Recent advances in the discovery and development of TLR ligands as novel therapeutics for chronic HBV and HIV infections

References

• Lozano R, Naghavi M, Foreman K, et al. Global and regional mortality from 235 causes of death for 20 age groups in 1990 and 2010: a systematic analysis for the Global Burden of Disease Study 2010. Lancet. 2012;380:2095–2128.
   PubMed Web of Science ®Google Scholar
• Schweitzer A, Horn J, Mikolajczyk RT, et al. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015;386:1546–1555.
   PubMed Web of Science ®Google Scholar
• Stanaway JD, Flaxman AD, Naghavi M, et al. The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013. Lancet. 2016;388:1081–1088.
   PubMed Web of Science ®Google Scholar
• Maartens G, Celum C, Lewin SR. HIV infection: epidemiology, pathogenesis, treatment, and prevention. Lancet. 2014;384:258–271.
   PubMed Web of Science ®Google Scholar
• European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370-398.
   Google Scholar
• Liu J, Kosinska A, Lu M, et al. New therapeutic vaccination strategies for the treatment of chronic hepatitis B. Virol Sin. 2014;29:10–16.
   PubMedGoogle Scholar
• Medzhitov R. Recognition of microorganisms and activation of the immune response. Nature. 2007;449:819–826.
   PubMed Web of Science ®Google Scholar
• Nosratabadi R, Alavian SM, Zare-Bidaki M, et al. Innate immunity related pathogen recognition receptors and chronic hepatitis B infection. Mol Immunol. 2017;90:64–73.
   PubMed Web of Science ®Google Scholar
• Gay NJ, Gangloff M. Structure and function of toll receptors and their ligands. Annu Rev Biochem. 2007;76:141–165.
   PubMed Web of Science ®Google Scholar
• Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006;124:783–801.
   PubMed Web of Science ®Google Scholar
• Lemaitre B, Nicolas E, Michaut L, et al. The dorsoventral regulatory gene cassette spatzle/toll/cactus controls the potent antifungal response in drosophila adults. Cell. 1996;86:973–983.
   PubMed Web of Science ®Google Scholar
• Tabeta K, Georgel P, Janssen E, et al. Toll-like receptors 9 and 3 as essential components of innate immune defense against mouse cytomegalovirus infection. Proc Natl Acad Sci U S A. 2004;101:3516–3521.
   PubMed Web of Science ®Google Scholar
• Seki E, Brenner DA. Toll-like receptors and adaptor molecules in liver disease: update. Hepatology. 2008;48:322–335.
   PubMed Web of Science ®Google Scholar
• Yarovinsky F. Innate immunity to Toxoplasma gondii infection. Nat Rev Immunol. 2014;14:109–121.
   PubMed Web of Science ®Google Scholar
• 15976025, Botos I, Segal DM, Davies DR, The structural biology of toll-like receptors. Structure. 2011;19:447–459.
   PubMed Web of Science ®Google Scholar
• Uematsu S, Akira S. Toll-like receptors and innate immunity. J Mol Med (Berl). 2006;84:712–725.
   PubMed Web of Science ®Google Scholar
• Kumar H, Kawai T, Akira S. Pathogen recognition in the innate immune response. Biochem J. 2009;420:1–16.
   PubMed Web of Science ®Google Scholar
• Zhang X, Kraft A, Broering R, et al. Preclinical development of TLR ligands as drugs for the treatment of chronic viral infections. Expert Opin Drug Discov. 2012;7:597–611.
   PubMed Web of Science ®Google Scholar
• Roach JC, Glusman G, Rowen L, et al. The evolution of vertebrate toll-like receptors. Proc Natl Acad Sci U S A. 2005;102:9577–9582.
   PubMed Web of Science ®Google Scholar
• Vacchelli E, Eggermont A, Sautes-Fridman C, et al. Trial watch: Toll-like receptor agonists for cancer therapy. Oncoimmunology. 2013;2:e25238.
   PubMed Web of Science ®Google Scholar
• Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003;21:335–376.
   PubMed Web of Science ®Google Scholar
• Kawai T, Adachi O, Ogawa T, et al. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity. 1999;11:115–122.
   PubMed Web of Science ®Google Scholar
• Akira S, Takeda K. Toll-like receptor signalling. Nat Rev Immunol. 2004;4:499–511.
   PubMed Web of Science ®Google Scholar
• Bagchi A, Herrup EA, Warren HS, et al. MyD88-dependent and MyD88-independent pathways in synergy, priming, and tolerance between TLR agonists. J Immunol. 2007;178:1164–1171.
   PubMed Web of Science ®Google Scholar
• Maini MK, Gehring AJ. The role of innate immunity in the immunopathology and treatment of HBV infection. J Hepatol. 2016;64:S60–70.
   PubMed Web of Science ®Google Scholar
• Wieland SF, Eustaquio A, Whitten-Bauer C, et al. Interferon prevents formation of replication-competent hepatitis B virus RNA-containing nucleocapsids. Proc Natl Acad Sci U S A. 2005;102:9913–9917.
   PubMed Web of Science ®Google Scholar
• Wieland S, Thimme R, Purcell RH, et al. Genomic analysis of the host response to hepatitis B virus infection. Proc Natl Acad Sci U S A. 2004;101:6669–6674.
   PubMed Web of Science ®Google Scholar
• 17943118, Wieland SF, Chisari FV, Stealth and cunning: hepatitis B and hepatitis C viruses. J Virol. 2005;79:9369–9380.
   PubMed Web of Science ®Google Scholar
• Cui X, Clark DN, Liu K, et al. Viral DNA-dependent induction of innate immune response to hepatitis B virus in immortalized mouse hepatocytes. J Virol. 2015;90:486–496.
   PubMed Web of Science ®Google Scholar
• Sato S, Li K, Kameyama T, et al. The RNA sensor RIG-I dually functions as an innate sensor and direct antiviral factor for hepatitis B virus. Immunity. 2015;42:123–132.
   PubMed Web of Science ®Google Scholar
• Zhang X, Ma Z, Liu H, et al. Role of Toll-like receptor 2 in the immune response against hepadnaviral infection. J Hepatol. 2012;57:522–528.
   PubMed Web of Science ®Google Scholar
• Luangsay S, Gruffaz M, Isorce N, et al. Early inhibition of hepatocyte innate responses by hepatitis B virus. J Hepatol. 2015;63:1314–1322.
   PubMed Web of Science ®Google Scholar
• Roggendorf M, Kosinska AD, Liu J, et al. The woodchuck, a nonprimate model for immunopathogenesis and therapeutic immunomodulation in chronic hepatitis B virus infection. Cold Spring Harb Perspect Med. 2015;5:a021451.
   Web of Science ®Google Scholar
• Bertoletti A, Ferrari C. Innate and adaptive immune responses in chronic hepatitis B virus infections: towards restoration of immune control of viral infection. Gut. 2012;61:1754–1764.
   PubMed Web of Science ®Google Scholar
• Chen Z, Cheng Y, Xu Y, et al. Expression profiles and function of toll-like receptors 2 and 4 in peripheral blood mononuclear cells of chronic hepatitis B patients. Clin Immunol. 2008;128:400–408.
   PubMed Web of Science ®Google Scholar
• Wu J, Meng Z, Jiang M, et al. Hepatitis B virus suppresses toll-like receptor-mediated innate immune responses in murine parenchymal and nonparenchymal liver cells. Hepatology. 2009;49:1132–1140.
   PubMed Web of Science ®Google Scholar
• Isogawa M, Robek MD, Furuichi Y, et al. Toll-like receptor signaling inhibits hepatitis B virus replication in vivo. J Virol. 2005;79:7269–7272.
   PubMed Web of Science ®Google Scholar
• Wu J, Lu M, Meng Z, et al. Toll-like receptor-mediated control of HBV replication by nonparenchymal liver cells in mice. Hepatology. 2007;46:1769–1778.
   PubMed Web of Science ®Google Scholar
• Wu J, Chen MF, Xia YC, et al. Toll-like receptor dependent innate immune responses by primary mouse hepatocytes and its control of HBV replication. Zhonghua Gan Zang Bing Za Zhi. 2011;19:838–842.
   PubMedGoogle Scholar
• Zhang X, Meng Z, Qiu S, et al. Lipopolysaccharide-induced innate immune responses in primary hepatocytes downregulates woodchuck hepatitis virus replication via interferon-independent pathways. Cell Microbiol. 2009;11:1624–1637.
   PubMed Web of Science ®Google Scholar
• Ma Z, Zhang E, Yang D, et al. Contribution of toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses. Cell Mol Immunol. 2015;12:273–282.
   PubMed Web of Science ®Google Scholar
• Visvanathan K, Skinner NA, Thompson AJ, et al. Regulation of toll-like receptor-2 expression in chronic hepatitis B by the precore protein. Hepatology. 2007;45:102–110.
   PubMed Web of Science ®Google Scholar
• Thompson AJ, Colledge D, Rodgers S, et al. Stimulation of the interleukin-1 receptor and toll-like receptor 2 inhibits hepatitis B virus replication in hepatoma cell lines in vitro. Antivir Ther. 2009;14:797–808.
   PubMed Web of Science ®Google Scholar
• Liu J, Jiang M, Ma Z, et al. TLR1/2 ligand-stimulated mouse liver endothelial cells secrete IL-12 and trigger CD8+ T cell immunity in vitro. J Immunol. 2013;191:6178–6190.
   PubMed Web of Science ®Google Scholar
• Ma Z, Liu J, Wu W, et al. The IL-1R/TLR signaling pathway is essential for efficient CD8+ T-cell responses against hepatitis B virus in the hydrodynamic injection mouse model. Cell Mol Immunol. 2017.
   Web of Science ®Google Scholar
• Kawai T, Akira S. Antiviral signaling through pattern recognition receptors. J Biochem. 2007;141:137–145.
   PubMed Web of Science ®Google Scholar
• Dong Z, Wei H, Sun R, et al. Involvement of natural killer cells in polyI:C-induced liver injury. J Hepatol. 2004;41:966–973.
   PubMed Web of Science ®Google Scholar
• Wang J, Sun R, Wei H, et al. Pre-activation of T lymphocytes by low dose of concanavalin A aggravates toll-like receptor-3 ligand-induced NK cell-mediated liver injury. Int Immunopharmacol. 2006;6:800–807.
   PubMed Web of Science ®Google Scholar
• Chen Y, Sun R, Jiang W, et al. Liver-specific HBsAg transgenic mice are over-sensitive to Poly(I:C)-induced liver injury in NK cell- and IFN-gamma-dependent manner. J Hepatol. 2007;47:183–190.
   PubMed Web of Science ®Google Scholar
• Wu J, Huang S, Zhao X, et al. Poly(I:C) treatment leads to interferon-dependent clearance of hepatitis B virus in a hydrodynamic injection mouse model. J Virol. 2014;88:10421–10431.
   PubMed Web of Science ®Google Scholar
• Chuai X, Chen H, Wang W, et al. Poly(I:C)/alum mixed adjuvant priming enhances HBV subunit vaccine-induced immunity in mice when combined with recombinant adenoviral-based HBV vaccine boosting. PLoS One. 2013;8:e54126.
   PubMed Web of Science ®Google Scholar
• Spruss A, Kanuri G, Wagnerberger S, et al. Toll-like receptor 4 is involved in the development of fructose-induced hepatic steatosis in mice. Hepatology. 2009;50:1094–1104.
   PubMed Web of Science ®Google Scholar
• Rivera CA, Adegboyega P, van Rooijen N, et al. Toll-like receptor-4 signaling and Kupffer cells play pivotal roles in the pathogenesis of non-alcoholic steatohepatitis. J Hepatol. 2007;47:571–579.
   PubMed Web of Science ®Google Scholar
• Das D, Sarkar N, Sengupta I, et al. Anti-viral role of toll like receptor 4 in hepatitis B virus infection: an in vitro study. World J Gastroenterol. 2016;22:10341–10352.
   PubMed Web of Science ®Google Scholar
• Zhang RN, Pan Q, Zhang Z, et al. Saturated fatty acid inhibits viral replication in chronic hepatitis B virus infection with nonalcoholic fatty liver disease by toll-like receptor 4-mediated innate immune response. Hepat Mon. 2015;15:e27909.
   PubMed Web of Science ®Google Scholar
• Kanzler H, Barrat FJ, Hessel EM, et al. Therapeutic targeting of innate immunity with toll-like receptor agonists and antagonists. Nat Med. 2007;13:552–559.
   PubMed Web of Science ®Google Scholar
• Evans JT, Cluff CW, Johnson DA, et al. Enhancement of antigen-specific immunity via the TLR4 ligands MPL adjuvant and Ribi.529. Expert Rev Vaccines. 2003;2:219–229.
   PubMedGoogle Scholar
• Dupont J, Altclas J, Lepetic A, et al. A controlled clinical trial comparing the safety and immunogenicity of a new adjuvanted hepatitis B vaccine with a standard hepatitis B vaccine. Vaccine. 2006;24:7167–7174.
   PubMed Web of Science ®Google Scholar
• Lindemann M, Zaslavskaya M, Fiedler M, et al. Humoral and cellular responses to a single dose of Fendrix in renal transplant recipients with non-response to previous hepatitis B vaccination. Scand J Immunol. 2017;85:51–57.
   PubMed Web of Science ®Google Scholar
• Di Paolo D, Lenci I, Cerocchi C, et al. One-year vaccination against hepatitis B virus with a MPL-vaccine in liver transplant patients for HBV-related cirrhosis. Transpl Int. 2010;23:1105–1112.
   PubMed Web of Science ®Google Scholar
• Barbalat R, Ewald SE, Mouchess ML, et al. Nucleic acid recognition by the innate immune system. Annu Rev Immunol. 2011;29:185–214.
   PubMed Web of Science ®Google Scholar
• Gibson SJ, Lindh JM, Riter TR, et al. Plasmacytoid dendritic cells produce cytokines and mature in response to the TLR7 agonists, imiquimod and resiquimod. Cell Immunol. 2002;218:74–86.
   PubMed Web of Science ®Google Scholar
• Hemmi H, Kaisho T, Takeuchi O, et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002;3:196–200.
   PubMed Web of Science ®Google Scholar
• Lan P, Zhang C, Han Q, et al. Therapeutic recovery of hepatitis B virus (HBV)-induced hepatocyte-intrinsic immune defect reverses systemic adaptive immune tolerance. Hepatology. 2013;58:73–85.
   PubMed Web of Science ®Google Scholar
• Menne S, Tumas DB, Liu KH, et al. Sustained efficacy and seroconversion with the toll-like receptor 7 agonist GS-9620 in the woodchuck model of chronic hepatitis B. J Hepatol. 2015;62:1237–1245.
   PubMed Web of Science ®Google Scholar
• Lanford RE, Guerra B, Chavez D, et al. GS-9620, an oral agonist of toll-like receptor-7, induces prolonged suppression of hepatitis B virus in chronically infected chimpanzees. Gastroenterology. 2013;144:1508–1517, 1517 e1501–1510.
   PubMed Web of Science ®Google Scholar
• Li L, Barry V, Daffis S, et al. Anti-HBV response to toll-like receptor 7 agonist GS-9620 is associated with intrahepatic aggregates of T cells and B cells. J Hepatol. 2017;68:912-921.
   Web of Science ®Google Scholar
• Niu C, Li L, Daffis S, et al. Toll-like receptor 7 agonist GS-9620 induces prolonged inhibition of HBV via a type I interferon-dependent mechanism. J Hepatol. 2017;68:922-931.
   Web of Science ®Google Scholar
• Gane EJ, Lim YS, Gordon SC, et al. The oral toll-like receptor-7 agonist GS-9620 in patients with chronic hepatitis B virus infection. J Hepatol. 2015;63:320–328.
   PubMed Web of Science ®Google Scholar
• Janssen HLA, Brunetto MR, Kim YJ, et al. Safety, efficacy and pharmacodynamics of vesatolimod (GS-9620) in virally suppressed patients with chronic hepatitis B. J Hepatol. 2017;68:431–440.
   Web of Science ®Google Scholar
• Krieg AM. CpG still rocks! Update on an accidental drug. Nucleic Acid Ther. 2012;22:77–89.
   PubMed Web of Science ®Google Scholar
• Krieg AM. Therapeutic potential of toll-like receptor 9 activation. Nat Rev Drug Discov. 2006;5:471–484.
   PubMed Web of Science ®Google Scholar
• Kumagai Y, Takeuchi O, Akira S. TLR9 as a key receptor for the recognition of DNA. Adv Drug Deliv Rev. 2008;60:795–804.
   PubMed Web of Science ®Google Scholar
• Hemmi H, Kaisho T, Takeda K, et al. The roles of toll-like receptor 9, MyD88, and DNA-dependent protein kinase catalytic subunit in the effects of two distinct CpG DNAs on dendritic cell subsets. J Immunol. 2003;170:3059–3064.
   PubMed Web of Science ®Google Scholar
• Tada R, Muto S, Iwata T, et al. Attachment of class B CpG ODN onto DOTAP/DC-chol liposome in nasal vaccine formulations augments antigen-specific immune responses in mice. BMC Res Notes. 2017;10:68.
   PubMedGoogle Scholar
• Vollmer J, Weeratna R, Payette P, et al. Characterization of three CpG oligodeoxynucleotide classes with distinct immunostimulatory activities. Eur J Immunol. 2004;34:251–262.
   PubMed Web of Science ®Google Scholar
• Samulowitz U, Weber M, Weeratna R, et al. A novel class of immune-stimulatory CpG oligodeoxynucleotides unifies high potency in type I interferon induction with preferred structural properties. Oligonucleotides. 2010;20:93–101.
   PubMedGoogle Scholar
• Verthelyi D, Ishii KJ, Gursel M, et al. Human peripheral blood cells differentially recognize and respond to two distinct CPG motifs. J Immunol. 2001;166:2372–2377.
   PubMed Web of Science ®Google Scholar
• Gursel M, Verthelyi D, Gursel I, et al. Differential and competitive activation of human immune cells by distinct classes of CpG oligodeoxynucleotide. J Leukoc Biol. 2002;71:813–820.
   PubMed Web of Science ®Google Scholar
• Meng Z, Zhang X, Pei R, et al. Combination therapy including CpG oligodeoxynucleotides and entecavir induces early viral response and enhanced inhibition of viral replication in a woodchuck model of chronic hepadnaviral infection. Antiviral Res. 2016;125:14–24.
   PubMed Web of Science ®Google Scholar
• Chen Z, Cao J, Liao X, et al. Plasmids enriched with CpG motifs activate human peripheral blood mononuclear cells in vitro and enhance th-1 immune responses to hepatitis B surface antigen in mice. Viral Immunol. 2011;24:199–209.
   PubMed Web of Science ®Google Scholar
• Wang S, Han Q, Zhang N, et al. HBcAg18-27 epitope fused to HIV-Tat 49-57 adjuvanted with CpG ODN induces immunotherapeutic effects in transgenic mice. Immunol Lett. 2010;127:143–149.
   PubMed Web of Science ®Google Scholar
• Wang S, Han Q, Zhang G, et al. CpG oligodeoxynucleotide-adjuvanted fusion peptide derived from HBcAg epitope and HIV-Tat may elicit favorable immune response in PBMCs from patients with chronic HBV infection in the immunotolerant phase. Int Immunopharmacol. 2011;11:406–411.
   PubMed Web of Science ®Google Scholar
• Okamura Y, Watari M, Jerud ES, et al. The extra domain A of fibronectin activates toll-like receptor 4. J Biol Chem. 2001;276:10229–10233.
   PubMed Web of Science ®Google Scholar
• Julier Z, Martino MM, de Titta A, et al. The TLR4 agonist fibronectin extra domain A is cryptic, exposed by elastase-2; use in a fibrin matrix cancer vaccine. Sci Rep. 2015;5:8569.
   PubMed Web of Science ®Google Scholar
• Mansilla C, Gorraiz M, Martinez M, et al. Immunization against hepatitis C virus with a fusion protein containing the extra domain A from fibronectin and the hepatitis C virus NS3 protein. J Hepatol. 2009;51:520–527.
   PubMed Web of Science ®Google Scholar
• Lasarte JJ, Casares N, Gorraiz M, et al. The extra domain A from fibronectin targets antigens to TLR4-expressing cells and induces cytotoxic T cell responses in vivo. J Immunol. 2007;178:748–756.
   PubMed Web of Science ®Google Scholar
• Julier Z, De Titta A, Grimm AJ, et al. Fibronectin EDA and CpG synergize to enhance antigen-specific Th1 and cytotoxic responses. Vaccine. 2016;34:2453–2459.
   PubMed Web of Science ®Google Scholar
• Gupta K, Cooper C. A review of the role of CpG oligodeoxynucleotides as toll-like receptor 9 agonists in prophylactic and therapeutic vaccine development in infectious diseases. Drugs R D. 2008;9:137–145.
   PubMed Web of Science ®Google Scholar
• Kobiyama K, Aoshi T, Narita H, et al. Nonagonistic Dectin-1 ligand transforms CpG into a multitask nanoparticulate TLR9 agonist. Proc Natl Acad Sci U S A. 2014;111:3086–3091.
   PubMed Web of Science ®Google Scholar
• Ito H, Ando T, Nakamura M, et al. Induction of humoral and cellular immune response to hepatitis B virus (HBV) vaccine can be upregulated by CpG oligonucleotides complexed with Dectin-1 ligand. J Viral Hepat. 2017;24:155–162.
   PubMed Web of Science ®Google Scholar
• Li J, Ge J, Ren S, et al. Hepatitis B surface antigen (HBsAg) and core antigen (HBcAg) combine CpG oligodeoxynucletides as a novel therapeutic vaccine for chronic hepatitis B infection. Vaccine. 2015;33:4247–4254.
   PubMed Web of Science ®Google Scholar
• Cooper CL, Davis HL, Morris ML, et al. CPG 7909, an immunostimulatory TLR9 agonist oligodeoxynucleotide, as adjuvant to Engerix-B HBV vaccine in healthy adults: a double-blind phase I/II study. J Clin Immunol. 2004;24:693–701.
   PubMed Web of Science ®Google Scholar
• Vincent IE, Lucifora J, Durantel D, et al. Inhibitory effect of the combination of CpG-induced cytokines with lamivudine against hepatitis B virus replication in vitro. Antivir Ther. 2009;14:131–135.
   PubMed Web of Science ®Google Scholar
• Lv S, Wang J, Dou S, et al. Nanoparticles encapsulating hepatitis B virus cytosine-phosphate-guanosine induce therapeutic immunity against HBV infection. Hepatology. 2014;59:385–394.
   PubMed Web of Science ®Google Scholar
• Huang LR, Wohlleber D, Reisinger F, et al. Intrahepatic myeloid-cell aggregates enable local proliferation of CD8(+) T cells and successful immunotherapy against chronic viral liver infection. Nat Immunol. 2013;14:574–583.
   PubMed Web of Science ®Google Scholar
• Knolle PA, Bottcher J, Huang LR. The role of hepatic immune regulation in systemic immunity to viral infection. Med Microbiol Immunol. 2015;204:21–27.
   PubMed Web of Science ®Google Scholar
• Knolle PA, Thimme R. Hepatic immune regulation and its involvement in viral hepatitis infection. Gastroenterology. 2014;146:1193–1207.
   PubMed Web of Science ®Google Scholar
• Ehlting C, Trilling M, Tiedje C, et al. MAPKAP kinase 2 regulates IL-10 expression and prevents formation of intrahepatic myeloid cell aggregates during cytomegalovirus infections. J Hepatol. 2016;64:380–389.
   PubMed Web of Science ®Google Scholar
• Campbell JD. Development of the CpG adjuvant 1018: a case study. Methods Mol Biol. 2017;1494:15–27.
   PubMedGoogle Scholar
• a two-dose hepatitis B vaccine for adults (Heplisav-B). Jama. 2018;319:822–823.
   PubMed Web of Science ®Google Scholar
• Hofmann H, Vanwalscappel B, Bloch N, et al. TLR7/8 agonist induces a post-entry SAMHD1-independent block to HIV-1 infection of monocytes. Retrovirology. 2016;13:83.
   PubMed Web of Science ®Google Scholar
• Buitendijk M, Eszterhas SK, Howell AL. Gardiquimod: a Toll-like receptor-7 agonist that inhibits HIV type 1 infection of human macrophages and activated T cells. AIDS Res Hum Retroviruses. 2013;29:907–918.
   PubMed Web of Science ®Google Scholar
• Campbell GR, Spector SA. Toll-like receptor 8 ligands activate a vitamin D mediated autophagic response that inhibits human immunodeficiency virus type 1. PLoS Pathog. 2012;8:e1003017.
   PubMed Web of Science ®Google Scholar
• Cardinaud S, Urrutia A, Rouers A, et al. Triggering of TLR-3, −4, NOD2, and DC-SIGN reduces viral replication and increases T-cell activation capacity of HIV-infected human dendritic cells. Eur J Immunol. 2017;47:818–829.
   PubMed Web of Science ®Google Scholar
• Trapp S, Derby NR, Singer R, et al. Double-stranded RNA analog poly(I:C) inhibits human immunodeficiency virus amplification in dendritic cells via type I interferon-mediated activation of APOBEC3G. J Virol. 2009;83:884–895.
   PubMed Web of Science ®Google Scholar
• Buitendijk M, Eszterhas SK, Howell AL. Toll-like receptor agonists are potent inhibitors of human immunodeficiency virus-type 1 replication in peripheral blood mononuclear cells. AIDS Res Hum Retroviruses. 2014;30:457–467.
   PubMed Web of Science ®Google Scholar
• Gibbert K, Dietze KK, Zelinskyy G, et al. Polyinosinic-polycytidylic acid treatment of Friend retrovirus-infected mice improves functional properties of virus-specific T cells and prevents virus-induced disease. J Immunol. 2010;185:6179–6189.
   PubMed Web of Science ®Google Scholar
• Olbrich AR, Schimmer S, Heeg K, et al. Effective postexposure treatment of retrovirus-induced disease with immunostimulatory DNA containing CpG motifs. J Virol. 2002;76:11397–11404.
   PubMed Web of Science ®Google Scholar
• Olbrich AR, Schimmer S, Dittmer U. Preinfection treatment of resistant mice with CpG oligodeoxynucleotides renders them susceptible to friend retrovirus-induced leukemia. J Virol. 2003;77:10658–10662.
   PubMed Web of Science ®Google Scholar
• Wang Y, Abel K, Lantz K, et al. The Toll-like receptor 7 (TLR7) agonist, imiquimod, and the TLR9 agonist, CpG ODN, induce antiviral cytokines and chemokines but do not prevent vaginal transmission of simian immunodeficiency virus when applied intravaginally to rhesus macaques. J Virol. 2005;79:14355–14370.
   PubMed Web of Science ®Google Scholar
• Cheng L, Zhang Z, Li G, et al. Human innate responses and adjuvant activity of TLR ligands in vivo in mice reconstituted with a human immune system. Vaccine. 2017;35:6143–6153.
   PubMed Web of Science ®Google Scholar
• Chang JJ, Altfeld M. Immune activation and the role of TLRs and TLR agonists in the pathogenesis of HIV-1 infection in the humanized mouse model. J Infect Dis. 2013;208(Suppl 2):S145–149.
   PubMedGoogle Scholar
• Lavender KJ, Pang WW, Messer RJ, et al. BLT-humanized C57BL/6 Rag2-/-gammac-/-CD47-/- mice are resistant to GVHD and develop B- and T-cell immunity to HIV infection. Blood. 2013;122:4013–4020.
   PubMed Web of Science ®Google Scholar
• Lavender KJ, Gibbert K, Peterson KE, et al. Interferon alpha subtype-specific suppression of HIV-1 infection in vivo. J Virol. 2016;90:6001–6013.
   PubMed Web of Science ®Google Scholar
• Schlaepfer E, Audige A, Joller H, et al. TLR7/8 triggering exerts opposing effects in acute versus latent HIV infection. J Immunol. 2006;176:2888–2895.
   PubMed Web of Science ®Google Scholar
• Schlaepfer E, Speck RF. TLR8 activates HIV from latently infected cells of myeloid-monocytic origin directly via the MAPK pathway and from latently infected CD4+ T cells indirectly via TNF-alpha. J Immunol. 2011;186:4314–4324.
   PubMed Web of Science ®Google Scholar
• Nowak P, Abdurahman S, Lindkvist A, et al. Impact of HMGB1/TLR ligand complexes on HIV-1 replication: possible role for flagellin during HIV-1 Infection. Int J Microbiol. 2012;2012:263836.
   PubMedGoogle Scholar
• Alvarez-Carbonell D, Garcia-Mesa Y, Milne S, et al. Toll-like receptor 3 activation selectively reverses HIV latency in microglial cells. Retrovirology. 2017;14:9.
   PubMed Web of Science ®Google Scholar
• Scheller C, Ullrich A, McPherson K, et al. CpG oligodeoxynucleotides activate HIV replication in latently infected human T cells. J Biol Chem. 2004;279:21897–21902.
   PubMed Web of Science ®Google Scholar
• Jones RB, Mueller S, O’Connor R, et al. A subset of latency-reversing agents expose HIV-infected resting CD4+ T-Cells to recognition by Cytotoxic T-Lymphocytes. PLoS Pathog. 2016;12:e1005545.
   PubMed Web of Science ®Google Scholar
• Novis CL, Archin NM, Buzon MJ, et al. Reactivation of latent HIV-1 in central memory CD4(+) T cells through TLR-1/2 stimulation. Retrovirology. 2013;10:119.
   PubMed Web of Science ®Google Scholar
• Tsai A, Irrinki A, Kaur J, et al. Toll-like receptor 7 agonist GS-9620 induces HIV expression and HIV-specific immunity in cells from HIV-infected individuals on suppressive antiretroviral therapy. J Virol. 2017;91:e02166-16.
   Web of Science ®Google Scholar
• Offersen R, Nissen SK, Rasmussen TA, et al. A novel Toll-like receptor 9 agonist, MGN1703, enhances HIV-1 transcription and NK cell-mediated inhibition of HIV-1-infected autologous CD4+ T cells. J Virol. 2016;90:4441–4453.
   PubMed Web of Science ®Google Scholar
• Winckelmann AA, Munk-Petersen LV, Rasmussen TA, et al. Administration of a Toll-like receptor 9 agonist decreases the proviral reservoir in virologically suppressed HIV-infected patients. PLoS One. 2013;8:e62074.
   PubMed Web of Science ®Google Scholar
• Caron G, Duluc D, Fremaux I, et al. Direct stimulation of human T cells via TLR5 and TLR7/8: flagellin and R-848 up-regulate proliferation and IFN-gamma production by memory CD4+ T cells. J Immunol. 2005;175:1551–1557.
   PubMed Web of Science ®Google Scholar
• Sokolova V, Shi Z, Huang S, et al. Delivery of the TLR ligand poly(I:C) to liver cells in vitro and in vivo by calcium phosphate nanoparticles leads to a pronounced immunostimulation. Acta Biomater. 2017;64:401–410.
   PubMed Web of Science ®Google Scholar
• Huang S, Zou S, Chen M, et al. Local stimulation of liver sinusoidal endothelial cells with a NOD1 agonist activates T cells and suppresses hepatitis B virus replication in mice. J Immunol. 2018;200:3170–3179.
   PubMed Web of Science ®Google Scholar