What is the problem with helper t cells carrying out this function in hiv infection?

1. McMichael AJ, Borrow P, Tomaras GD, Goonetilleke N, Haynes BF: The immune response during acute HIV-1 infection: clues for vaccine development. Nat Rev Immunol. 2010, 10: 11-23. 10.1038/nri2674.

   PubMed Central  CAS  PubMed  Google Scholar 

2. Cadogan M, Dalgleish AG: HIV immunopathogenesis and strategies for intervention. Lancet Infect Dis. 2008, 8: 675-684. 10.1016/S1473-3099(08)70205-6.

   CAS  PubMed  Google Scholar 

3. Warrilow D, Stenzel D, Harrich D: Isolated HIV-1 core is active for reverse transcription. Retrovirology. 2007, 4: 77-10.1186/1742-4690-4-77.

   PubMed Central  PubMed  Google Scholar 

4. Grossman Z, Meier-Schellersheim M, Paul WE, Picker LJ: Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nat Med. 2006, 12: 289-295. 10.1038/nm1380.

   CAS  PubMed  Google Scholar 

5. Finkel TH, Tudor-Williams G, Banda NK, Cotton MF, Curiel T, Monks C, Baba TW, Ruprecht RM, Kupfer A: Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med. 1995, 1: 129-134. 10.1038/nm0295-129.

   CAS  PubMed  Google Scholar 

6. Hazenberg MD, Stuart JW, Otto SA, Borleffs JC, Boucher CA, de Boer RJ, Miedema F, Hamann D: T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). Blood. 2000, 95: 249-255.

   CAS  PubMed  Google Scholar 

7. Broder S, Gallo RC: A pathogenic retrovirus (HTLV-III) linked to AIDS. N Engl J Med. 1984, 311: 1292-1297. 10.1056/NEJM198411153112006.

   CAS  PubMed  Google Scholar 

8. Barré-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, Dauguet C, Axler-Blin C, Vézinet-Brun F, Rouzioux C, Rozenbaum W, Montagnier L: Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science. 1983, 220: 868-871. 10.1126/science.6189183.

   PubMed  Google Scholar 

9. Keele BF, Giorgi EE, Salazar-Gonzalez JF, Decker JM, Pham KT, Salazar MG, Sun C, Grayson T, Wang S, Li H, Wei X, Jiang C, Kirchherr JL, Gao F, Anderson JA, Ping LH, Swanstrom R, Tomaras GD, Blattner WA, Goepfert PA, Kilby JM, Saag MS, Delwart EL, Busch MP, Cohen MS, Montefiori DC, Haynes BF, Gaschen B, Athreya GS, Lee HY, Wood N, Seoighe C, Perelson AS, Bhattacharya T, Korber BT, Hahn BH, Shaw GM: Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci USA. 2008, 105: 7552-7557. 10.1073/pnas.0802203105.

   PubMed Central  CAS  PubMed  Google Scholar 

10. Derdeyn CA, Decker JM, Bibollet-Ruche F, Mokili JL, Muldoon M, Denham SA, Heil ML, Kasolo F, Musonda R, Hahn BH, Shaw GM, Korber BT, Allen S, Hunter E: Envelope-constrained neutralization-sensitive HIV-1 after heterosexual transmission. Science. 2004, 303: 2019-2022. 10.1126/science.1093137.

    CAS  PubMed  Google Scholar 

11. Salazar-Gonzalez JF, Salazar MG, Keele BF, Learn GH, Giorgi EE, Li H, Decker JM, Wang S, Baalwa J, Kraus MH, Parrish NF, Shaw KS, Guffey MB, Bar KJ, Davis KL, Ochsenbauer-Jambor C, Kappes JC, Saag MS, Cohen MS, Mulenga J, Derdeyn CA, Allen S, Hunter E, Markowitz M, Hraber P, Perelson AS, Bhattacharya T, Haynes BF, Korber BT, Hahn BH, Shaw GM: Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection. J Exp Med. 2009, 206: 1273-1289. 10.1084/jem.20090378.

    PubMed Central  CAS  PubMed  Google Scholar 

12. Veazey RS, Marx PA, Lackner AA: Vaginal CD4+ T cells express high levels of CCR5 and are rapidly depleted in simian immunodeficiency virus infection. J Infect Dis. 2003, 187: 769-776. 10.1086/368386.

    CAS  PubMed  Google Scholar 

13. Geijtenbeek TB, Kwon DS, Torensma R, van Vliet SJ, van Duijnhoven GC, Middel J, Cornelissen IL, Nottet HS, KewalRamani VN, Littman DR, Figdor CG, van Kooyk Y: DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell. 2000, 100: 587-597. 10.1016/S0092-8674(00)80694-7.

    CAS  PubMed  Google Scholar 

14. Moir S, Malaspina A, Li Y, Chun TW, Lowe T, Adelsberger J, Baseler M, Ehler LA, Liu S, Davey RT, Mican JA, Fauci AS: B cells of HIV-1-infected patients bind virions through CD21-complement interactions and transmit infectious virus to activated T cells. J Exp Med. 2000, 192: 637-646. 10.1084/jem.192.5.637.

    PubMed Central  CAS  PubMed  Google Scholar 

15. Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, Nguyen PL, Khoruts A, Larson M, Haase AT, Douek DC: CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med. 2004, 200: 749-759. 10.1084/jem.20040874.

    PubMed Central  CAS  PubMed  Google Scholar 

16. Veazey RS, Mansfield KG, Tham IC, Carville AC, Shvetz DE, Forand AE, Lackner AA: Dynamics of CCR5 expression by CD4(+) T cells in lymphoid tissues during simian immunodeficiency virus infection. J Virol. 2000, 74: 11001-11007. 10.1128/JVI.74.23.11001-11007.2000.

    PubMed Central  CAS  PubMed  Google Scholar 

17. Veazey RS, Tham IC, Mansfield KG, DeMaria M, Forand AE, Shvetz DE, Chalifoux LV, Sehgal PK, Lackner AA: Identifying the target cell in primary simian immunodeficiency virus (SIV) infection: highly activated memory CD4(+) T cells are rapidly eliminated in early SIV infection in vivo. J Virol. 2000, 74: 57-64. 10.1128/JVI.74.1.57-64.2000.

    PubMed Central  CAS  PubMed  Google Scholar 

18. Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR, Knight HL, Rosenzweig M, Johnson RP, Desrosiers RC, Lackner AA: Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science. 1998, 280: 427-431. 10.1126/science.280.5362.427.

    CAS  PubMed  Google Scholar 

19. Mehandru S, Poles MA, Tenner-Racz K, Horowitz A, Hurley A, Hogan C, Boden D, Racz P, Markowitz M: Primary HIV-1 infection is associated with preferential depletion of CD4+ T lymphocytes from effector sites in the gastrointestinal tract. J Exp Med. 2004, 200: 761-770. 10.1084/jem.20041196.

    PubMed Central  CAS  PubMed  Google Scholar 

20. Mattapallil JJ, Douek DC, Hill B, Nishimura Y, Martin M, Roederer M: Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature. 2005, 434: 1093-1097. 10.1038/nature03501.

    CAS  PubMed  Google Scholar 

21. Li Q, Duan L, Estes JD, Ma ZM, Rourke T, Wang Y, Reilly C, Carlis J, Miller CJ, Haase AT: Peak SIV replication in resting memory CD4+ T cells depletes gut lamina propria CD4+ T cells. Nature. 2005, 434: 1148-1152.

    CAS  PubMed  Google Scholar 

22. Guadalupe M, Reay E, Sankaran S, Prindiville T, Flamm J, McNeil A, Dandekar S: Severe CD4+ T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy. J Virol. 2003, 77: 11708-11717. 10.1128/JVI.77.21.11708-11717.2003.

    PubMed Central  CAS  PubMed  Google Scholar 

23. Picker LJ, Watkins DI: HIV pathogenesis: the first cut is the deepest. Nat Immunol. 2005, 6: 430-432. 10.1038/ni0505-430.

    CAS  PubMed  Google Scholar 

24. Kahn JO, Walker BD: Acute human immunodeficiency virus type 1 infection. N Engl J Med. 1998, 339: 33-39. 10.1056/NEJM199807023390107.

    CAS  PubMed  Google Scholar 

25. Dinoso JB, Kim SY, Wiegand AM, Palmer SE, Gange SJ, Cranmer L, O'Shea A, Callender M, Spivak A, Brennan T, Kearney MF, Proschan MA, Mican JM, Rehm CA, Coffin JM, Mellors JW, Siliciano RF, Maldarelli F: Treatment intensification does not reduce residual HIV-1 viremia in patients on highly active antiretroviral therapy. Proc Natl Acad Sci USA. 2009, 106: 9403-9408. 10.1073/pnas.0903107106.

    PubMed Central  CAS  PubMed  Google Scholar 

26. Schacker TW, Hughes JP, Shea T, Coombs RW, Corey L: Biological and virologic characteristics of primary HIV infection. Ann Intern Med. 1998, 128: 613-620.

    CAS  PubMed  Google Scholar 

27. Schmitz JE, Kuroda MJ, Santra S, Sasseville VG, Simon MA, Lifton MA, Racz P, Tenner-Racz K, Dalesandro M, Scallon BJ, Ghrayeb J, Forman MA, Montefiori DC, Rieber EP, Letvin NL, Reimann KA: Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science. 1999, 283: 857-860. 10.1126/science.283.5403.857.

    CAS  PubMed  Google Scholar 

28. Jin X, Bauer DE, Tuttleton SE, Lewin S, Gettie A, Blanchard J, Irwin CE, Safrit JT, Mittler J, Weinberger L, Kostrikis LG, Zhang L, Perelson AS, Ho DD: Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques. J Exp Med. 1999, 189: 991-998. 10.1084/jem.189.6.991.

    PubMed Central  CAS  PubMed  Google Scholar 

29. Pantaleo G, Demarest JF, Soudeyns H, Graziosi C, Denis F, Adelsberger JW, Borrow P, Saag MS, Shaw GM, Sekaly RP, et al: Major expansion of CD8+ T cells with a predominant V beta usage during the primary immune response to HIV. Nature. 1994, 370: 463-467. 10.1038/370463a0.

    CAS  PubMed  Google Scholar 

30. Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MB: Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection. J Virol. 1994, 68: 6103-6110.

    PubMed Central  CAS  PubMed  Google Scholar 

31. Davenport MP, Petravic J: CD8+ T cell control of HIV--a known unknown. PLoS Pathog. 2010, 6: e1000728-10.1371/journal.ppat.1000728.

    PubMed Central  PubMed  Google Scholar 

32. Wong JK, Strain MC, Porrata R, Reay E, Sankaran-Walters S, Ignacio CC, Russell T, Pillai SK, Looney DJ, Dandekar S: In vivo CD8+ T-cell suppression of siv viremia is not mediated by CTL clearance of productively infected cells. PLoS Pathog. 2010, 6: e1000748-10.1371/journal.ppat.1000748.

    PubMed Central  PubMed  Google Scholar 

33. Klatt NR, Shudo E, Ortiz AM, Engram JC, Paiardini M, Lawson B, Miller MD, Else J, Pandrea I, Estes JD, Apetrei C, Schmitz JE, Ribeiro RM, Perelson AS, Silvestri G: CD8+ lymphocytes control viral replication in SIVmac239-infected rhesus macaques without decreasing the lifespan of productively infected cells. PLoS Pathog. 2010, 6: e1000747-10.1371/journal.ppat.1000747.

    PubMed Central  PubMed  Google Scholar 

34. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M: Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995, 373: 123-126. 10.1038/373123a0.

    CAS  PubMed  Google Scholar 

35. Ford ES, Puronen CE, Sereti I: Immunopathogenesis of asymptomatic chronic HIV Infection: the calm before the storm. Curr Opin HIV AIDS. 2009, 4: 206-214. 10.1097/COH.0b013e328329c68c.

    PubMed Central  PubMed  Google Scholar 

36. Liu Z, Cumberland WG, Hultin LE, Prince HE, Detels R, Giorgi JV: Elevated CD38 antigen expression on CD8+ T cells is a stronger marker for the risk of chronic HIV disease progression to AIDS and death in the Multicenter AIDS Cohort Study than CD4+ cell count, soluble immune activation markers, or combinations of HLA-DR and CD38 expression. J Acquir Immune Defic Syndr Hum Retrovirol. 1997, 16: 83-92.

    CAS  PubMed  Google Scholar 

37. Picker LJ: Immunopathogenesis of acute AIDS virus infection. Curr Opin Immunol. 2006, 18: 399-405. 10.1016/j.coi.2006.05.001.

    CAS  PubMed  Google Scholar 

38. Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, Kazzaz Z, Bornstein E, Lambotte O, Altmann D, Blazar BR, Rodriguez B, Teixeira-Johnson L, Landay A, Martin JN, Hecht FM, Picker LJ, Lederman MM, Deeks SG, Douek DC: Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006, 12: 1365-1371. 10.1038/nm1511.

    CAS  PubMed  Google Scholar 

39. Boasso A, Shearer GM: Chronic innate immune activation as a cause of HIV-1 immunopathogenesis. Clin Immunol. 2008, 126: 235-242. 10.1016/j.clim.2007.08.015.

    PubMed Central  CAS  PubMed  Google Scholar 

40. Grossman Z, Meier-Schellersheim M, Sousa AE, Victorino RM, Paul WE: CD4+ T-cell depletion in HIV infection: are we closer to understanding the cause?. Nat Med. 2002, 8: 319-323. 10.1038/nm0402-319.

    CAS  PubMed  Google Scholar 

41. Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA: Changes in thymic function with age and during the treatment of HIV infection. Nature. 1998, 396: 690-695. 10.1038/25374.

    CAS  PubMed  Google Scholar 

42. Douek DC, Picker LJ, Koup RA: T cell dynamics in HIV-1 infection. Annu Rev Immunol. 2003, 21: 265-304. 10.1146/annurev.immunol.21.120601.141053.

    CAS  PubMed  Google Scholar 

43. Estes JD, Wietgrefe S, Schacker T, Southern P, Beilman G, Reilly C, Milush JM, Lifson JD, Sodora DL, Carlis JV, Haase AT: Simian immunodeficiency virus-induced lymphatic tissue fibrosis is mediated by transforming growth factor beta 1-positive regulatory T cells and begins in early infection. J Infect Dis. 2007, 195: 551-561. 10.1086/510852.

    CAS  PubMed  Google Scholar 

44. Alam SM, Scearce RM, Parks RJ, Plonk K, Plonk SG, Sutherland LL, Gorny MK, Zolla-Pazner S, Vanleeuwen S, Moody MA, Xia SM, Montefiori DC, Tomaras GD, Weinhold KJ, Karim SA, Hicks CB, Liao HX, Robinson J, Shaw GM, Haynes BF: Human immunodeficiency virus type 1 gp41 antibodies that mask membrane proximal region epitopes: antibody binding kinetics, induction, and potential for regulation in acute infection. J Virol. 2008, 82: 115-125. 10.1128/JVI.00927-07.

    PubMed Central  CAS  PubMed  Google Scholar 

45. He B, Qiao X, Klasse PJ, Chiu A, Chadburn A, Knowles DM, Moore JP, Cerutti A: HIV-1 envelope triggers polyclonal Ig class switch recombination through a CD40-independent mechanism involving BAFF and C-type lectin receptors. J Immunol. 2006, 176: 3931-3941.

    CAS  PubMed  Google Scholar 

46. Van Duyne R, Pedati C, Guendel I, Carpio L, Kehn-Hall K, Saifuddin M, Kashanchi F: The utilization of humanized mouse models for the study of human retroviral infections. Retrovirology. 2009, 6: 76-10.1186/1742-4690-6-76.

    PubMed Central  PubMed  Google Scholar 

47. Silvestri G, Sodora DL, Koup RA, Paiardini M, O'Neil SP, McClure HM, Staprans SI, Feinberg MB: Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity. 2003, 18: 441-452. 10.1016/S1074-7613(03)00060-8.

    CAS  PubMed  Google Scholar 

48. Durudas A, Milush JM, Chen HL, Engram JC, Silvestri G, Sodora DL: Elevated levels of innate immune modulators in lymph nodes and blood are associated with more-rapid disease progression in simian immunodeficiency virus-infected monkeys. J Virol. 2009, 83: 12229-12240. 10.1128/JVI.01311-09.

    PubMed Central  CAS  PubMed  Google Scholar 

49. Medzhitov R, Janeway C: Innate immunity. N Engl J Med. 2000, 343: 338-344. 10.1056/NEJM200008033430506.

    CAS  PubMed  Google Scholar 

50. Mogensen TH: Pathogen recognition and inflammatory signaling in innate immune defenses. Clin Microbiol Rev. 2009, 22: 240-73. 10.1128/CMR.00046-08. Table

    PubMed Central  CAS  PubMed  Google Scholar 

51. Janeway CA: Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989, 54 (Pt 1): 1-13.

    CAS  PubMed  Google Scholar 

52. Kurt-Jones EA, Popova L, Kwinn L, Haynes LM, Jones LP, Tripp RA, Walsh EE, Freeman MW, Golenbock DT, Anderson LJ, Finberg RW: Pattern recognition receptors TLR4 and CD14 mediate response to respiratory syncytial virus. Nat Immunol. 2000, 1: 398-401. 10.1038/80833.

    CAS  PubMed  Google Scholar 

53. Compton T, Kurt-Jones EA, Boehme KW, Belko J, Latz E, Golenbock DT, Finberg RW: Human cytomegalovirus activates inflammatory cytokine responses via CD14 and Toll-like receptor 2. J Virol. 2003, 77: 4588-4596. 10.1128/JVI.77.8.4588-4596.2003.

    PubMed Central  CAS  PubMed  Google Scholar 

54. Rassa JC, Meyers JL, Zhang Y, Kudaravalli R, Ross SR: Murine retroviruses activate B cells via interaction with toll-like receptor 4. Proc Natl Acad Sci USA. 2002, 99: 2281-2286. 10.1073/pnas.042355399.

    PubMed Central  CAS  PubMed  Google Scholar 

55. 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. 10.1084/jem.20030162.

    PubMed Central  CAS  PubMed  Google Scholar 

56. Heil F, Hemmi H, Hochrein H, Ampenberger F, Kirschning C, Akira S, Lipford G, Wagner H, Bauer S: Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004, 303: 1526-1529. 10.1126/science.1093620.

    CAS  PubMed  Google Scholar 

57. Diebold SS, Kaisho T, Hemmi H, Akira S: Reis e Sousa: Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004, 303: 1529-1531. 10.1126/science.1093616.

    CAS  PubMed  Google Scholar 

58. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA: Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001, 413: 732-738. 10.1038/35099560.

    CAS  PubMed  Google Scholar 

59. Wang T, Town T, Alexopoulou L, Anderson JF, Fikrig E, Flavell RA: Toll-like receptor 3 mediates West Nile virus entry into the brain causing lethal encephalitis. Nat Med. 2004, 10: 1366-1373. 10.1038/nm1140.

    CAS  PubMed  Google Scholar 

60. Takeuchi O, Akira S: Pattern recognition receptors and inflammation. Cell. 2010, 140: 805-820. 10.1016/j.cell.2010.01.022.

    CAS  PubMed  Google Scholar 

61. Geijtenbeek TB, Krooshoop DJ, Bleijs DA, van Vliet SJ, van Duijnhoven GC, Grabovsky V, Alon R, Figdor CG, van Kooyk Y: DC-SIGN-ICAM-2 interaction mediates dendritic cell trafficking. Nat Immunol. 2000, 1: 353-357. 10.1038/79815.

    CAS  PubMed  Google Scholar 

62. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T, Miyagishi M, Taira K, Akira S, Fujita T: The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol. 2004, 5: 730-737. 10.1038/ni1087.

    CAS  PubMed  Google Scholar 

63. Kato H, Takeuchi O, Sato S, Yoneyama M, Yamamoto M, Matsui K, Uematsu S, Jung A, Kawai T, Ishii KJ, Yamaguchi O, Otsu K, Tsujimura T, Koh CS, Reis e Sousa C, Matsuura Y, Fujita T, Akira S: Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006, 441: 101-105. 10.1038/nature04734.

    CAS  PubMed  Google Scholar 

64. Hornung V, Ellegast J, Kim S, Brzózka K, Jung A, Kato H, Poeck H, Akira S, Conzelmann KK, Schlee M, Endres S, Hartmann G: 5'-Triphosphate RNA is the ligand for RIG-I. Science. 2006, 314: 994-997. 10.1126/science.1132505.

    PubMed  Google Scholar 

65. Pichlmair A, Schulz O, Tan CP, Näslund TI, Liljeström P, Weber F, Reis e Sousa C: RIG-I-mediated antiviral responses to single-stranded RNA bearing 5'-phosphates. Science. 2006, 314: 997-1001. 10.1126/science.1132998.

    CAS  PubMed  Google Scholar 

66. Kato H, Takeuchi O, Mikamo-Satoh E, Hirai R, Kawai T, Matsushita K, Hiiragi A, Dermody TS, Fujita T, Akira S: Length-dependent recognition of double-stranded ribonucleic acids by retinoic acid-inducible gene-I and melanoma differentiation-associated gene 5. J Exp Med. 2008, 205: 1601-1610. 10.1084/jem.20080091.

    PubMed Central  CAS  PubMed  Google Scholar 

67. Pichlmair A, Schulz O, Tan CP, Rehwinkel J, Kato H, Takeuchi O, Akira S, Way M, Schiavo G, Reis e Sousa C: Activation of MDA5 requires higher-order RNA structures generated during virus infection. J Virol. 2009, 83: 10761-10769. 10.1128/JVI.00770-09.

    PubMed Central  CAS  PubMed  Google Scholar 

68. Schlee M, Roth A, Hornung V, Hagmann CA, Wimmenauer V, Barchet W, Coch C, Janke M, Mihailovic A, Wardle G, Juranek S, Kato H, Kawai T, Poeck H, Fitzgerald KA, Takeuchi O, Akira S, Tuschl T, Latz E, Ludwig J, Hartmann G: Recognition of 5' triphosphate by RIG-I helicase requires short blunt double-stranded RNA as contained in panhandle of negative-strand virus. Immunity. 2009, 31: 25-34. 10.1016/j.immuni.2009.05.008.

    PubMed Central  CAS  PubMed  Google Scholar 

69. Takaoka A, Wang Z, Choi MK, Yanai H, Negishi H, Ban T, Lu Y, Miyagishi M, Kodama T, Honda K, Ohba Y, Taniguchi T: DAI (DLM-1/ZBP1) is a cytosolic DNA sensor and an activator of innate immune response. Nature. 2007, 448: 501-505. 10.1038/nature06013.

    CAS  PubMed  Google Scholar 

70. Ablasser A, Bauernfeind F, Hartmann G, Latz E, Fitzgerald KA, Hornung V: RIG-I-dependent sensing of poly(dA:dT) through the induction of an RNA polymerase III-transcribed RNA intermediate. Nat Immunol. 2009, 10: 1065-1072. 10.1038/ni.1779.

    CAS  PubMed  Google Scholar 

71. Chiu YH, Macmillan JB, Chen ZJ: RNA polymerase III detects cytosolic DNA and induces type I interferons through the RIG-I pathway. Cell. 2009, 138: 576-591. 10.1016/j.cell.2009.06.015.

    PubMed Central  CAS  PubMed  Google Scholar 

72. Stetson DB, Ko JS, Heidmann T, Medzhitov R: Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell. 2008, 134: 587-598. 10.1016/j.cell.2008.06.032.

    PubMed Central  CAS  PubMed  Google Scholar 

73. Stetson DB, Medzhitov R: Type I interferons in host defense. Immunity. 2006, 25: 373-381. 10.1016/j.immuni.2006.08.007.

    CAS  PubMed  Google Scholar 

74. Iwasaki A, Medzhitov R: Regulation of adaptive immunity by the innate immune system. Science. 2010, 327: 291-295. 10.1126/science.1183021.

    PubMed Central  CAS  PubMed  Google Scholar 

75. Freed EO, Martin MA, et al: HIVs and their replication. Field's Virology. Edited by: Knipe DM, Howley PM, Griffin DE, Lamb RA, Martin MA, Roizman B. 2007, Lippincot, Williams & Wilkins

    Google Scholar 

76. Dalgleish AG, Beverley PC, Clapham PR, Crawford DH, Greaves MF, Weiss RA: The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus. Nature. 1984, 312: 763-767. 10.1038/312763a0.

    CAS  PubMed  Google Scholar 

77. Feng Y, Broder CC, Kennedy PE, Berger EA: HIV-1 entry cofactor: functional cDNA cloning of a seven-transmembrane, G protein-coupled receptor. Science. 1996, 272: 872-877. 10.1126/science.272.5263.872.

    CAS  PubMed  Google Scholar 

78. Deng H, Liu R, Ellmeier W, Choe S, Unutmaz D, Burkhart M, Di Marzio P, Marmon S, Sutton RE, Hill CM, Davis CB, Peiper SC, Schall TJ, Littman DR, Landau NR: Identification of a major co-receptor for primary isolates of HIV-1. Nature. 1996, 381: 661-666. 10.1038/381661a0.

    CAS  PubMed  Google Scholar 

79. Dragic T, Litwin V, Allaway GP, Martin SR, Huang Y, Nagashima KA, Cayanan C, Maddon PJ, Koup RA, Moore JP, Paxton WA: HIV-1 entry into CD4+ cells is mediated by the chemokine receptor CC-CKR-5. Nature. 1996, 381: 667-673. 10.1038/381667a0.

    CAS  PubMed  Google Scholar 

80. Gougeon ML, Piacentini M: New insights on the role of apoptosis and autophagy in HIV pathogenesis. Apoptosis. 2009, 14: 501-508. 10.1007/s10495-009-0314-1.

    CAS  PubMed  Google Scholar 

81. Moore MD, Hu WS: HIV-1 RNA dimerization: It takes two to tango. AIDS Rev. 2009, 11: 91-102.

    PubMed Central  PubMed  Google Scholar 

82. Suzuki Y, Craigie R: The road to chromatin - nuclear entry of retroviruses. Nat Rev Microbiol. 2007, 5: 187-196. 10.1038/nrmicro1579.

    CAS  PubMed  Google Scholar 

83. Petitjean G, Al Tabaa Y, Tuaillon E, Mettling C, Baillat V, Reynes J, Segondy M, Vendrell JP: Unintegrated HIV-1 provides an inducible and functional reservoir in untreated and highly active antiretroviral therapy-treated patients. Retrovirology. 2007, 4: 60-10.1186/1742-4690-4-60.

    PubMed Central  PubMed  Google Scholar 

84. Stetson DB, Medzhitov R: Recognition of cytosolic DNA activates an IRF3-dependent innate immune response. Immunity. 2006, 24: 93-103. 10.1016/j.immuni.2005.12.003.

    CAS  PubMed  Google Scholar 

85. Lempicki RA, Kovacs JA, Baseler MW, Adelsberger JW, Dewar RL, Natarajan V, Bosche MC, Metcalf JA, Stevens RA, Lambert LA, Alvord WG, Polis MA, Davey RT, Dimitrov DS, Lane HC: Impact of HIV-1 infection and highly active antiretroviral therapy on the kinetics of CD4+ and CD8+ T cell turnover in HIV-infected patients. Proc Natl Acad Sci USA. 2000, 97: 13778-13783. 10.1073/pnas.250472097.

    PubMed Central  CAS  PubMed  Google Scholar 

86. Meier A, Alter G, Frahm N, Sidhu H, Li B, Bagchi A, Teigen N, Streeck H, Stellbrink HJ, Hellman J, van Lunzen J, Altfeld M: MyD88-dependent immune activation mediated by human immunodeficiency virus type 1-encoded Toll-like receptor ligands. J Virol. 2007, 81: 8180-8191. 10.1128/JVI.00421-07.

    PubMed Central  CAS  PubMed  Google Scholar 

87. Tilling R, Kinloch S, Goh LE, Cooper D, Perrin L, Lampe F, Zaunders J, Hoen B, Tsoukas C, Andersson J, Janossy G, Quest Study Group: Parallel decline of CD8+/CD38++ T cells and viraemia in response to quadruple highly active antiretroviral therapy in primary HIV infection. AIDS. 2002, 16: 589-596. 10.1097/00002030-200203080-00010.

    CAS  PubMed  Google Scholar 

88. Alter G, Suscovich TJ, Teigen N, Meier A, Streeck H, Brander C, Altfeld M: Single-stranded RNA derived from HIV-1 serves as a potent activator of NK cells. J Immunol. 2007, 178: 7658-7666.

    CAS  PubMed  Google Scholar 

89. Beignon AS, McKenna K, Skoberne M, Manches O, DaSilva I, Kavanagh DG, Larsson M, Gorelick RJ, Lifson JD, Bhardwaj N: Endocytosis of HIV-1 activates plasmacytoid dendritic cells via Toll-like receptor-viral RNA interactions. J Clin Invest. 2005, 115: 3265-3275. 10.1172/JCI26032.

    PubMed Central  CAS  PubMed  Google Scholar 

90. Gringhuis SI, van d V, van den Berg LM, den Dunnen J, Litjens M, Geijtenbeek TB: HIV-1 exploits innate signaling by TLR8 and DC-SIGN for productive infection of dendritic cells. Nat Immunol. 2010, 11: 419-426. 10.1038/ni.1858.

    CAS  PubMed  Google Scholar 

91. Schlaepfer E, Audige A, Joller H, Speck RF: TLR7/8 triggering exerts opposing effects in acute versus latent HIV infection. J Immunol. 2006, 176: 2888-2895.

    CAS  PubMed  Google Scholar 

92. Schlaepfer E, Speck RF: Anti-HIV activity mediated by natural killer and CD8+ cells after toll-like receptor 7/8 triggering. PLoS ONE. 2008, 3: e1999-10.1371/journal.pone.0001999.

    PubMed Central  PubMed  Google Scholar 

93. Baenziger S, Heikenwalder M, Johansen P, Schlaepfer E, Hofer U, Miller RC, Diemand S, Honda K, Kundig TM, Aguzzi A, Speck RF: Triggering TLR7 in mice induces immune activation and lymphoid system disruption, resembling HIV-mediated pathology. Blood. 2009, 113: 377-388. 10.1182/blood-2008-04-151712.

    CAS  PubMed  Google Scholar 

94. Heikenwalder M, Polymenidou M, Junt T, Sigurdson C, Wagner H, Akira S, Zinkernagel R, Aguzzi A: Lymphoid follicle destruction and immunosuppression after repeated CpG oligodeoxynucleotide administration. Nat Med. 2004, 10: 187-192. 10.1038/nm987.

    CAS  PubMed  Google Scholar 

95. Breckpot K, Escors D, Arce F, Lopes L, Karwacz K, Van Lint S, Keyaerts M, Collins M: HIV-1 lentiviral vector immunogenicity is mediated by Toll-like receptor 3 (TLR3) and TLR7. J Virol. 2010, 84: 5627-5636. 10.1128/JVI.00014-10.

    PubMed Central  CAS  PubMed  Google Scholar 

96. Bafica A, Scanga CA, Schito M, Chaussabel D, Sher A: Influence of coinfecting pathogens on HIV expression: evidence for a role of Toll-like receptors. J Immunol. 2004, 172: 7229-7234.

    CAS  PubMed  Google Scholar 

97. Funderburg N, Luciano AA, Jiang W, Rodriguez B, Sieg SF, Lederman MM: Toll-like receptor ligands induce human T cell activation and death, a model for HIV pathogenesis. PLoS ONE. 2008, 3: e1915-10.1371/journal.pone.0001915.

    PubMed Central  PubMed  Google Scholar 

98. Equils O, Faure E, Thomas L, Bulut Y, Trushin S, Arditi M: Bacterial lipopolysaccharide activates HIV long terminal repeat through Toll-like receptor 4. J Immunol. 2001, 166: 2342-2347.

    CAS  PubMed  Google Scholar 

99. Bachelerie F, Alcami J, Arenzana-Seisdedos F, Virelizier JL: HIV enhancer activity perpetuated by NF-kappa B induction on infection of monocytes. Nature. 1991, 350: 709-712. 10.1038/350709a0.

    CAS  PubMed  Google Scholar 

100. Lester RT, Yao XD, Ball TB, McKinnon LR, Omange WR, Kaul R, Wachihi C, Jaoko W, Rosenthal KL, Plummer FA: HIV-1 RNA dysregulates the natural TLR response to subclinical endotoxemia in Kenyan female sex-workers. PLoS ONE. 2009, 4: e5644-10.1371/journal.pone.0005644.

     PubMed Central  PubMed  Google Scholar 

101. Nowroozalizadeh S, Månsson F, da Silva Z, Repits J, Dabo B, Pereira C, Biague A, Albert J, Nielsen J, Aaby P, Fenyö EM, Norrgren H, Holmgren B, Jansson M: Microbial Translocation Correlates with the Severity of Both HIV-1 and HIV-2 Infections. J Infect Dis. 2010, 201: 1150-1154. 10.1086/651430.

     CAS  PubMed  Google Scholar 

102. Jiang W, Lederman MM, Hunt P, Sieg SF, Haley K, Rodriguez B, Landay A, Martin J, Sinclair E, Asher AI, Deeks SG, Douek DC, Brenchley JM: Plasma levels of bacterial DNA correlate with immune activation and the magnitude of immune restoration in persons with antiretroviral-treated HIV infection. J Infect Dis. 2009, 199: 1177-1185. 10.1086/597476.

     PubMed Central  CAS  PubMed  Google Scholar 

103. Brenchley JM, Douek DC: The mucosal barrier and immune activation in HIV pathogenesis. Curr Opin HIV AIDS. 2008, 3: 356-361. 10.1097/COH.0b013e3282f9ae9c.

     PubMed Central  PubMed  Google Scholar 

104. Pandrea IV, Gautam R, Ribeiro RM, Brenchley JM, Butler IF, Pattison M, Rasmussen T, Marx PA, Silvestri G, Lackner AA, Perelson AS, Douek DC, Veazey RS, Apetrei C: Acute loss of intestinal CD4+ T cells is not predictive of simian immunodeficiency virus virulence. J Immunol. 2007, 179: 3035-3046.

     PubMed Central  CAS  PubMed  Google Scholar 

105. Gordon SN, Klatt NR, Bosinger SE, Brenchley JM, Milush JM, Engram JC, Dunham RM, Paiardini M, Klucking S, Danesh A, Strobert EA, Apetrei C, Pandrea IV, Kelvin D, Douek DC, Staprans SI, Sodora DL, Silvestri G: Severe depletion of mucosal CD4+ T cells in AIDS-free simian immunodeficiency virus-infected sooty mangabeys. J Immunol. 2007, 179: 3026-3034.

     PubMed Central  CAS  PubMed  Google Scholar 

106. Vrisekoop N, Mandl JN, Germain RN: Life and death as a T lymphocyte: from immune protection to HIV pathogenesis. J Biol. 2009, 8: 91-10.1186/jbiol198.

     PubMed Central  PubMed  Google Scholar 

107. Brown JN, Kohler JJ, Coberley CR, Sleasman JW, Goodenow MM: HIV-1 activates macrophages independent of Toll-like receptors. PLoS ONE. 2008, 3: e3664-10.1371/journal.pone.0003664.

     PubMed Central  PubMed  Google Scholar 

108. Lester RT, Yao XD, Ball TB, McKinnon LR, Kaul R, Wachihi C, Jaoko W, Plummer FA, Rosenthal KL: Toll-like receptor expression and responsiveness are increased in viraemic HIV-1 infection. AIDS. 2008, 22: 685-694. 10.1097/QAD.0b013e3282f4de35.

     CAS  PubMed  Google Scholar 

109. Noursadeghi M, Katz DR, Miller RF: HIV-1 infection of mononuclear phagocytic cells: the case for bacterial innate immune deficiency in AIDS. Lancet Infect Dis. 2006, 6: 794-804. 10.1016/S1473-3099(06)70656-9.

     PubMed  Google Scholar 

110. Herbein G, Varin A: The macrophage in HIV-1 infection: from activation to deactivation?. Retrovirology. 2010, 7: 33-10.1186/1742-4690-7-33.

     PubMed Central  PubMed  Google Scholar 

111. Xu D, Komai-Koma M, Liew FY: Expression and function of Toll-like receptor on T cells. Cell Immunol. 2005, 233: 85-89. 10.1016/j.cellimm.2005.04.019.

     CAS  PubMed  Google Scholar 

112. Caron G, Duluc D, Frémaux I, Jeannin P, David C, Gascan H, Delneste Y: 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.

     CAS  PubMed  Google Scholar 

113. Holm CK, Petersen CC, Hvid M, Petersen L, Paludan SR, Deleuran B, Hokland M: TLR3 ligand polyinosinic:polycytidylic acid induces IL-17A and IL-21 synthesis in human Th cells. J Immunol. 2009, 183: 4422-4431. 10.4049/jimmunol.0804318.

     CAS  PubMed  Google Scholar 

114. Thibault S, Imbeault M, Tardif MR, Tremblay MJ: TLR5 stimulation is sufficient to trigger reactivation of latent HIV-1 provirus in T lymphoid cells and activate virus gene expression in central memory CD4+ T cells. Virology. 2009, 389: 20-25. 10.1016/j.virol.2009.04.019.

     CAS  PubMed  Google Scholar 

115. Nabel G, Baltimore D: An inducible transcription factor activates expression of human immunodeficiency virus in T cells. Nature. 1987, 326: 711-713. 10.1038/326711a0.

     CAS  PubMed  Google Scholar 

116. Alcamí J, Laín de Lera T, Folgueira L, Pedraza MA, Jacqué JM, Bachelerie F, Noriega AR, Hay RT, Harrich D, Gaynor RB, et al: Absolute dependence on kappa B responsive elements for initiation and Tat-mediated amplification of HIV transcription in blood CD4 T lymphocytes. EMBO J. 1995, 14: 1552-1560.

     PubMed Central  PubMed  Google Scholar 

117. Paya CV, Ten RM, Bessia C, Alcami J, Hay RT, Virelizier JL: NF-kappa B-dependent induction of the NF-kappa B p50 subunit gene promoter underlies self-perpetuation of human immunodeficiency virus transcription in monocytic cells. Proc Natl Acad Sci USA. 1992, 89: 7826-7830. 10.1073/pnas.89.16.7826.

     PubMed Central  CAS  PubMed  Google Scholar 

118. Centlivre M, Sala M, Wain-Hobson S, Berkhout B: In HIV-1 pathogenesis the die is cast during primary infection. AIDS. 2007, 21: 1-11. 10.1097/QAD.0b013e3280117f7f.

     PubMed  Google Scholar 

119. Hunt PW, Brenchley J, Sinclair E, McCune JM, Roland M, Page-Shafer K, Hsue P, Emu B, Krone M, Lampiris H, Douek D, Martin JN, Deeks SG: Relationship between T cell activation and CD4+ T cell count in HIV-seropositive individuals with undetectable plasma HIV RNA levels in the absence of therapy. J Infect Dis. 2008, 197: 126-133. 10.1086/524143.

     PubMed Central  PubMed  Google Scholar 

120. Stacey AR, Norris PJ, Qin L, Haygreen EA, Taylor E, Heitman J, Lebedeva M, DeCamp A, Li D, Grove D, Self SG, Borrow P: Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. J Virol. 2009, 83: 3719-3733. 10.1128/JVI.01844-08.

     PubMed Central  CAS  PubMed  Google Scholar 

121. Kanneganti TD, Lamkanfi M, Nunez G: Intracellular NOD-like receptors in host defense and disease. Immunity. 2007, 27: 549-559. 10.1016/j.immuni.2007.10.002.

     CAS  PubMed  Google Scholar 

122. Iannello A, Samarani S, Debbeche O, Ahmad R, Boulassel MR, Tremblay C, Toma E, Routy JP, Ahmad A: Potential role of interleukin-18 in the immunopathogenesis of AIDS: involvement in fratricidal killing of NK cells. J Virol. 2009, 83: 5999-6010. 10.1128/JVI.02350-08.

     PubMed Central  CAS  PubMed  Google Scholar 

123. Barre-Sinoussi F, Montagnier L, Lidereau R, Sisman J, Wood J, Chermann JC: Enhancement of retrovirus production by anti-interferon serum. Ann Microbiol (Paris). 1979, 130B: 349-362.

     CAS  Google Scholar 

124. Hovanessian AG, Barre-Sinoussi F, Montagnier L: Interferon-mediated protein kinase in mouse cells treated with iododeoxyuridine (IdUrd) and induced to express endogenous retroviruses. J Gen Virol. 1981, 52: 199-204. 10.1099/0022-1317-52-1-199.

     CAS  PubMed  Google Scholar 

125. Herbeuval JP, Nilsson J, Boasso A, Hardy AW, Kruhlak MJ, Anderson SA, Dolan MJ, Dy M, Andersson J, Shearer GM: Differential expression of IFN-alpha and TRAIL/DR5 in lymphoid tissue of progressor versus nonprogressor HIV-1-infected patients. Proc Natl Acad Sci USA. 2006, 103: 7000-7005. 10.1073/pnas.0600363103.

     PubMed Central  CAS  PubMed  Google Scholar 

126. Herbeuval JP, Shearer GM: HIV-1 immunopathogenesis: how good interferon turns bad. Clin Immunol. 2007, 123: 121-128. 10.1016/j.clim.2006.09.016.

     PubMed Central  CAS  PubMed  Google Scholar 

127. Kornbluth RS, Oh PS, Munis JR, Cleveland PH, Richman DD: Interferons and bacterial lipopolysaccharide protect macrophages from productive infection by human immunodeficiency virus in vitro. J Exp Med. 1989, 169: 1137-1151. 10.1084/jem.169.3.1137.

     CAS  PubMed  Google Scholar 

128. Michaelis B, Levy JA: HIV replication can be blocked by recombinant human interferon beta. AIDS. 1989, 3: 27-31.

     CAS  PubMed  Google Scholar 

129. Shirazi Y, Pitha PM: Interferon alpha-mediated inhibition of human immunodeficiency virus type 1 provirus synthesis in T-cells. Virology. 1993, 193: 303-312. 10.1006/viro.1993.1126.

     CAS  PubMed  Google Scholar 

130. Ank N, Paludan SR: Type III IFNs: new layers of complexity in innate antiviral immunity. Biofactors. 2009, 35: 82-87. 10.1002/biof.19.

     CAS  PubMed  Google Scholar 

131. Hou W, Wang X, Ye L, Zhou L, Yang ZQ, Riedel E, Ho WZ: Lambda interferon inhibits human immunodeficiency virus type 1 infection of macrophages. J Virol. 2009, 83: 3834-3842. 10.1128/JVI.01773-08.

     PubMed Central  CAS  PubMed  Google Scholar 

132. Vendrame D, Sourisseau M, Perrin V, Schwartz O, Mammano F: Partial inhibition of human immunodeficiency virus replication by type I interferons: impact of cell-to-cell viral transfer. J Virol. 2009, 83: 10527-10537. 10.1128/JVI.01235-09.

     PubMed Central  CAS  PubMed  Google Scholar 

133. Khatissian E, Tovey MG, Cumont MC, Monceaux V, Lebon P, Montagnier L, Hurtrel B, Chakrabarti L: The relationship between the interferon alpha response and viral burden in primary SIV infection. AIDS Res Hum Retroviruses. 1996, 12: 1273-1278. 10.1089/aid.1996.12.1273.

     CAS  PubMed  Google Scholar 

134. Mandl JN, Barry AP, Vanderford TH, Kozyr N, Chavan R, Klucking S, Barrat FJ, Coffman RL, Staprans SI, Feinberg MB: Divergent TLR7 and TLR9 signaling and type I interferon production distinguish pathogenic and nonpathogenic AIDS virus infections. Nat Med. 2008, 14: 1077-1087. 10.1038/nm.1871.

     CAS  PubMed  Google Scholar 

135. Silvestri G, Paiardini M, Pandrea I, Lederman MM, Sodora DL: Understanding the benign nature of SIV infection in natural hosts. J Clin Invest. 2007, 117: 3148-3154. 10.1172/JCI33034.

     PubMed Central  CAS  PubMed  Google Scholar 

136. Jacquelin B, Mayau V, Targat B, Liovat AS, Kunkel D, Petitjean G, Dillies MA, Roques P, Butor C, Silvestri G, Giavedoni LD, Lebon P, Barré-Sinoussi F, Benecke A, Müller-Trutwin MC: Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response. J Clin Invest. 2009, 119: 3544-3555.

     PubMed Central  CAS  PubMed  Google Scholar 

137. Bosinger SE, Li Q, Gordon SN, Klatt NR, Duan L, Xu L, Francella N, Sidahmed A, Smith AJ, Cramer EM, Zeng M, Masopust D, Carlis JV, Ran L, Vanderford TH, Paiardini M, Isett RB, Baldwin DA, Else JG, Staprans SI, Silvestri G, Haase AT, Kelvin DJ: Global genomic analysis reveals rapid control of a robust innate response in SIV-infected sooty mangabeys. J Clin Invest. 2009, 119: 3556-3572.

     PubMed Central  CAS  PubMed  Google Scholar 

138. Harris LD, Tabb B, Sodora DL, Paiardini M, Klatt NR, Douek DC, Silvestri G, Muller-Trutwin M, Vasile-Pandrea I, Apetrei C, Hirsch V, Lifson J, Brenchley JM, Estes JD: Down-Regulation of Robust Acute Type I IFN Responses Distinguishes Non-Pathogenic SIV Infection of Natural Hosts from Pathogenic SIV Infection of Rhesus Macaques. J Virol. 2010

     Google Scholar 

139. Soumelis V, Scott I, Gheyas F, Bouhour D, Cozon G, Cotte L, Huang L, Levy JA, Liu YJ: Depletion of circulating natural type 1 interferon-producing cells in HIV-infected AIDS patients. Blood. 2001, 98: 906-912. 10.1182/blood.V98.4.906.

     CAS  PubMed  Google Scholar 

140. Zuniga EI, Liou LY, Mack L, Mendoza M, Oldstone MB: Persistent virus infection inhibits type I interferon production by plasmacytoid dendritic cells to facilitate opportunistic infections. Cell Host Microbe. 2008, 4: 374-386. 10.1016/j.chom.2008.08.016.

     PubMed Central  CAS  PubMed  Google Scholar 

141. Stoddart CA, Keir ME, McCune JM: IFN-alpha-induced upregulation of CCR5 leads to expanded HIV tropism in vivo. PLoS Pathog. 2010, 6: e1000766-10.1371/journal.ppat.1000766.

     PubMed Central  PubMed  Google Scholar 

142. Guo B, Chang EY, Cheng G: The type I IFN induction pathway constrains Th17-mediated autoimmune inflammation in mice. J Clin Invest. 2008, 118: 1680-1690. 10.1172/JCI33342.

     PubMed Central  CAS  PubMed  Google Scholar 

143. Cecchinato V, Trindade CJ, Laurence A, Heraud JM, Brenchley JM, Ferrari MG, Zaffiri L, Tryniszewska E, Tsai WP, Vaccari M, Parks RW, Venzon D, Douek DC, O'Shea JJ, Franchini G: Altered balance between Th17 and Th1 cells at mucosal sites predicts AIDS progression in simian immunodeficiency virus-infected macaques. Mucosal Immunol. 2008, 1: 279-288. 10.1038/mi.2008.14.

     PubMed Central  CAS  PubMed  Google Scholar 

144. Hardy AW, Graham DR, Shearer GM, Herbeuval JP: HIV turns plasmacytoid dendritic cells (pDC) into TRAIL-expressing killer pDC and down-regulates HIV coreceptors by Toll-like receptor 7-induced IFN-alpha. Proc Natl Acad Sci USA. 2007, 104: 17453-17458. 10.1073/pnas.0707244104.

     PubMed Central  CAS  PubMed  Google Scholar 

145. Herbeuval JP, Hardy AW, Boasso A, Anderson SA, Dolan MJ, Dy M, Shearer GM: Regulation of TNF-related apoptosis-inducing ligand on primary CD4+ T cells by HIV-1: role of type I IFN-producing plasmacytoid dendritic cells. Proc Natl Acad Sci USA. 2005, 102: 13974-13979. 10.1073/pnas.0505251102.

     PubMed Central  CAS  PubMed  Google Scholar 

146. Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, Boulassel MR, Delwart E, Sepulveda H, Balderas RS, Routy JP, Haddad EK, Sekaly RP: Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med. 2006, 12: 1198-1202. 10.1038/nm1482.

     CAS  PubMed  Google Scholar 

147. Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, Mackey EW, Miller JD, Leslie AJ, DePierres C, Mncube Z, Duraiswamy J, Zhu B, Eichbaum Q, Altfeld M, Wherry EJ, Coovadia HM, Goulder PJ, Klenerman P, Ahmed R, Freeman GJ, Walker BD: PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature. 2006, 443: 350-354. 10.1038/nature05115.

     CAS  PubMed  Google Scholar 

148. Meier A, Bagchi A, Sidhu HK, Alter G, Suscovich TJ, Kavanagh DG, Streeck H, Brockman MA, LeGall S, Hellman J, Altfeld M: Upregulation of PD-L1 on monocytes and dendritic cells by HIV-1 derived TLR ligands. AIDS. 2008, 22: 655-658. 10.1097/QAD.0b013e3282f4de23.

     PubMed Central  CAS  PubMed  Google Scholar 

149. Piguet V, Steinman RM: The interaction of HIV with dendritic cells: outcomes and pathways. Trends Immunol. 2007, 28: 503-510. 10.1016/j.it.2007.07.010.

     CAS  PubMed  Google Scholar 

150. Macatonia SE, Lau R, Patterson S, Pinching AJ, Knight SC: Dendritic cell infection, depletion and dysfunction in HIV-infected individuals. Immunology. 1990, 71: 38-45.

     PubMed Central  CAS  PubMed  Google Scholar 

151. Knight SC, Patterson S, Macatonia SE: Stimulatory and suppressive effects of infection of dendritic cells with HIV-1. Immunol Lett. 1991, 30: 213-218. 10.1016/0165-2478(91)90028-9.

     CAS  PubMed  Google Scholar 

152. Blanchet FP, Moris A, Nikolic DS, Lehmann M, Cardinaud S, Stalder R, Garcia E, Dinkins C, Leuba F, Wu L, Schwartz O, Deretic V, Piguet V: Human immunodeficiency virus-1 inhibition of immunoamphisomes in dendritic cells impairs early innate and adaptive immune responses. Immunity. 2010, 32: 654-669. 10.1016/j.immuni.2010.04.011.

     PubMed Central  CAS  PubMed  Google Scholar 

153. Thibault S, Fromentin R, Tardif MR, Tremblay MJ: TLR2 and TLR4 triggering exerts contrasting effects with regard to HIV-1 infection of human dendritic cells and subsequent virus transfer to CD4+ T cells. Retrovirology. 2009, 6: 42-10.1186/1742-4690-6-42.

     PubMed Central  PubMed  Google Scholar 

154. Groot F, van Capel TM, Kapsenberg ML, Berkhout B, de Jong EC: Opposing roles of blood myeloid and plasmacytoid dendritic cells in HIV-1 infection of T cells: transmission facilitation versus replication inhibition. Blood. 2006, 108: 1957-1964. 10.1182/blood-2006-03-010918.

     CAS  PubMed  Google Scholar 

155. Wu L, KewalRamani VN: Dendritic-cell interactions with HIV: infection and viral dissemination. Nat Rev Immunol. 2006, 6: 859-868. 10.1038/nri1960.

     PubMed Central  CAS  PubMed  Google Scholar 

156. Biancotto A, Iglehart SJ, Vanpouille C, Condack CE, Lisco A, Ruecker E, Hirsch I, Margolis LB, Grivel JC: HIV-1 induced activation of CD4+ T cells creates new targets for HIV-1 infection in human lymphoid tissue ex vivo. Blood. 2008, 111: 699-704. 10.1182/blood-2007-05-088435.

     PubMed Central  CAS  PubMed  Google Scholar 

157. Boasso A, Herbeuval JP, Hardy AW, Anderson SA, Dolan MJ, Fuchs D, Shearer GM: HIV inhibits CD4+ T-cell proliferation by inducing indoleamine 2,3-dioxygenase in plasmacytoid dendritic cells. Blood. 2007, 109: 3351-3359. 10.1182/blood-2006-07-034785.

     PubMed Central  CAS  PubMed  Google Scholar 

158. Dong C: TH17 cells in development: an updated view of their molecular identity and genetic programming. Nat Rev Immunol. 2008, 8: 337-348. 10.1038/nri2295.

     CAS  PubMed  Google Scholar 

159. Brenchley JM, Paiardini M, Knox KS, Asher AI, Cervasi B, Asher TE, Scheinberg P, Price DA, Hage CA, Kholi LM, Khoruts A, Frank I, Else J, Schacker T, Silvestri G, Douek DC: Differential Th17 CD4 T-cell depletion in pathogenic and nonpathogenic lentiviral infections. Blood. 2008, 112: 2826-2835. 10.1182/blood-2008-05-159301.

     PubMed Central  CAS  PubMed  Google Scholar 

160. Favre D, Lederer S, Kanwar B, Ma ZM, Proll S, Kasakow Z, Mold J, Swainson L, Barbour JD, Baskin CR, Palermo R, Pandrea I, Miller CJ, Katze MG, McCune JM: Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection. PLoS Pathog. 2009, 5: e1000295-10.1371/journal.ppat.1000295.

     PubMed Central  PubMed  Google Scholar 

161. Prendergast A, Prado JG, Kang YH, Chen F, Riddell LA, Luzzi G, Goulder P, Klenerman P: HIV-1 infection is characterized by profound depletion of CD161+ Th17 cells and gradual decline in regulatory T cells. AIDS. 2010, 24: 491-502. 10.1097/QAD.0b013e3283344895.

     PubMed  Google Scholar 

162. El Hed A, Khaitan A, Kozhaya L, Manel N, Daskalakis D, Borkowsky W, Valentine F, Littman DR, Unutmaz D: Susceptibility of human Th17 cells to human immunodeficiency virus and their perturbation during infection. J Infect Dis. 2010, 201: 843-854. 10.1086/651021.

     CAS  PubMed  Google Scholar 

163. Sakaguchi S: Naturally arising CD4+ regulatory t cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol. 2004, 22: 531-562. 10.1146/annurev.immunol.21.120601.141122.

     CAS  PubMed  Google Scholar 

164. Cao W, Jamieson BD, Hultin LE, Hultin PM, Detels R: Regulatory T cell expansion and immune activation during untreated HIV type 1 infection are associated with disease progression. AIDS Res Hum Retroviruses. 2009, 25: 183-191. 10.1089/aid.2008.0140.

     PubMed Central  CAS  PubMed  Google Scholar 

165. Apoil PA, Puissant B, Roubinet F, Abbal M, Massip P, Blancher A: FOXP3 mRNA levels are decreased in peripheral blood CD4+ lymphocytes from HIV-positive patients. J Acquir Immune Defic Syndr. 2005, 39: 381-385. 10.1097/01.qai.0000169662.30783.2d.

     CAS  PubMed  Google Scholar 

166. Eggena MP, Barugahare B, Jones N, Okello M, Mutalya S, Kityo C, Mugyenyi P, Cao H: Depletion of regulatory T cells in HIV infection is associated with immune activation. J Immunol. 2005, 174: 4407-4414.

     CAS  PubMed  Google Scholar 

167. Tsang J, Chain BM, Miller RF, Webb BL, Barclay W, Towers GJ, Katz DR, Noursadeghi M: HIV-1 infection of macrophages is dependent on evasion of innate immune cellular activation. AIDS. 2009, 23: 2255-2263. 10.1097/QAD.0b013e328331a4ce.

     PubMed Central  CAS  PubMed  Google Scholar 

168. Nordone SK, Ignacio GA, Su L, Sempowski GD, Golenbock DT, Li L, Dean GA: Failure of TLR4-driven NF-kappa B activation to stimulate virus replication in models of HIV type 1 activation. AIDS Res Hum Retroviruses. 2007, 23: 1387-1395. 10.1089/aid.2007.0033.

     PubMed Central  CAS  PubMed  Google Scholar 

169. Tachado SD, Zhang J, Zhu J, Patel N, Koziel H: HIV impairs TNF-alpha release in response to Toll-like receptor 4 stimulation in human macrophages in vitro. Am J Respir Cell Mol Biol. 2005, 33: 610-621. 10.1165/rcmb.2004-0341OC.

     CAS  PubMed  Google Scholar 

170. Chambers KA, Parks RJ, Angel JB: Disruption of MAP kinase activation and nuclear factor binding to the IL-12 p40 promoter in HIV-infected myeloid cells. Clin Exp Immunol. 2004, 137: 329-340. 10.1111/j.1365-2249.2004.02513.x.

     PubMed Central  CAS  PubMed  Google Scholar 

171. Fantuzzi L, Purificato C, Donato K, Belardelli F, Gessani S: Human immunodeficiency virus type 1 gp120 induces abnormal maturation and functional alterations of dendritic cells: a novel mechanism for AIDS pathogenesis. J Virol. 2004, 78: 9763-9772. 10.1128/JVI.78.18.9763-9772.2004.

     PubMed Central  CAS  PubMed  Google Scholar 

172. Leulier F, Marchal C, Miletich I, Limbourg-Bouchon B, Benarous R, Lemaitre B: Directed expression of the HIV-1 accessory protein Vpu in Drosophila fat-body cells inhibits Toll-dependent immune responses. EMBO Rep. 2003, 4: 976-981. 10.1038/sj.embor.embor936.

     PubMed Central  CAS  PubMed  Google Scholar 

173. Lee SB, Park J, Jung JU, Chung J: Nef induces apoptosis by activating JNK signaling pathway and inhibits NF-kappaB-dependent immune responses in Drosophila. J Cell Sci. 2005, 118: 1851-1859. 10.1242/jcs.02312.

     CAS  PubMed  Google Scholar 

174. Martinelli E, Cicala C, Van Ryk D, Goode DJ, Macleod K, Arthos J, Fauci AS: HIV-1 gp120 inhibits TLR9-mediated activation and IFN-{alpha} secretion in plasmacytoid dendritic cells. Proc Natl Acad Sci USA. 2007, 104: 3396-3401. 10.1073/pnas.0611353104.

     PubMed Central  CAS  PubMed  Google Scholar 

175. Doehle BP, Hladik F, McNevin JP, McElrath MJ, Gale M: Human immunodeficiency virus type 1 mediates global disruption of innate antiviral signaling and immune defenses within infected cells. J Virol. 2009, 83: 10395-10405. 10.1128/JVI.00849-09.

     PubMed Central  CAS  PubMed  Google Scholar 

176. Malim MH: APOBEC proteins and intrinsic resistance to HIV-1 infection. Philos Trans R Soc Lond B Biol Sci. 2009, 364: 675-687. 10.1098/rstb.2008.0185.

     PubMed Central  CAS  PubMed  Google Scholar 

177. Sheehy AM, Gaddis NC, Choi JD, Malim MH: Isolation of a human gene that inhibits HIV-1 infection and is suppressed by the viral Vif protein. Nature. 2002, 418: 646-650. 10.1038/nature00939.

     CAS  PubMed  Google Scholar 

178. Bishop KN, Holmes RK, Sheehy AM, Malim MH: APOBEC-mediated editing of viral RNA. Science. 2004, 305: 645-10.1126/science.1100658.

     CAS  PubMed  Google Scholar 

179. Sheehy AM, Gaddis NC, Malim MH: The antiretroviral enzyme APOBEC3G is degraded by the proteasome in response to HIV-1 Vif. Nat Med. 2003, 9: 1404-1407. 10.1038/nm945.

     CAS  PubMed  Google Scholar 

180. Lin TY, Emerman M: Determinants of cyclophilin A-dependent TRIM5 alpha restriction against HIV-1. Virology. 2008, 379: 335-341. 10.1016/j.virol.2008.06.037.

     PubMed Central  CAS  PubMed  Google Scholar 

181. Wu X, Anderson JL, Campbell EM, Joseph AM, Hope TJ: Proteasome inhibitors uncouple rhesus TRIM5alpha restriction of HIV-1 reverse transcription and infection. Proc Natl Acad Sci USA. 2006, 103: 7465-7470. 10.1073/pnas.0510483103.

     PubMed Central  CAS  PubMed  Google Scholar 

182. Zhang F, Perez-Caballero D, Hatziioannou T, Bieniasz PD: No effect of endogenous TRIM5alpha on HIV-1 production. Nat Med. 2008, 14: 235-236. 10.1038/nm0308-235.

     PubMed  Google Scholar 

183. Neil SJ, Zang T, Bieniasz PD: Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature. 2008, 451: 425-430. 10.1038/nature06553.

     CAS  PubMed  Google Scholar 

184. Perez-Caballero D, Zang T, Ebrahimi A, McNatt MW, Gregory DA, Johnson MC, Bieniasz PD: Tetherin inhibits HIV-1 release by directly tethering virions to cells. Cell. 2009, 139: 499-511. 10.1016/j.cell.2009.08.039.

     PubMed Central  CAS  PubMed  Google Scholar 

185. Liu R, Paxton WA, Choe S, Ceradini D, Martin SR, Horuk R, MacDonald ME, Stuhlmann H, Koup RA, Landau NR: Homozygous defect in HIV-1 coreceptor accounts for resistance of some multiply-exposed individuals to HIV-1 infection. Cell. 1996, 86: 367-377. 10.1016/S0092-8674(00)80110-5.

     CAS  PubMed  Google Scholar 

186. den Uyl D, van der Horst-Bruinsma IE, van Agtmael M: Progression of HIV to AIDS: a protective role for HLA-B27?. AIDS Rev. 2004, 6: 89-96.

     PubMed  Google Scholar 

187. Pontillo A, Brandao LA, Guimaraes RL, Segat L, Athanasakis E, Crovella S: A 3'UTR SNP in NLRP3 Gene is Associated With Susceptibility to HIV-1 Infection. J Acquir Immune Defic Syndr. 2010

     Google Scholar 

188. Bochud PY, Hersberger M, Taffé P, Bochud M, Stein CM, Rodrigues SD, Calandra T, Francioli P, Telenti A, Speck RF, Aderem A, Swiss HIV Cohort Study: Polymorphisms in Toll-like receptor 9 influence the clinical course of HIV-1 infection. AIDS. 2007, 21: 441-446. 10.1097/QAD.0b013e328012b8ac.

     CAS  PubMed  Google Scholar 

189. Pine SO, McElrath MJ, Bochud PY: Polymorphisms in toll-like receptor 4 and toll-like receptor 9 influence viral load in a seroincident cohort of HIV-1-infected individuals. AIDS. 2009, 23: 2387-2395. 10.1097/QAD.0b013e328330b489.

     PubMed Central  CAS  PubMed  Google Scholar 

190. Oh DY, Baumann K, Hamouda O, Eckert JK, Neumann K, Kücherer C, Bartmeyer B, Poggensee G, Oh N, Pruss A, Jessen H, Schumann RR: A frequent functional toll-like receptor 7 polymorphism is associated with accelerated HIV-1 disease progression. AIDS. 2009, 23: 297-307. 10.1097/QAD.0b013e32831fb540.

     CAS  PubMed  Google Scholar 

191. Meier A, Chang JJ, Chan ES, Pollard RB, Sidhu HK, Kulkarni S, Wen TF, Lindsay RJ, Orellana L, Mildvan D, Bazner S, Streeck H, Alter G, Lifson JD, Carrington M, Bosch RJ, Robbins GK, Altfeld M: Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1. Nat Med. 2009, 15: 955-959. 10.1038/nm.2004.

     PubMed Central  CAS  PubMed  Google Scholar 

192. Farzadegan H, Hoover DR, Astemborski J, Lyles CM, Margolick JB, Markham RB, Quinn TC, Vlahov D: Sex differences in HIV-1 viral load and progression to AIDS. Lancet. 1998, 352: 1510-1514. 10.1016/S0140-6736(98)02372-1.

     CAS  PubMed  Google Scholar 

193. Medzhitov R, Littman D: HIV immunology needs a new direction. Nature. 2008, 455: 591-10.1038/455591a.

     CAS  PubMed  Google Scholar 

Page 2

Potential roles of the innate immune system during HIV infection. (1) Following exposure at mucosal surfaces, HIV is transmitted with very low transmission efficiency, indicating that innate antiviral mechanisms are operative to prevent establishment of infection. (2) The early inflammatory response leads to recruitment and activation of various leukocytes, some of which serve as target cells for de novo HIV infection. (3) After acute infection, circulating viral load is generally decreased to a low level. This is mediated by the adaptive immune response, which is activated through processes driven by the innate immune response. Moreover, direct innate antiviral mechanisms contribute to control of virus replication during the chronic phase. (4) Persistent immune activation during chronic HIV infection involves activities stimulated by HIV-derived or opportunistic PAMPs through PRRs.