accessory Cells 1 , 2005, The Journal of Immunology.

[151]  Dong Yu,et al.  Immunomodulatory oligonucleotides containing a cytosine-phosphate-2'-deoxy-7-deazaguanosine motif as potent toll-like receptor 9 agonists. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[152]  I. Haga,et al.  Vaccinia virus protein A46R targets multiple Toll-like–interleukin-1 receptor adaptors and contributes to virulence , 2005, The Journal of experimental medicine.

[153]  Stanley M Lemon,et al.  Immune evasion by hepatitis C virus NS3/4A protease-mediated cleavage of the Toll-like receptor 3 adaptor protein TRIF. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[154]  M. Tomai,et al.  Synthetic TLR Agonists Reveal Functional Differences between Human TLR7 and TLR8 , 2005, The Journal of Immunology.

[155]  P. Lambert,et al.  Co-administration of CpG oligonucleotides enhances the late affinity maturation process of human anti-hepatitis B vaccine response. , 2004, Vaccine.

[156]  E. Fikrig,et al.  Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis , 2004, Nature Medicine.

[157]  D. Golenbock,et al.  Hepatitis C core and nonstructural 3 proteins trigger toll-like receptor 2-mediated pathways and inflammatory activation. , 2004, Gastroenterology.

[158]  A. Falsey,et al.  Respiratory syncytial virus and other pneumoviruses: a review of the international symposium--RSV 2003. , 2004, Virus research.

[159]  O. Levy,et al.  Selective Impairment of TLR-Mediated Innate Immunity in Human Newborns: Neonatal Blood Plasma Reduces Monocyte TNF-α Induction by Bacterial Lipopeptides, Lipopolysaccharide, and Imiquimod, but Preserves the Response to R-8481 , 2004, The Journal of Immunology.

[160]  N. Petrovsky,et al.  Vaccine adjuvants: Current state and future trends , 2004, Immunology and cell biology.

[161]  Y. Li,et al.  Safety and immunogenicity of CPG 7909 injection as an adjuvant to Fluarix influenza vaccine. , 2004, Vaccine.

[162]  F. Schmitz,et al.  Herpes simplex virus type-1 induces IFN-α production via Toll-like receptor 9-dependent and -independent pathways , 2004 .

[163]  Shizuo Akira,et al.  Toll-like receptor signalling , 2004, Nature Reviews Immunology.

[164]  S. Akira,et al.  TLR9-dependent recognition of MCMV by IPC and DC generates coordinated cytokine responses that activate antiviral NK cell function. , 2004, Immunity.

[165]  S. Akira,et al.  Species-Specific Recognition of Single-Stranded RNA via Toll-like Receptor 7 and 8 , 2004, Science.

[166]  Shizuo Akira,et al.  TLR signaling pathways. , 2004, Seminars in immunology.

[167]  Dong Yu,et al.  A dinucleotide motif in oligonucleotides shows potent immunomodulatory activity and overrides species-specific recognition observed with CpG motif , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[168]  P. Neuhaus,et al.  Immunization with an adjuvant hepatitis B vaccine after liver transplantation for hepatitis B‐related disease , 2003, Hepatology.

[169]  D. Golenbock,et al.  Human Cytomegalovirus Activates Inflammatory Cytokine Responses via CD14 and Toll-Like Receptor 2 , 2003, Journal of Virology.

[170]  D. Persing,et al.  Enhancement of antigen-specific immunity via the TLR4 ligands MPL™ adjuvant and Ribi.529 , 2003, Expert review of vaccines.

[171]  F. Gusovsky,et al.  Inhibition of Endotoxin Response by E5564, a Novel Toll-Like Receptor 4-Directed Endotoxin Antagonist , 2003, Journal of Pharmacology and Experimental Therapeutics.

[172]  I. Haga,et al.  The Poxvirus Protein A52R Targets Toll-like Receptor Signaling Complexes to Suppress Host Defense , 2003, The Journal of experimental medicine.

[173]  V. ter meulen,et al.  Hemagglutinin Protein of Wild-Type Measles Virus Activates Toll-Like Receptor 2 Signaling , 2002, Journal of Virology.

[174]  S. Ross,et al.  Murine retroviruses activate B cells via interaction with toll-like receptor 4 , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[175]  S. Akira,et al.  Small anti-viral compounds activate immune cells via the TLR7 MyD88–dependent signaling pathway , 2002, Nature Immunology.

[176]  J. Vekemans,et al.  Monophosphoryl Lipid A Activates Both Human Dendritic Cells and T Cells1 , 2002, The Journal of Immunology.

[177]  G. Prince,et al.  Vaccine-enhanced respiratory syncytial virus disease in cotton rats following immunization with Lot 100 or a newly prepared reference vaccine. , 2001, The Journal of general virology.

[178]  L. Anderson,et al.  Involvement of Toll-Like Receptor 4 in Innate Immunity to Respiratory Syncytial Virus , 2001, Journal of Virology.

[179]  R. Flavell,et al.  Recognition of double-stranded RNA and activation of NF-κB by Toll-like receptor 3 , 2001, Nature.

[180]  G. Prince,et al.  Monophosphoryl lipid A adjuvant reverses a principal histologic parameter of formalin-inactivated respiratory syncytial virus vaccine-induced disease. , 2001, Vaccine.

[181]  Douglas T. Golenbock,et al.  Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus , 2000, Nature Immunology.

[182]  A. Bowie,et al.  A46R and A52R from vaccinia virus are antagonists of host IL-1 and toll-like receptor signaling. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[183]  Jun Yuan,et al.  A cyclic antimicrobial peptide produced in primate leukocytes by the ligation of two truncated alpha-defensins. , 1999, Science.

[184]  R. Lehrer,et al.  Protegrins: leukocyte antimicrobial peptides that combine features of corticostatic defensins and tachyplesins , 1993, FEBS letters.

[185]  R. Fukuda,et al.  Binding of influenza A virus NS1 protein to dsRNA in vitro. , 1992, The Journal of general virology.

[186]  D M Crothers,et al.  Fragments of the HIV-1 Tat protein specifically bind TAR RNA. , 1990, Science.

[187]  E. Walsh,et al.  Enhancement of respiratory syncytial virus pulmonary pathology in cotton rats by prior intramuscular inoculation of formalin-inactiva ted virus , 1986, Journal of virology.

[188]  N. Qureshi,et al.  Purification and structural determination of nontoxic lipid A obtained from the lipopolysaccharide of Salmonella typhimurium. , 1982, The Journal of biological chemistry.

[189]  V. Devita,et al.  A phase I-II trial of multiple-dose polyriboinosic-polyribocytidylic acid in patieonts with leukemia or solid tumors. , 1976, Journal of the National Cancer Institute.

[190]  J. Kagan,et al.  The Dorsoventral Regulatory Gene Cassette spätzle / Toll / cactus Controls the Potent Antifungal Response in Drosophila Adults , 2015 .

[191]  P. H. van der Graaf,et al.  Use of modelling and simulation techniques to support decision making on the progression of PF-04878691, a TLR7 agonist being developed for hepatitis C. , 2012, British journal of clinical pharmacology.

[192]  Seung Hee Kang,et al.  Inhibition of homodimerization of toll-like receptor 4 by 4-oxo-4-(2-oxo-oxazolidin-3-yl)-but-2-enoic acid ethyl ester. , 2011, International immunopharmacology.

[193]  R. Medzhitov,et al.  The control of adaptive immune responses by the innate immune system. , 2011, Advances in immunology.

[194]  M. Sioud Development of TLR7/8 small RNA antagonists. , 2010, Methods in molecular biology.

[195]  C. Jones,et al.  The EBV-encoded dUTPase activates NF-kappa B through the TLR2 and MyD88-dependent signaling pathway. , 2009, Journal of immunology.

[196]  R. Flavell,et al.  Toll-like receptor 3 is an essential component of the innate stress response in virus-induced cardiac injury. , 2007, American journal of physiology. Heart and circulatory physiology.

[197]  A. Fauci,et al.  HIV-1 gp120 inhibits TLR9-mediated activation and IFN-{alpha} secretion in plasmacytoid dendritic cells. , 2007, Proceedings of the National Academy of Sciences of the United States of America.

[198]  Y. Nakagawa,et al.  Polyriboinosinic polyribocytidylic acid [poly(I:C)]/TLR3 signaling allows class I processing of exogenous protein and induction of HIV-specific CD8+ cytotoxic T lymphocytes. , 2004, International immunology.

[199]  F. Schmitz,et al.  Herpes simplex virus type-1 induces IFN-alpha production via Toll-like receptor 9-dependent and -independent pathways. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[200]  H. Rho,et al.  Hepatitis B viral core protein activates the hepatitis B viral enhancer II/pregenomic promoter through the nuclear factor kappaB binding site. , 2002, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[201]  H. Rho,et al.  Hepatitis B viral core protein activates the hepatitis B viral enhancer II/pregenomic promoter through the nuclear factor κB binding site , 2002 .

[202]  A. Vitiello,et al.  Development of a lipopeptide-based therapeutic vaccine to treat chronic HBV infection. I. Induction of a primary cytotoxic T lymphocyte response in humans. , 1995, The Journal of clinical investigation.

[203]  C. Janeway Approaching the asymptote? Evolution and revolution in immunology. , 1989, Cold Spring Harbor symposia on quantitative biology.