Immune Netw.  2014 Aug;14(4):187-200. 10.4110/in.2014.14.4.187.

Prophylactic and Therapeutic Modulation of Innate and Adaptive Immunity Against Mucosal Infection of Herpes Simplex Virus

• Uyangaa E
• Patil AM
• Eo SK

• KMID: 2150807
• DOI: http://doi.org/10.4110/in.2014.14.4.187

Abstract

Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are the most common cause of genital ulceration in humans worldwide. Typically, HSV-1 and 2 infections via mucosal route result in a lifelong latent infection after peripheral replication in mucosal tissues, thereby providing potential transmission to neighbor hosts in response to reactivation. To break the transmission cycle, immunoprophylactics and therapeutic strategies must be focused on prevention of infection or reduction of infectivity at mucosal sites. Currently, our understanding of the immune responses against mucosal infection of HSV remains intricate and involves a balance between innate signaling pathways and the adaptive immune responses. Numerous studies have demonstrated that HSV mucosal infection induces type I interferons (IFN) via recognition of Toll-like receptors (TLRs) and activates multiple immune cell populations, including NK cells, conventional dendritic cells (DCs), and plasmacytoid DCs. This innate immune response is required not only for the early control of viral replication at mucosal sites, but also for establishing adaptive immune responses against HSV antigens. Although the contribution of humoral immune response is controversial, CD4+ Th1 T cells producing IFN-gamma are believed to play an important role in eradicating virus from the hosts. In addition, the recent experimental successes of immunoprophylactic and therapeutic compounds that enhance resistance and/or reduce viral burden at mucosal sites have accumulated. This review focuses on attempts to modulate innate and adaptive immunity against HSV mucosal infection for the development of prophylactic and therapeutic strategies. Notably, cells involved in innate immune regulations appear to shape adaptive immune responses. Thus, we summarized the current evidence of various immune mediators in response to mucosal HSV infection, focusing on the importance of innate immune responses.

Keyword

Herpes simplex virus; Mucosal infection; Innate immunity; Adaptive immunity; Toll-like receptors; Type I IFN receptors

MeSH Terms

Adaptive Immunity*
Dendritic Cells
Herpesvirus 1, Human
Humans
Immunity, Humoral
Immunity, Innate
Interferon Type I
Killer Cells, Natural
Mucous Membrane
Simplexvirus*
Social Control, Formal
T-Lymphocytes
Toll-Like Receptors
Ulcer
Viral Load
Interferon Type I
Toll-Like Receptors

Reference

1. Mansur DS, Kroon EG, Nogueira ML, Arantes RM, Rodrigues SC, Akira S, Gazzinelli RT, Campos MA. Lethal encephalitis in myeloid differentiation factor 88-deficient mice infected with herpes simplex virus 1. Am J Pathol. 2005; 166:1419–1426. PMID: 15855642.

2. Roizman B, Knipe DM. Herpes simplex viruses and their replication. In : Knipe DM, Howley PM, editors. Fields Virology. 4th edition. Lippincott Williams & Wilkins;2001. p. 2399–2459.

3. Ellermann-Eriksen S. Macrophages and cytokines in the early defence against herpes simplex virus. Virol J. 2005; 2:59. PMID: 16076403.

4. Chan T, Barra NG, Lee AJ, Ashkar AA. Innate and adaptive immunity against herpes simplex virus type 2 in the genital mucosa. J Reprod Immunol. 2011; 88:210–218. PMID: 21334750.

5. Wakimoto H, Johnson PR, Knipe DM, Chiocca EA. Effects of innate immunity on herpes simplex virus and its ability to kill tumor cells. Gene Ther. 2003; 10:983–990. PMID: 12756419.

6. Kim M, Osborne NR, Zeng W, Donaghy H, McKinnon K, Jackson DC, Cunningham AL. Herpes simplex virus antigens directly activate NK cells via TLR2, thus facilitating their presentation to CD4 T lymphocytes. J Immunol. 2012; 188:4158–4170. PMID: 22467654.

7. Harandi AM, Svennerholm B, Holmgren J, Eriksson K. Differential roles of B cells and IFN-gamma-secreting CD4(+) T cells in innate and adaptive immune control of genital herpes simplex virus type 2 infection in mice. J Gen Virol. 2001; 82:845–853. PMID: 11257190.

8. Verschoor A, Brockman MA, Knipe DM, Carroll MC. Cutting edge: myeloid complement C3 enhances the humoral response to peripheral viral infection. J Immunol. 2001; 167:2446–2451. PMID: 11509581.

9. Da Costa XJ, Brockman MA, Alicot E, Ma M, Fischer MB, Zhou X, Knipe DM, Carroll MC. Humoral response to herpes simplex virus is complement-dependent. Proc Natl Acad Sci U S A. 1999; 96:12708–12712. PMID: 10535987.

10. Kwant-Mitchell A, Ashkar AA, Rosenthal KL. Mucosal innate and adaptive immune responses against herpes simplex virus type 2 in a humanized mouse model. J Virol. 2009; 83:10664–10676. PMID: 19656896.

11. Gebhardt BM, Focher F, Eberle R, Manikowski A, Wright GE. Effect of combinations of antiviral drugs on herpes simplex encephalitis. Drug Des Devel Ther. 2009; 3:289–294.

12. Bourne KZ, Bourne N, Reising SF, Stanberry LR. Plant products as topical microbicide candidates: assessment of in vitro and in vivo activity against herpes simplex virus type 2. Antiviral Res. 1999; 42:219–226. PMID: 10443534.

13. Bernstein DI, Stanberry LR. Herpes simplex virus vaccines. Vaccine. 1999; 17:1681–1689. PMID: 10194823.

14. Kawai T, Akira S. Pathogen recognition with Toll-like receptors. Curr Opin Immunol. 2005; 17:338–344. PMID: 15950447.

15. Takeda K, Kaisho T, Akira S. Toll-like receptors. Annu Rev Immunol. 2003; 21:335–376. PMID: 12524386.

16. Kawai T, Akira S. TLR signaling. Cell Death Differ. 2006; 13:816–825. PMID: 16410796.

17. Doyle SL, O'Neill LA. Toll-like receptors: from the discovery of NFkappaB to new insights into transcriptional regulations in innate immunity. Biochem Pharmacol. 2006; 72:1102–1113. PMID: 16930560.

18. Menasria R, Boivin N, Lebel M, Piret J, Gosselin J, Boivin G. Both TRIF and IPS-1 adaptor proteins contribute to the cerebral innate immune response against herpes simplex virus 1 infection. J Virol. 2013; 87:7301–7308. PMID: 23596298.

19. Wang JP, Bowen GN, Zhou S, Cerny A, Zacharia A, Knipe DM, Finberg RW, Kurt-Jones EA. Role of specific innate immune responses in herpes simplex virus infection of the central nervous system. J Virol. 2012; 86:2273–2281. PMID: 22171256.

20. Aravalli RN, Hu S, Rowen TN, Palmquist JM, Lokensgard JR. Cutting edge: TLR2-ediated proinflammatory cytokine and chemokine production by microglial cells in response to herpes simplex virus. J Immunol. 2005; 175:4189–4193. PMID: 16177057.

21. Schachtele SJ, Hu S, Little MR, Lokensgard JR. Herpes simplex virus induces neural oxidative damage via microglial cell Toll-like receptor-2. J Neuroinflammation. 2010; 7:35. PMID: 20584314.

22. Krieg AM, Yi AK, Matson S, Waldschmidt TJ, Bishop GA, Teasdale R, Koretzky GA, Klinman DM. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature. 1995; 374:546–459. PMID: 7700380.

23. Hochrein H, Schlatter B, O'Keeffe M, Wagner C, Schmitz F, Schiemann M, Bauer S, Suter M, Wagner H. Herpes simplex virus type-1 induces IFN-alpha production via Toll-like receptor 9-dependent and -independent pathways. Proc Natl Acad Sci U S A. 2004; 101:11416–11421. PMID: 15272082.

24. Sorensen LN, Reinert LS, Malmgaard L, Bartholdy C, Thomsen AR, Paludan SR. TLR2 and TLR9 synergistically control herpes simplex virus infection in the brain. J Immunol. 2008; 181:8604–8612. PMID: 19050280.

25. Krug A, Luker GD, Barchet W, Leib DA, Akira S, Colonna M. Herpes simplex virus type 1 activates murine natural interferon-producing cells through toll-like receptor 9. Blood. 2004; 103:1433–1437. PMID: 14563635.

26. Tengvall S, Harandi AM. Importance of myeloid differentiation factor 88 in innate and acquired immune protection against genital herpes infection in mice. J Reprod Immunol. 2008; 78:49–57. PMID: 17945349.

27. Guo Y, Audry M, Ciancanelli M, Alsina L, Azevedo J, Herman M, Anguiano E, Sancho-Shimizu V, Lorenzo L, Pauwels E, Philippe PB, Perez de DR, Cardon A, Vogt G, Picard C, Andrianirina ZZ, Rozenberg F, Lebon P, Plancoulaine S, Tardieu M, Valerie D, Jouanguy E, Chaussabel D, Geissmann F, Abel L, Casanova JL, Zhang SY. Herpes simplex virus encephalitis in a patient with complete TLR3 deficiency: TLR3 is otherwise redundant in protective immunity. J Exp Med. 2011; 208:2083–2098. PMID: 21911422.

28. Reinert LS, Harder L, Holm CK, Iversen MB, Horan KA, gnaes-Hansen F, Ulhoi BP, Holm TH, Mogensen TH, Owens T, Nyengaard JR, Thomsen AR, Paludan SR. TLR3 deficiency renders astrocytes permissive to herpes simplex virus infection and facilitates establishment of CNS infection in mice. J Clin Invest. 2012; 122:1368–1376. PMID: 22426207.

29. Swann JB, Hayakawa Y, Zerafa N, Sheehan KC, Scott B, Schreiber RD, Hertzog P, Smyth MJ. Type I IFN contributes to NK cell homeostasis, activation, and antitumor function. J Immunol. 2007; 178:7540–7549. PMID: 17548588.

30. Isaacs A, Lindenmann J, Valentine RC. Virus interference. II. Some properties of interferon. Proc R Soc Lond B Biol Sci. 1957; 147:268–273. PMID: 13465721.

31. Liu YJ. IPC: professional type 1 interferon-producing cells and plasmacytoid dendritic cell precursors. Annu Rev Immunol. 2005; 23:275–306. PMID: 15771572.

32. Janeway CA, Travers P, Walport M, Shlomchik MJ. Immunobiology. The immune system in health and disease. 6th Edition. New York: Garland Science;2005. p. 461–516.

33. Kotenko SV, Gallagher G, Baurin VV, Lewis-Antes A, Shen M, Shah NK, Langer JA, Sheikh F, Dickensheets H, Donnelly RP. IFN-lambdas mediate antiviral protection through a distinct class II cytokine receptor complex. Nat Immunol. 2003; 4:69–77. PMID: 12483210.

34. Sheppard P, Kindsvogel W, Xu W, Henderson K, Schlutsmeyer S, Whitmore TE, Kuestner R, Garrigues U, Birks C, Roraback J, Ostrander C, Dong D, Shin J, Presnell S, Fox B, Haldeman B, Cooper E, Taft D, Gilbert T, Grant FJ, Tackett M, Krivan W, McKnight G, Clegg C, Foster D, Klucher KM. IL-28, IL-29 and their class II cytokine receptor IL-28R. Nat Immunol. 2003; 4:63–68. PMID: 12469119.

35. Gill N, Deacon PM, Lichty B, Mossman KL, Ashkar AA. Induction of innate immunity against herpes simplex virus type 2 infection via local delivery of Toll-like receptor ligands correlates with beta interferon production. J Virol. 2006; 80:9943–9950. PMID: 17005672.

36. Rasmussen SB, Sorensen LN, Malmgaard L, Ank N, Baines JD, Chen ZJ, Paludan SR. Type I interferon production during herpes simplex virus infection is controlled by cell-type-specific viral recognition through Toll-like receptor 9, the mitochondrial antiviral signaling protein pathway, and novel recognition systems. J Virol. 2007; 81:13315–13324. PMID: 17913820.

37. Conrady CD, Halford WP, Carr DJ. Loss of the type I interferon pathway increases vulnerability of mice to genital herpes simplex virus 2 infection. J Virol. 2011; 85:1625–1633. PMID: 21147921.

38. Conrady CD, Jones H, Zheng M, Carr DJ. A functional type I interferon pathway drives resistance to cornea herpes simplex virus type 1 infection by recruitment of leukocytes. J Biomed Res. 2011; 25:111–119. PMID: 21709805.

39. Conrady CD, Zheng M, Mandal NA, van RN, Carr DJ. IFN-alpha-driven CCL2 production recruits inflammatory monocytes to infection site in mice. Mucosal Immunol. 2013; 6:45–55. PMID: 22692455.

40. Gill N, Chenoweth MJ, Verdu EF, Ashkar AA. NK cells require type I IFN receptor for antiviral responses during genital HSV-2 infection. Cell Immunol. 2011; 269:29–37. PMID: 21477795.

41. Milligan GN, Bernstein DI. Interferon-gamma enhances resolution of herpes simplex virus type 2 infection of the murine genital tract. Virology. 1997; 229:259–268. PMID: 9123869.

42. Mikloska Z, Cunningham AL. Alpha and gamma interferons inhibit herpes simplex virus type 1 infection and spread in epidermal cells after axonal transmission. J Virol. 2001; 75:11821–11826. PMID: 11689663.

43. Dobbs ME, Strasser JE, Chu CF, Chalk C, Milligan GN. Clearance of herpes simplex virus type 2 by CD8⁺ T cells requires gamma interferon and either perforin- or Fas-mediated cytolytic mechanisms. J Virol. 2005; 79:14546–14554. PMID: 16282454.

44. Cantin E, Tanamachi B, Openshaw H. Role for gamma interferon in control of herpes simplex virus type 1 reactivation. J Virol. 1999; 73:3418–3423. PMID: 10074196.

45. Doyle SE, Schreckhise H, Khuu-Duong K, Henderson K, Rosler R, Storey H, Yao L, Liu H, Barahmand-pour F, Sivakumar P, Chan C, Birks C, Foster D, Clegg CH, Wietzke-Braun P, Mihm S, Klucher KM. Interleukin-29 uses a type 1 interferon-like program to promote antiviral responses in human hepatocytes. Hepatology. 2006; 44:896–906. PMID: 17006906.

46. Zhou Z, Hamming OJ, Ank N, Paludan SR, Nielsen AL, Hartmann R. Type III interferon (IFN) induces a type I IFN-like response in a restricted subset of cells through signaling pathways involving both the Jak-STAT pathway and the mitogen-activated protein kinases. J Virol. 2007; 81:7749–7758. PMID: 17507495.

47. Marcello T, Grakoui A, Barba-Spaeth G, Machlin ES, Kotenko SV, MacDonald MR, Rice CM. Interferons alpha and lambda inhibit hepatitis C virus replication with distinct signal transduction and gene regulation kinetics. Gastroenterology. 2006; 131:1887–1898. PMID: 17087946.

48. Ank N, West H, Bartholdy C, Eriksson K, Thomsen AR, Paludan SR. Lambda interferon (IFN-lambda), a type III IFN, is induced by viruses and IFNs and displays potent antiviral activity against select virus infections in vivo. J Virol. 2006; 4501–4509. PMID: 16611910.

49. Ank N, Iversen MB, Bartholdy C, Staeheli P, Hartmann R, Jensen UB, gnaes-Hansen F, Thomsen AR, Chen Z, Haugen H, Klucher K, Paludan SR. An important role for type III interferon (IFN-lambda/IL-28) in TLR-induced antiviral activity. J Immunol. 2008; 180:2474–2485. PMID: 18250457.

50. Iversen MB, Ank N, Melchjorsen J, Paludan SR. Expression of type III interferon (IFN) in the vaginal mucosa is mediated primarily by dendritic cells and displays stronger dependence on NF-kappaB than type I IFNs. J Virol. 2010; 84:4579–4586. PMID: 20181703.

51. Li J, Hu S, Zhou L, Ye L, Wang X, Ho J, Ho W. Interferon lambda inhibits herpes simplex virus type I infection of human astrocytes and neurons. Glia. 2011; 59:58–67. PMID: 20878770.

52. Li J, Ye L, Wang X, Hu S, Ho W. Induction of interferon-gamma contributes to Toll-like receptor 3-mediated herpes simplex virus type 1 inhibition in astrocytes. J Neurosci Res. 2012; 90:399–406. PMID: 22057682.

53. Ghiasi H, Cai S, Perng GC, Nesburn AB, Wechsler SL. The role of natural killer cells in protection of mice against death and corneal scarring following ocular HSV-1 infection. Antiviral Res. 2000; 45:33–45. PMID: 10774588.

54. Lehmann C, Zeis M, Uharek L. Activation of natural killer cells with interleukin 2 (IL-2) and IL-12 increases perforin binding and subsequent lysis of tumour cells. Br J Haematol. 2001; 114:660–665. PMID: 11552995.

55. Ashkar AA, Rosenthal KL. Interleukin-15 and natural killer and NKT cells play a critical role in innate protection against genital herpes simplex virus type 2 infection. J Virol. 2003; 77:10168–10171. PMID: 12941930.

56. Reading PC, Whitney PG, Barr DP, Wojtasiak M, Mintern JD, Waithman J, Brooks AG. IL-18, but not IL-12, regulates NK cell activity following intranasal herpes simplex virus type 1 infection. J Immunol. 2007; 179:3214–3221. PMID: 17709537.

57. Nandakumar S, Woolard SN, Yuan D, Rouse BT, Kumaraguru U. Natural killer cells as novel helpers in anti-herpes simplex virus immune response. J Virol. 2008; 82:10820–10831. PMID: 18715907.

58. Staats HF, Oakes JE, Lausch RN. Anti-glycoprotein D monoclonal antibody protects against herpes simplex virus type 1-induced diseases in mice functionally depleted of selected T-cell subsets or asialo GM1⁺ cells. J Virol. 1991; 65:6008–6014. PMID: 1920624.

59. Kassim SH, Rajasagi NK, Zhao X, Chervenak R, Jennings SR. In vivo ablation of CD11c-positive dendritic cells increases susceptibility to herpes simplex virus type 1 infection and diminishes NK and T-cell responses. J Virol. 2006; 80:3985–3993. PMID: 16571815.

60. Zhao X, Deak E, Soderberg K, Linehan M, Spezzano D, Zhu J, Knipe DM, Iwasaki A. Vaginal submucosal dendritic cells, but not Langerhans cells, induce protective Th1 responses to herpes simplex virus-2. J Exp Med. 2003; 197:153–162. PMID: 12538655.

61. Sato A, Iwasaki A. Induction of antiviral immunity requires Toll-like receptor signaling in both stromal and dendritic cell compartments. Proc Natl Acad Sci U S A. 2004; 101:16274–16279. PMID: 15534227.

62. Reske A, Pollara G, Krummenacher C, Katz DR, Chain BM. Glycoprotein-dependent and TLR2-independent innate immune recognition of herpes simplex virus-1 by dendritic cells. J Immunol. 2008; 180:7525–7536. PMID: 18490753.

63. Kassim SH, Rajasagi NK, Ritz BW, Pruett SB, Gardner EM, Chervenak R, Jennings SR. Dendritic cells are required for optimal activation of natural killer functions following primary infection with herpes simplex virus type 1. J Virol. 2009; 83:3175–3186. PMID: 19144708.

64. Frank GM, Buela KA, Maker DM, Harvey SA, Hendricks RL. Early responding dendritic cells direct the local NK response to control herpes simplex virus 1 infection within the cornea. J Immunol. 2012; 188:1350–1359. PMID: 22210909.

65. Bryant-Hudson KM, Carr DJ. PD-L1-expressing dendritic cells contribute to viral resistance during acute HSV-1 infection. Clin Dev Immunol. 2012; 2012:924619. PMID: 22474484.

66. Lund J, Sato A, Akira S, Medzhitov R, Iwasaki A. Toll-like receptor 9-mediated recognition of Herpes simplex virus-2 by plasmacytoid dendritic cells. J Exp Med. 2003; 198:513–520. PMID: 12900525.

67. Shen H, Iwasaki A. A crucial role for plasmacytoid dendritic cells in antiviral protection by CpG ODN-based vaginal microbicide. J Clin Invest. 2006; 116:2237–2243. PMID: 16878177.

68. Lund JM, Linehan MM, Iijima N, Iwasaki A. Cutting Edge: Plasmacytoid dendritic cells provide innate immune protection against mucosal viral infection in situ. J Immunol. 2006; 177:7510–7514. PMID: 17114418.

69. Mott KR, Underhill D, Wechsler SL, Town T, Ghiasi H. A role for the JAK-STAT1 pathway in blocking replication of HSV-1 in dendritic cells and macrophages. Virol J. 2009; 6:56. PMID: 19439086.

70. Swaminathan S, Hu X, Zheng X, Kriga Y, Shetty J, Zhao Y, Stephens R, Tran B, Baseler MW, Yang J, Lempicki RA, Huang D, Lane HC, Imamichi T. Interleukin-27 treated human macrophages induce the expression of novel microRNAs which may mediate anti-viral properties. Biochem Biophys Res Commun. 2013; 434:228–234. PMID: 23535375.

71. Mott KR, Gate D, Zandian M, Allen SJ, Rajasagi NK, van RN, Chen S, Arditi M, Rouse BT, Flavell RA, Town T, Ghiasi H. Macrophage IL-12p70 signaling prevents HSV-1-induced CNS autoimmunity triggered by autoaggressive CD4⁺ Tregs. Invest Ophthalmol Vis Sci. 2011; 52:2321–2333. PMID: 21220560.

72. Zolini GP, Lima GK, Lucinda N, Silva MA, Dias MF, Pessoa NL, Coura BP, Cartelle CT, Arantes RM, Kroon EG, Campos MA. Defense against HSV-1 in a murine model is mediated by iNOS and orchestrated by the activation of TLR2 and TLR9 in trigeminal ganglia. J Neuroinflammation. 2014; 11:20. PMID: 24479442.

73. Iijima N, Mattei LM, Iwasaki A. Recruited inflammatory monocytes stimulate antiviral Th1 immunity in infected tissue. Proc Natl Acad Sci U S A. 2011; 108:284–289. PMID: 21173243.

74. Milligan GN. Neutrophils aid in protection of the vaginal mucosae of immune mice against challenge with herpes simplex virus type 2. J Virol. 1999; 73:6380–6386. PMID: 10400730.

75. Molesworth-Kenyon SJ, Popham N, Milam A, Oakes JE, Lausch RN. Resident corneal cells communicate with neutrophils leading to the production of IP-10 during the primary inflammatory response to HSV-1 infection. Int J Inflam. 2012; 2012:810359. PMID: 22518343.

76. Wojtasiak M, Pickett DL, Tate MD, Londrigan SL, Bedoui S, Brooks AG, Reading PC. Depletion of Gr-1⁺, but not Ly6G⁺, immune cells exacerbates virus replication and disease in an intranasal model of herpes simplex virus type 1 infection. J Gen Virol. 2010; 91:2158–2166. PMID: 20538903.

77. Parr MB, Parr EL. Immunity to vaginal herpes simplex virus-2 infection in B-cell knockout mice. Immunology. 2000; 101:126–131. PMID: 11012763.

78. Gorander S, Harandi AM, Lindqvist M, Bergstrom T, Liljeqvist JA. Glycoprotein G of herpes simplex virus 2 as a novel vaccine antigen for immunity to genital and neurological disease. J Virol. 2012; 86:7544–7553. PMID: 22553328.

79. Liu K, Jiang D, Zhang L, Yao Z, Chen Z, Yu S, Wang X. Identification of B- and T-cell epitopes from glycoprotein B of herpes simplex virus 2 and evaluation of their immunogenicity and protection efficacy. Vaccine. 2012; 30:3034–3041. PMID: 22008818.

80. Deshpande SP, Zheng M, Daheshia M, Rouse BT. Pathogenesis of herpes simplex virus-induced ocular immunoinflammatory lesions in B-cell-deficient mice. J Virol. 2000; 74:3517–3524. PMID: 10729125.

81. Peek R, Verjans GM, Meek B. Herpes simplex virus infection of the human eye induces a compartmentalized virus-specific B cell response. J Infect Dis. 2002; 186:1539–1546. PMID: 12447728.

82. Iijima N, Linehan MM, Zamora M, Butkus D, Dunn R, Kehry MR, Laufer TM, Iwasaki A. Dendritic cells and B cells maximize mucosal Th1 memory response to herpes simplex virus. J Exp Med. 2008; 205:3041–3052. PMID: 19047439.

83. Del Campo J, Lindqvist M, Cuello M, Backstrom M, Cabrerra O, Persson J, Perez O, Harandi AM. Intranasal immunization with a proteoliposome-derived cochleate containing recombinant gD protein confers protective immunity against genital herpes in mice. Vaccine. 2010; 28:1193–1200. PMID: 19945418.

84. Cortesi R, Ravani L, Rinaldi F, Marconi P, Drechsler M, Manservigi M, Argnani R, Menegatti E, Esposito E, Manservigi R. Intranasal immunization in mice with non-ionic surfactants vesicles containing HSV immunogens: a preliminary study as possible vaccine against genital herpes. Int J Pharm. 2013; 440:229–237. PMID: 22743007.

85. Chiuppesi F, Vannucci L, De LA, Lai M, Matteoli B, Freer G, Manservigi R, Ceccherini-Nelli L, Maggi F, Bendinelli M, Pistello M. A lentiviral vector-based, herpes simplex virus 1 (HSV-1) glycoprotein B vaccine affords cross-protection against HSV-1 and HSV-2 genital infections. J Virol. 2012; 86:6563–6574. PMID: 22491465.

86. Kuklin NA, Daheshia M, Chun S, Rouse BT. Role of mucosal immunity in herpes simplex virus infection. J Immunol. 1998; 160:5998–6003. PMID: 9637514.

87. Dudley KL, Bourne N, Milligan GN. Immune protection against HSV-2 in B-cell-deficient mice. Virology. 2000; 270:454–463. PMID: 10793004.

88. Morrison LA, Zhu L, hebeau LG. Vaccine-induced serum immunoglobin contributes to protection from herpes simplex virus type 2 genital infection in the presence of immune T cells. J Virol. 2001; 75:1195–1204. PMID: 11152492.

89. Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of T(H)17 cells. Nature. 2008; 453:1051–1057. PMID: 18563156.

90. Suryawanshi A, Veiga-Parga T, Rajasagi NK, Reddy PB, Sehrawat S, Sharma S, Rouse BT. Role of IL-17 and Th17 cells in herpes simplex virus-induced corneal immunopathology. J Immunol. 2011; 187:1919–1930. PMID: 21765013.

91. Eo SK, Lee S, Chun S, Rouse BT. Modulation of immunity against herpes simplex virus infection via mucosal genetic transfer of plasmid DNA encoding chemokines. J Virol. 2001; 75:569–578. PMID: 11134269.

92. Kumamoto Y, Mattei LM, Sellers S, Payne GW, Iwasaki A. CD4⁺ T cells support cytotoxic T lymphocyte priming by controlling lymph node input. Proc Natl Acad Sci U S A. 2011; 108:8749–8754. PMID: 21555577.

93. Rajasagi NK. The role of CD4⁺ Helper T cells, IL-2 and IL-15 in the generation of an optimal CD8⁺ T cell response following infection with herpes simplex virus-1 (HSV-1). 2007. 56–61. Louisiana State University Health Sciences Center-Shreveport, ProQuest, UMI Dissertations Publishing Number: 3311956.

94. Ghiasi H, Cai S, Perng GC, Nesburn AB, Wechsler SL. Both CD4⁺ and CD8⁺ T cells are involved in protection against HSV-1 induced corneal scarring. Br J Ophthalmol. 2000; 84:408–412. PMID: 10729300.

95. Koelle DM, Posavad CM, Barnum GR, Johnson ML, Frank JM, Corey L. Clearance of HSV-2 from recurrent genital lesions correlates with infiltration of HSV-specific cytotoxic T lymphocytes. J Clin Invest. 1998; 101:1500–1508. PMID: 9525993.

96. Coleman CA, Muller-Trutwin MC, Apetrei C, Pandrea I. T regulatory cells: aid or hindrance in the clearance of disease? J Cell Mol Med. 2007; 11:1291–1325. PMID: 18205702.

97. Dasgupta G, Chentoufi AA, You S, Falatoonzadeh P, Urbano LA, Akhtarmalik A, Nguyen K, Ablabutyan L, Nesburn AB, BenMohamed L. Engagement of TLR2 reverses the suppressor function of conjunctiva CD4⁺CD25⁺ regulatory T cells and promotes herpes simplex virus epitope-specific CD4⁺CD25^- effector T cell responses. Invest Ophthalmol Vis Sci. 2011; 52:3321–3333. PMID: 21273544.

98. Sehrawat S, Suvas S, Sarangi PP, Suryawanshi A, Rouse BT. In vitro-generated antigen-specific CD4⁺ CD25⁺ Foxp3⁺ regulatory T cells control the severity of herpes simplex virus-induced ocular immunoinflammatory lesions. J Virol. 2008; 82:6838–6851. PMID: 18480441.

99. Kim JO, Cha HR, Kim ED, Kweon MN. Pathological effect of IL-17A-producing TCRgammadelta(+) T cells in mouse genital mucosa against HSV-2 infection. Immunol Lett. 2012; 147:34–40. PMID: 22698680.

100. Jirmo AC, Nagel CH, Bohnen C, Sodeik B, Behrens GM. Contribution of direct and cross-presentation to CTL immunity against herpes simplex virus 1. J Immunol. 2009; 182:283–292. PMID: 19109159.

101. St Leger AJ, Peters B, Sidney J, Sette A, Hendricks RL. Defining the herpes simplex virus-specific CD8⁺ T cell repertoire in C57BL/6 mice. J Immunol. 2011; 186:3927–3933. PMID: 21357536.

102. van Lint A, Ayers M, Brooks AG, Coles RM, Heath WR, Carbone FR. Herpes simplex virus-specific CD8⁺ T cells can clear established lytic infections from skin and nerves and can partially limit the early spread of virus after cutaneous inoculation. J Immunol. 2004; 172:392–397. PMID: 14688347.

103. Koelle DM, Posavad CM, Barnum GR, Johnson ML, Frank JM, Corey L. Clearance of HSV-2 from recurrent genital lesions correlates with infiltration of HSV-specific cytotoxic T lymphocytes. J Clin Invest. 1998; 101:1500–1508. PMID: 9525993.

104. Himmelein S, St Leger AJ, Knickelbein JE, Rowe A, Freeman ML, Hendricks RL. Circulating herpes simplex type 1 (HSV-1)-specific CD8⁺ T cells do not access HSV-1 latently infected trigeminal ganglia. Herpesviridae. 2011; 2:5. PMID: 21429183.

105. Koelle DM, Corey L. Herpes simplex: insights on pathogenesis and possible vaccines. Annu Rev Med. 2008; 59:381–395. PMID: 18186706.

106. Wilson SS, Fakioglu E, Herold BC. Novel approaches in fighting herpes simplex virus infections. Expert Rev Anti Infect Ther. 2009; 7:559–568. PMID: 19485796.

107. Petrera E, Coto CE. Effect of the potent antiviral 1-cinnamoyl-3,11-dihydroxymeliacarpin on cytokine production by murine macrophages stimulated with HSV-2. Phytother Res. 2014; 28:104–109. PMID: 23512754.

108. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell. 2006; 124:783–801. PMID: 16497588.

109. Miller RL, Tomai MA, Harrison CJ, Bernstein DI. Immunomodulation as a treatment strategy for genital herpes: review of the evidence. Int Immunopharmacol. 2002; 2:443–451. PMID: 11962724.

110. Ashkar AA, Yao XD, Gill N, Sajic D, Patrick AJ, Rosenthal KL. Toll-like receptor (TLR)-3, but not TLR4, agonist protects against genital herpes infection in the absence of inflammation seen with CpG DNA. J Infect Dis. 2004; 190:1841–1849. PMID: 15499542.

111. Boivin N, Sergerie Y, Rivest S, Boivin G. Effect of pretreatment with toll-like receptor agonists in a mouse model of herpes simplex virus type 1 encephalitis. J Infect Dis. 2008; 198:664–672. PMID: 18662130.

112. Ashkar AA, Bauer S, Mitchell WJ, Vieira J, Rosenthal KL. Local delivery of CpG oligodeoxynucleotides induces rapid changes in the genital mucosa and inhibits replication, but not entry, of herpes simplex virus type 2. J Virol. 2003; 77:8948–8956. PMID: 12885911.

113. Gill N, Davies EJ, Ashkar AA. The role of toll-like receptor ligands/agonists in protection against genital HSV-2 infection. Am J Reprod Immunol. 2008; 59:35–43. PMID: 18154594.

114. Sajic D, Patrick AJ, Rosenthal KL. Mucosal delivery of CpG oligodeoxynucleotides expands functional dendritic cells and macrophages in the vagina. Immunology. 2005; 114:213–224. PMID: 15667566.

115. Tumpey TM, Cheng H, Yan XT, Oakes JE, Lausch RN. Chemokine synthesis in the HSV-1-infected cornea and its suppression by interleukin-10. J Leukoc Biol. 1998; 63:486–492. PMID: 9544579.

116. Kratholm SK, Iversen MB, Reinert L, Jensen SK, Hokland M, Andersen T, Rankin A, Young D, Frische S, Paludan SR, Holm CK. Interleukin-21 receptor signalling is important for innate immune protection against HSV-2 infections. PLoS One. 2013; 8:e81790. PMID: 24358128.

117. Kim SB, Han YW, Rahman MM, Kim SJ, Yoo DJ, Kang SH, Kim K, Eo SK. Modulation of protective immunity against herpes simplex virus via mucosal genetic co-transfer of DNA vaccine with beta2-adrenergic agonist. Exp Mol Med. 2009; 41:812–823. PMID: 19641376.

118. Lindqvist M, Persson J, Thorn K, Harandi AM. The mucosal adjuvant effect of alpha-galactosylceramide for induction of protective immunity to sexually transmitted viral infection. J Immunol. 2009; 182:6435–6443. PMID: 19414797.

119. Uyangaa E, Lee HK, Eo SK. Glutamine and leucine provide enhanced protective immunity against mucosal infection with herpes simplex virus type 1. Immune Netw. 2012; 12:196–206. PMID: 23213313.

120. Kuo YC, Lee YC, Leu YL, Tsai WJ, Chang SC. Efficacy of orally administered Lobelia chinensis extracts on herpes simplex virus type 1 infection in BALB/c mice. Antiviral Res. 2008; 80:206–212. PMID: 18621082.

121. Cho A, Roh YS, Uyangaa E, Park S, Kim JW, Lim KH, Kwon J, Eo SK, Lim CW, Kim B. Protective effects of red ginseng extract against vaginal herpes simplex virus infection. J Ginseng Res. 2013; 37:210–218. PMID: 23717174.

122. Petrera E, Coto CE. Effect of the potent antiviral 1-cinnamoyl-3,11-dihydroxymeliacarpin on cytokine production by murine macrophages stimulated with HSV-2. Phytother Res. 2014; 28:104–109. PMID: 23512754.

123. Ushio C, Ariyasu H, Ariyasu T, Arai S, Ohta T, Fukuda S. Suppressive effects of a cyanine dye against herpes simplex virus (HSV)-1 infection. Biomed Res. 2009; 30:365–368. PMID: 20051646.

124. Balzarini J, Andrei G, Balestra E, Huskens D, Vanpouille C, Introini A, Zicari S, Liekens S, Snoeck R, Holy A, Perno CF, Margolis L, Schols D. A multi-targeted drug candidate with dual anti-HIV and anti-HSV activity. PLoS Pathog. 2013; 9:e1003456. PMID: 23935482.

125. Hu K, He X, Yu F, Yuan X, Hu W, Liu C, Zhao F, Dou J. Immunization with DNA vaccine expressing herpes simplex virus type 1 gD and IL-21 protects against mouse herpes keratitis. Immunol Invest. 2011; 40:265–278. PMID: 21204603.

126. Awasthi S, Balliet JW, Flynn JA, Lubinski JM, Shaw CE, DiStefano DJ, Cai M, Brown M, Smith JF, Kowalski R, Swoyer R, Galli J, Copeland V, Rios S, Davidson RC, Salnikova M, Kingsley S, Bryan J, Casimiro DR, Friedman HM. Protection provided by a herpes simplex virus 2 (HSV-2) glycoprotein C and D subunit antigen vaccine against genital HSV-2 infection in HSV-1-seropositive guinea pigs. J Virol. 2014; 88:2000–2010. PMID: 24284325.

127. Brans R, Yao F. Immunization with a dominant-negative recombinant Herpes Simplex Virus (HSV) type 1 protects against HSV-2 genital disease in guinea pigs. BMC Microbiol. 2010; 10:163. PMID: 20525279.

128. Koelle DM, Magaret A, McClurkan CL, Remington ML, T . Warren, Teofilovici F, Wald A. Phase I dose-escalation study of a monovalent heat shock protein 70-herpes simplex virus type 2 (HSV-2) peptide-based vaccine designed to prime or boost CD8 T-cell responses in HSV-naive and HSV-2-infected subjects. Clin Vaccine Immunol. 2008; 15:773–782. PMID: 18353920.

129. Zhang X, Chentoufi AA, Dasgupta G, Nesburn AB, Wu M, Zhu X, Carpenter D, Wechsler SL, You S, BenMohamed L. A genital tract peptide epitope vaccine targeting TLR-2 efficiently induces local and systemic CD8⁺ T cells and protects against herpes simplex virus type 2 challenge. Mucosal Immunol. 2009; 2:129–143. PMID: 19129756.

130. Jamali A, Roostaee MH, Soleimanjahi H, Ghaderi PF, Bamdad T. DNA vaccine-encoded glycoprotein B of HSV-1 fails to protect chronic morphine-treated mice against HSV-1 challenge. Comp Immunol Microbiol Infect Dis. 2007; 30:71–80. PMID: 17126902.

131. Johnston C, Koelle DM, Wald A. HSV-2: in pursuit of a vaccine. J Clin Invest. 2011; 121:4600–4609. PMID: 22133885.

132. Belshe RB, Leone PA, Bernstein DI, Wald A, Levin MJ, Stapleton JT, Gorfinkel I, Morrow RL, Ewell MG, Stokes-Riner A, Dubin G, Heineman TC, Schulte JM, Deal CD. Efficacy results of a trial of a herpes simplex vaccine. N Engl J Med. 2012; 366:34–43. PMID: 22216840.

133. Stanberry LR, Bernstein DI, Burke RL, Pachl C, Myers MG. Vaccination with recombinant herpes simplex virus glycoproteins: protection against initial and recurrent genital herpes. J Infect Dis. 1987; 155:914–920. PMID: 3031173.

134. Bourne N, Bravo FJ, Francotte M, Bernstein DI, Myers MG, Slaoui M, Stanberry LR. Herpes simplex virus (HSV) type 2 glycoprotein D subunit vaccines and protection against genital HSV-1 or HSV-2 disease in guinea pigs. J Infect Dis. 2003; 187:542–549. PMID: 12599070.

135. Bourne N, Milligan GN, Stanberry LR, Stegall R, Pyles RB. Impact of immunization with glycoprotein D2/AS04 on herpes simplex virus type 2 shedding into the genital tract in guinea pigs that become infected. J Infect Dis. 2005; 192:2117–2123. PMID: 16288376.

136. Stanberry LR, Spruance SL, Cunningham AL, Bernstein DI, Mindel A, Sacks S, Tyring S, Aoki FY, Slaoui M, Denis M, Vandepapeliere P, Dubin G. Glycoprotein-D-adjuvant vaccine to prevent genital herpes. N Engl J Med. 2002; 347:1652–1661. PMID: 12444179.

137. Corey L, Langenberg AG, Ashley R, Sekulovich RE, Izu AE, Douglas JM Jr, Handsfield HH, Warren T, Marr L, Tyring S, DiCarlo R, Adimora AA, Leone P, Dekker CL, Burke RL, Leong WP, Straus SE. Chiron HSV Vaccine Study Group. Recombinant glycoprotein vaccine for the prevention of genital HSV-2 infection: two randomized controlled trials. JAMA. 1999; 282:331–340. PMID: 10432030.

138. Ghasemi M, Erturk M, Buruk K, Sonmez M. Induction of potent protection against acute and latent herpes simplex virus infection in mice vaccinated with dendritic cells. Cytotherapy. 2013; 15:352–361. PMID: 23579060.