Journal of Clinical Immunology

, Volume 26, Issue 1, pp 40–54 | Cite as

HIV-1-Specific CD4+ T Cell Responses in Chronically HIV-1 Infected Blippers on Antiretroviral Therapy in Relation to Viral Replication Following Treatment Interruption

  • Emmanouil Papasavvas
  • Jay R. Kostman
  • Brian Thiel
  • Maxwell Pistilli
  • Agnieszka Mackiewicz
  • Andrea Foulkes
  • Robert Gross
  • Kimberly A. Jordan
  • Douglas F. Nixon
  • Robert Grant
  • Jean-francois Poulin
  • Joseph M. Mccune
  • Karam Mounzer
  • Luis J. Montaner


The impact of transient viral load blips on anti-HIV-1 immune responses and on HIV-1 rebound following treatment interruption (TI) is not known. Clinical and immunological parameters were measured during 40 weeks of antiretroviral therapy (ART) and following TI in an observational cohort of 16 chronically HIV-1-infected subjects with or without observed viral load blips during ART. During therapy, blips in seven subjects were associated with higher anti-HIV-1 (p24) CD4+ T cell lymphoproliferative responses (p = 0.04), without a significant difference in T cell activation or total anti-HIV-1 CD8+ T cell interferon-γ (IFN-γ) responses when compared to nine matched non-blippers. Therapy interruption resulted in a significantly higher viral rebound in blippers by 8 week despite retention of higher lymphoproliferative p24 responses (p = 0.01) and a rise in CD3+ T cell activation (p = 0.04) and anti-HIV-1 CD8+ T cell responses in blippers by week 4 when compared to non-blippers. Past week 4 of interruption, therapy re-initiation criteria were also met by a higher frequency in blippers by week 14 (p < 0.04) with no difference between groups by week 24. These data support that blippers have higher anti-HIV lymphoproliferative responses while on ART but experience equal to higher viral rebound as compared to matched non-blippers upon TI.


Blips HIV treatment interruption CD4+ T cell responses 


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  1. 1.
    Gulick RM, Mellors JW, Havlir D, Eron JJ, Gonzalez C, McMahon D, Richman DD, Valentine FT, Jonas L, Meibohm A, Emini EA, Chodakewitz JA: Treatment with indinavir, zidovudine, and lamivudine in adults with human immunodeficiency virus infection and prior antiretroviral therapy. N Engl J Med 337:734–739, 1997CrossRefPubMedGoogle Scholar
  2. 2.
    Hammer SM, Squires KE, Hughes MD, Grimes JM, Demeter LM, Currier JS, Eron JJ Jr, Feinberg JE, Balfour HH Jr, Deyton LR, Chodakewitz JA, Fischl MA: A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med 337:725–733, 1997CrossRefPubMedGoogle Scholar
  3. 3.
    Palella FJ Jr, Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, Aschman DJ, Holmberg SD: Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J Med 338:853–860, 1998CrossRefPubMedGoogle Scholar
  4. 4.
    Detels R, Munoz A, McFarlane G, Kingsley LA, Margolick JB, Giorgi J, Schrager LK, Phair JP: Effectiveness of potent antiretroviral therapy on time to AIDS and death in men with known HIV infection duration. Multicenter AIDS Cohort Study Investigators. JAMA 280:1497–1503, 1998CrossRefPubMedGoogle Scholar
  5. 5.
    Vittinghoff E, Scheer S, O'Malley P, Colfax G, Holmberg SD, Buchbinder SP: Combination antiretroviral therapy and recent declines in AIDS incidence and mortality. J Infect Dis 179:717–720, 1999CrossRefPubMedGoogle Scholar
  6. 6.
    Mocroft A, Vella S, Benfield TL, Chiesi A, Miller V, Gargalianos P, d'Arminio Monforte A, Yust I, Bruun JN, Phillips AN, Lundgren JD: Changing patterns of mortality across Europe in patients infected with HIV-1. EuroSIDA Study Group. Lancet 352:1725–1730, 1998CrossRefPubMedGoogle Scholar
  7. 7.
    Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, Katlama C, Debre P, Leibowitch J: Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 277:112–116, 1997CrossRefPubMedGoogle Scholar
  8. 8.
    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 396:690–695, 1998PubMedGoogle Scholar
  9. 9.
    Gorochov G, Neumann AU, Kereveur A, Parizot C, Li T, Katlama C, Karmochkine M, Raguin G, Autran B, Debre P: Perturbation of CD4+ and CD8+ T-cell repertoires during progression to AIDS and regulation of the CD4+ repertoire during antiviral therapy. Nat Med 4:215–221, 1998CrossRefPubMedGoogle Scholar
  10. 10.
    Komanduri KV, Viswanathan MN, Wieder ED, Schmidt DK, Bredt BM, Jacobson MA, McCune JM: Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1. Nat Med 4:953–956, 1998CrossRefPubMedGoogle Scholar
  11. 11.
    Lederman MM, Connick E, Landay A, Kuritzkes DR, Spritzler J, St Clair M, Kotzin BL, Fox L, Chiozzi MH, Leonard JM, Rousseau F, Wade M, Roe JD, Martinez A, Kessler H: Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: Results of AIDS Clinical Trials Group Protocol 315. J Infect Dis 178:70–79, 1998PubMedGoogle Scholar
  12. 12.
    Li TS, Tubiana R, Katlama C, Calvez V, Ait Mohand H, Autran B: Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease. Lancet 351:1682–1686, 1998PubMedGoogle Scholar
  13. 13.
    Markowitz M, Vesanen M, Tenner-Racz K, Cao Y, Binley JM, Talal A, Hurley A, Jin X, Chaudhry MR, Yaman M, Frankel S, Heath-Chiozzi M, Leonard JM, Moore JP, Racz P, Nixon DF, Ho DD, J X: The effect of commencing combination antiretroviral therapy soon after human immunodeficiency virus type 1 infection on viral replication and antiviral immune responses. J Infect Dis 179:527–537, 1999CrossRefPubMedGoogle Scholar
  14. 14.
    Merrill DP, Martinez-Picado J, Tremblay C, Sax PE, Boswell SL, Wong JT, D'Aquila RT, Walker BD, Hirsch MS: Improved CD4 lymphocyte outgrowth in response to effective antiretroviral therapy. J Infect Dis 179:345–351, 1999CrossRefPubMedGoogle Scholar
  15. 15.
    Mezzaroma I, Carlesimo M, Pinter E, Alario C, Sacco G, Muratori DS, Bernardi ML, Paganelli R, Aiuti F: Long-term evaluation of T-cell subsets and T-cell function after HAART in advanced stage HIV-1 disease. AIDS 13:1187–1193, 1999CrossRefPubMedGoogle Scholar
  16. 16.
    O'Sullivan CE, Drew WL, McMullen DJ, Miner R, Lee JY, Kaslow RA, Lazar JG, Saag MS: Decrease of cytomegalovirus replication in human immunodeficiency virus infected-patients after treatment with highly active antiretroviral therapy. J Infect Dis 180:847–849, 1999CrossRefPubMedGoogle Scholar
  17. 17.
    Pontesilli O, Kerkhof-Garde S, Notermans DW, Foudraine NA, Roos MT, Klein MR, Danner SA, Lange JM, Miedema F: Functional T cell reconstitution and human immunodeficiency virus-1-specific cell-mediated immunity during highly active antiretroviral therapy. J Infect Dis 180:76–86, 1999CrossRefPubMedGoogle Scholar
  18. 18.
    Mira JA, Macias J, Nogales C, Fernandez-Rivera J, Garcia-Garcia JA, Ramos A, Pineda JA: Transient rebounds of low-level viraemia among HIV-infected patients under HAART are not associated with virological or immunological failure. Antivir Ther 7:251–256, 2002PubMedGoogle Scholar
  19. 19.
    Ramratnam B, Mittler JE, Zhang L, Boden D, Hurley A, Fang F, Macken CA, Perelson AS, Markowitz M, Ho DD: The decay of the latent reservoir of replication-competent HIV-1 is inversely correlated with the extent of residual viral replication during prolonged anti-retroviral therapy. Nat Med 6:82–85, 2000PubMedGoogle Scholar
  20. 20.
    Cohen Stuart JW, Wensing AM, Kovacs C, Righart M, de Jong D, Kaye S, Schuurman R, Visser CJ, Boucher CA: Transient relapses (blips) of plasma HIV RNA levels during HAART are associated with drug resistance. J Acquir Immune Defic Syndr 28:105–113, 2001PubMedGoogle Scholar
  21. 21.
    Dornadula G, Zhang H, VanUitert B, Stern J, Livornese L Jr, Ingerman MJ, Witek J, Kedanis RJ, Natkin J, DeSimone J, Pomerantz RJ: Residual HIV-1 RNA in blood plasma of patients taking suppressive highly active antiretroviral therapy. JAMA 282:1627–1632, 1999CrossRefPubMedGoogle Scholar
  22. 22.
    Havlir DV, Bassett R, Levitan D, Gilbert P, Tebas P, Collier AC, Hirsch MS, Ignacio C, Condra J, Gunthard HF, Richman DD, Wong JK: Prevalence and predictive value of intermittent viremia with combination hiv therapy. JAMA 286:171–179, 2001CrossRefPubMedGoogle Scholar
  23. 23.
    Moore AL, Youle M, Lipman M, Cozzi-Lepri A, Lampe F, Madge S, Nesaratnam S, Tyrer M, Cuthbertson Z, Ransom D, Loveday C, Johnson MA, Phillips AN: Raised viral load in patients with viral suppression on highly active antiretroviral therapy: Transient increase or treatment failure? AIDS 16:615–618, 2002PubMedGoogle Scholar
  24. 24.
    Sklar PA, Ward DJ, Baker RK, Wood KC, Gafoor Z, Alzola CF, Moorman AC, Holmberg SD: Prevalence and clinical correlates of HIV viremia (‘blips’) in patients with previous suppression below the limits of quantification. AIDS 16:2035–2041, 2002CrossRefPubMedGoogle Scholar
  25. 25.
    Yerly S, Perneger TV, Vora S, Hirschel B, Perrin L: Decay of cell-associated HIV-1 DNA correlates with residual replication in patients treated during acute HIV-1 infection. AIDS 14:2805–2812, 2000CrossRefPubMedGoogle Scholar
  26. 26.
    Martinez-Picado J, DePasquale MP, Kartsonis N, Hanna GJ, Wong J, Finzi D, Rosenberg E, Gunthard HF, Sutton L, Savara A, Petropoulos CJ, Hellmann N, Walker BD, Richman DD, Siliciano R, D'Aquila RT: Antiretroviral resistance during successful therapy of HIV type 1 infection. Proc Natl Acad Sci USA 97:10948–10953, 2000CrossRefPubMedGoogle Scholar
  27. 27.
    Nettles RE, Kieffer TL, Simmons RP, Cofrancesco J Jr, Moore RD, Gallant JE, Persaud D, Siliciano RF: Genotypic resistance in HIV-1-infected patients with persistently detectable low-level viremia while receiving highly active antiretroviral therapy. Clin Infect Dis 39:1030–1037, 2004CrossRefPubMedGoogle Scholar
  28. 28.
    Katzenstein TL, Ullum H, Roge BT, Wandall J, Dickmeiss E, Barrington T, Skinhoj P, Gerstoft J: Virological and immunological profiles among patients with undetectable viral load followed prospectively for 24 months. HIV Med 4:53–61, 2003CrossRefPubMedGoogle Scholar
  29. 29.
    Brambilla D, Reichelderfer PS, Bremer JW, Shapiro DE, Hershow RC, Katzenstein DA, Hammer SM, Jackson B, Collier AC, Sperling RS, Fowler MG, Coombs RW: The contribution of assay variation and biological variation to the total variability of plasma HIV-1 RNA measurements. The Women Infant Transmission Study Clinics. Virology Quality Assurance Program. AIDS 13:2269–2279, 1999PubMedGoogle Scholar
  30. 30.
    Bollinger RC, Egan MA, Chun TW, Mathieson B, Siliciano RF: Cellular immune responses to HIV-1 in progressive and non-progressive infections. AIDS 10(Suppl A):S85–S96, 1996PubMedGoogle Scholar
  31. 31.
    Pontesilli O, Carotenuto P, Kerkhof-Garde SR, Roos MT, Keet IP, Coutinho RA, Goudsmit J, Miedema F: Lymphoproliferative response to HIV type 1 p24 in long-term survivors of HIV type 1 infection is predictive of persistent AIDS-free infection. AIDS Res Hum Retroviruses 15:973–981, 1999CrossRefPubMedGoogle Scholar
  32. 32.
    Dyer WB, Ogg GS, Demoitie MA, Jin X, Geczy AF, Rowland-Jones SL, McMichael AJ, Nixon DF, Sullivan JS: Strong human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte activity in Sydney Blood Bank Cohort patients infected with nef-defective HIV type 1. J Virol 73:436–443, 1999PubMedGoogle Scholar
  33. 33.
    Rowland-Jones S: Long-term non-progression in HIV infection: Clinico pathological issues. J Infect 38:67–70, 1999CrossRefPubMedGoogle Scholar
  34. 34.
    Rowland-Jones SL, Dong T, Dorrell L, Ogg G, Hansasuta P, Krausa P, Kimani J, Sabally S, Ariyoshi K, Oyugi J, MacDonald KS, Bwayo J, Whittle H, Plummer FA, McMichael AJ: Broadly cross-reactive HIV-specific cytotoxic T-lymphocytes in highly-exposed persistently seronegative donors. Immunol Lett 66:9–14, 1999CrossRefPubMedGoogle Scholar
  35. 35.
    Clerici M, Seminari E, Suter F, Castelli F, Pan A, Biasin M, Colombo F, Trabattoni D, Maggiolo F, Carosi G, Maserati R: Different immunologic profiles characterize HIV infection in highly active antiretroviral therapy-treated and antiretroviral-naive patients with undetectable viraemia. The Master Group. AIDS 14:109–116, 2000PubMedGoogle Scholar
  36. 36.
    Fowke KR, Dong T, Rowland-Jones SL, Oyugi J, Rutherford WJ, Kimani J, Krausa P, Bwayo J, Simonsen JN, Shearer GM, Plummer FA: HIV type 1 resistance in Kenyan sex workers is not associated with altered cellular susceptibility to HIV type 1 infection or enhanced beta-chemokine production. AIDS Res Hum Retroviruses 14:1521–1530, 1998PubMedGoogle Scholar
  37. 37.
    Matloubian M, Concepcion RJ, Ahmed R: CD4+ T cells are required to sustain CD8+ cytotoxic T-cell responses during chronic viral infection. J Virol 68:8056–8063, 1994PubMedGoogle Scholar
  38. 38.
    Papasavvas E, Kostman JR, Mounzer K, Grant RM, Gross R, Gallo C, Azzoni L, Foulkes A, Thiel B, Pistilli M, Mackiewicz A, Shull J, Montaner LJ: Randomized, controlled trial of therapy interruption in chronic HIV-1 infection. PLOS Medicine 1:218–228, 2004CrossRefGoogle Scholar
  39. 39.
    Papasavvas E, Grant RM, Sun J, Mackiewicz A, Pistilli M, Gallo C, Kostman JR, Mounzer K, Shull J, Montaner LJ: Lack of persistent drug-resistant mutations evaluated within and between treatment interruptions in chronically HIV-1-infected patients. AIDS 17:2337–2343, 2003PubMedGoogle Scholar
  40. 40.
    Papasavvas E, Sandberg JK, Rutstein R, Moore EC, Mackiewicz A, Thiel B, Pistilli M, June RR, Jordan KA, Gross R, Maino VC, Nixon DF, Montaner LJ: Presence of human immunodeficiency virus-1-specific CD4 and CD8 cellular immune responses in children with full or partial virus suppression. J Infect Dis 188:873–882, 2003CrossRefPubMedGoogle Scholar
  41. 41.
    Papasavvas E, Ortiz GM, Gross R, Sun J, Moore EC, Heymann JJ, Moonis M, Sandberg JK, Drohan LA, Gallagher B, Shull J, Nixon DF, Kostman JR, Montaner LJ: Enhancement of human immunodeficiency virus type 1-specific CD4 and CD8 T cell responses in chronically infected persons after temporary treatment interruption. J Infect Dis 182:766–775, 2000CrossRefPubMedGoogle Scholar
  42. 42.
    Rosenberg ES, Billingsley JM, Caliendo AM, Boswell SL, Sax PE, Kalams SA, Walker BD: Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 278:1447–1450, 1997CrossRefPubMedGoogle Scholar
  43. 43.
    Ruiz L, Carcelain G, Martinez-Picado J, Frost S, Marfil S, Paredes R, Romeu J, Ferrer E, Morales-Lopetegi K, Autran B, Clotet B: HIV dynamics and T-cell immunity after three structured treatment interruptions in chronic HIV-1 infection. AIDS 15:F19–F27, 2001CrossRefPubMedGoogle Scholar
  44. 44.
    Lacabaratz-Porret C, Viard JP, Goujard C, Levy Y, Rodallec A, Deveau C, Venet A, Sinet M: Presence of HIV-specific CD4+ T-cell responses in HIV-infected subjects with sustained virologic control after highly active antiretroviral therapy. J Acquir Immune Defic Syndr 36:594–599, 2004PubMedGoogle Scholar
  45. 45.
    Imami N, Hardy G, Burton C, Pires A, Pido-Lopez J, Moss R, Gazzard B, Gotch F: Immune responses and reconstitution in HIV-1 infected individuals: Impact of anti-retroviral therapy, cytokines and therapeutic vaccination. Immunol Lett 79:63–76, 2001CrossRefPubMedGoogle Scholar
  46. 46.
    Ortiz GM, Nixon DF, Trkola A, Binley J, Jin X, Bonhoeffer S, Kuebler PJ, Donahoe SM, Demoitie MA, Kakimoto WM, Ketas T, Clas B, Heymann JJ, Zhang L, Cao Y, Hurley A, Moore JP, Ho DD, Markowitz M: HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J Clin Invest 104:R13–R18, 1999PubMedGoogle Scholar
  47. 47.
    Larsson M, Jin X, Ramratnam B, Ogg GS, Engelmayer J, Demoitie MA, McMichael AJ, Cox WI, Steinman RM, Nixon D, Bhardwaj N: A recombinant vaccinia virus based ELISPOT assay detects high frequencies of Pol-specific CD8 T cells in HIV-1-positive individuals. AIDS 13:767–777, 1999CrossRefPubMedGoogle Scholar
  48. 48.
    Poulin JF, Sylvestre M, Champagne P, Dion ML, Kettaf N, Dumont A, Lainesse M, Fontaine P, Roy DC, Perreault C, Sekaly RP, Cheynier R: Evidence for adequate thymic function but impaired naive T-cell survival following allogeneic hematopoietic stem cell transplantation in the absence of chronic graft-versus-host disease. Blood 102:4600–4607, 2003CrossRefPubMedGoogle Scholar
  49. 49.
    Grant RM, Kuritzkes DR, Johnson VA, Mellors JW, Sullivan JL, Swanstrom R, D'Aquila RT, Van Gorder M, Holodniy M, Lloyd RM Jr, Reid C, Morgan GF, Winslow DL: Accuracy of the TRUGENE HIV-1 genotyping kit. J Clin Microbiol 41:1586–1593, 2003CrossRefPubMedGoogle Scholar
  50. 50.
    D'Aquila RT, Schapiro JM, Brun-Vezinet F, Clotet B, Conway B, Demeter L, Grant RM, Johnson VA, Kuritzkes DR, Loveday C, Shafer RW, Richman D: Update on drug resistance mutations in HIV-1. Top HIV Med. 11:92–96, 2003PubMedGoogle Scholar
  51. 51.
    Grant RM, Hecht FM, Warmerdam M, Liu L, Liegler T, Petropoulos CJ, Hellmann NS, Chesney M, Busch MP, Kahn JO: Time trends in primary HIV-1 drug resistance among recently infected persons. JAMA 288:181–188, 2002CrossRefPubMedGoogle Scholar
  52. 52.
    Lang T, Sesic M: How to report statistics in medicine. American College of Physicians (ACP) Series, 1997Google Scholar
  53. 53.
    Tenorio AR, Smith KY, Kuritzkes DR, Sha BE, Donoval B, Young R, Jennings C, Bremer J, Shott S, Landay A, Kessler HA: HIV-1-infected antiretroviral-treated patients with prolonged partial viral suppression: Clinical, virologic, and immunologic course. J Acquir Immune Defic Syndr 34:491–496, 2003PubMedGoogle Scholar
  54. 54.
    Sullivan AK, Hardy GA, Nelson MR, Gotch F, Gazzard BG, Imami N: Interleukin-2-associated viral breakthroughs induce HIV-1-specific CD4 T cell responses in patients on fully suppressive highly active antiretroviral therapy. AIDS 17:628–629, 2003CrossRefPubMedGoogle Scholar
  55. 55.
    Carcelain G, Tubiana R, Samri A, Calvez V, Delaugerre C, Agut H, Katlama C, Autran B: Transient mobilization of human immunodeficiency virus (HIV)-specific CD4 T-helper cells fails to control virus rebounds during intermittent antiretroviral therapy in chronic HIV type 1 infection. J Virol 75:234–241, 2001CrossRefPubMedGoogle Scholar
  56. 56.
    McNeil AC, Shupert WL, Iyasere CA, Hallahan CW, Mican JA, Davey RT Jr, Connors M: High-level HIV-1 viremia suppresses viral antigen-specific CD4(+) T cell proliferation. Proc Natl Acad Sci USA 98:13878–13883, 2001PubMedGoogle Scholar
  57. 57.
    Musey LK, Krieger JN, Hughes JP, Schacker TW, Corey L, McElrath MJ: Early and persistent human immunodeficiency virus type 1 (HIV-1)-specific T helper dysfunction in blood and lymph nodes following acute HIV-1 infection. J Infect Dis 180:278–284, 1999CrossRefPubMedGoogle Scholar
  58. 58.
    Casazza JP, Betts MR, Picker LJ, Koup RA: Decay kinetics of human immunodeficiency virus-specific CD8+ T cells in peripheral blood after initiation of highly active antiretroviral therapy. J Virol 75:6508–6516, 2001CrossRefPubMedGoogle Scholar
  59. 59.
    Cao Y, Qin L, Zhang L, Safrit J, Ho DD: Virologic and immunologic characterization of long-term survivors of human immunodeficiency virus type 1 infection. N Engl J Med 332:201–208, 1995CrossRefPubMedGoogle Scholar
  60. 60.
    Pitcher CJ, Quittner C, Peterson DM, Connors M, Koup RA, Maino VC, Picker LJ: HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nat Med 5:518–525, 1999CrossRefPubMedGoogle Scholar
  61. 61.
    Lori F, Foli A, Maserati R, Seminari E, Xu J, Whitman L, Ravot E, Alberici F, Lopalco L, Lisziewicz J: Control of HIV during a structured treatment interruption in chronically infected individuals with vigorous T cell responses. HIV Clin Trials 3:115–124, 2002PubMedGoogle Scholar
  62. 62.
    Garcia F, Plana M, Vidal C, Cruceta A, O'Brien WA, Pantaleo G, Pumarola T, Gallart T, Miro JM, Gatell JM: Dynamics of viral load rebound and immunological changes after stopping effective antiretroviral therapy. AIDS 13:F79–F86, 1999PubMedGoogle Scholar
  63. 63.
    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 283:857–860, 1999CrossRefPubMedGoogle Scholar
  64. 64.
    Gloster SE, Newton P, Cornforth D, Lifson JD, Williams I, Shaw GM, Borrow P: Association of strong virus-specific CD4 T cell responses with efficient natural control of primary HIV-1 infection. AIDS 18:749–755, 2004PubMedGoogle Scholar
  65. 65.
    Chehimi J, Campbell DE, Azzoni L, Bacheller D, Papasavvas E, Jerandi G, Mounzer K, Kostman J, Trinchieri G, Montaner LJ: Persistent decreases in blood plasmacytoid dendritic cell number and function despite effective highly active antiretroviral therapy and increased blood myeloid dendritic cells in HIV-infected individuals. J Immunol 168:4796–4801, 2002PubMedGoogle Scholar
  66. 66.
    Azzoni L, Papasavvas E, Chehimi J, Kostman JR, Mounzer K, Ondercin J, Perussia B, Montaner LJ: Sustained impairment of IFN-gamma secretion in suppressed HIV-infected patients despite mature NK cell recovery: Evidence for a defective reconstitution of innate immunity. J Immunol 168:5764–5770, 2002PubMedGoogle Scholar
  67. 67.
    Pantaleo G, Soudeyns H, Demarest JF, Vaccarezza M, Graziosi C, Paolucci S, Daucher M, Cohen OJ, Denis F, Biddison WE, Sekaly RP, Fauci AS: Evidence for rapid disappearance of initially expanded HIV-specific CD8+ T cell clones during primary HIV infection. Proc Natl Acad Sci USA 94:9848–9853, 1997PubMedGoogle Scholar
  68. 68.
    Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L, Ogg GS, King A, Lechner F, Spina CA, Little S, Havlir DV, Richman DD, Gruener N, Pape G, Waters A, Easterbrook P, Salio M, Cerundolo V, McMichael AJ, Rowland-Jones SL: Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 8:379–385, 2002CrossRefPubMedGoogle Scholar
  69. 69.
    Appay V, Nixon DF, Donahoe SM, Gillespie GM, Dong T, King A, Ogg GS, Spiegel HM, Conlon C, Spina CA, Havlir DV, Richman DD, Waters A, Easterbrook P, McMichael AJ, Rowland-Jones SL: HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J Exp Med 192:63–75, 2000CrossRefPubMedGoogle Scholar
  70. 70.
    Dybul M, Daucher M, Jensen MA, Hallahan CW, Chun TW, Belson M, Hidalgo B, Nickle DC, Yoder C, Metcalf JA, Davey RT, Ehler L, Kress-Rock D, Nies-Kraske E, Liu S, Mullins JI, Fauci AS: Genetic characterization of rebounding human immunodeficiency virus type 1 in plasma during multiple interruptions of highly active antiretroviral therapy. J Virol 77:3229–3237, 2003CrossRefPubMedGoogle Scholar
  71. 71.
    Altfeld M, Rosenberg ES, Shankarappa R, Mukherjee JS, Hecht FM, Eldridge RL, Addo MM, Poon SH, Phillips MN, Robbins GK, Sax PE, Boswell S, Kahn JO, Brander C, Goulder PJ, Levy JA, Mullins JI, Walker BD: Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection. J Exp Med 193:169–180, 2001CrossRefPubMedGoogle Scholar
  72. 72.
    Malim MH, Emerman M: HIV-1 sequence variation: Drift, shift, and attenuation. Cell 104:469–472, 2001CrossRefPubMedGoogle Scholar
  73. 73.
    Pantaleo G, Cohen OJ, Schacker T, Vaccarezza M, Graziosi C, Rizzardi GP, Kahn J, Fox CH, Schnittman SM, Schwartz DH, Corey L, Fauci AS: Evolutionary pattern of human immunodeficiency virus (HIV) replication and distribution in lymph nodes following primary infection: Implications for antiviral therapy. Nat Med 4:341–345, 1998CrossRefPubMedGoogle Scholar
  74. 74.
    Azzoni L, Papasavvas E, Montaner LJ: Lessons learned from HIV treatment interruption: Safety, correlates of immune control, and drug sparing. Curr HIV Res 1:329–342, 2003CrossRefPubMedGoogle Scholar
  75. 75.
    Greub G, Cozzi-Lepri A, Ledergerber B, Staszewski S, Perrin L, Miller V, Francioli P, Furrer H, Battegay M, Vernazza P, Bernasconi E, Gunthard HF, Hirschel B, Phillips AN, Telenti A: Intermittent and sustained low-level HIV viral rebound in patients receiving potent antiretroviral therapy. AIDS 16:1967–1969, 2002PubMedGoogle Scholar
  76. 76.
    Lichterfeld M, Kaufmann DE, Yu XG, Mui SK, Addo MM, Johnston MN, Cohen D, Robbins GK, Pae E, Alter G, Wurcel A, Stone D, Rosenberg ES, Walker BD, Altfeld M: Loss of HIV-1-specific CD8+ T cell proliferation after acute HIV-1 infection and restoration by vaccine-induced HIV-1-specific CD4+ T cells. J Exp Med 200:701–712, 2004CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science + Business Media, Inc. 2006

Authors and Affiliations

  • Emmanouil Papasavvas
    • 1
  • Jay R. Kostman
    • 2
    • 3
  • Brian Thiel
    • 1
  • Maxwell Pistilli
    • 1
  • Agnieszka Mackiewicz
    • 1
  • Andrea Foulkes
    • 4
  • Robert Gross
    • 3
    • 4
  • Kimberly A. Jordan
    • 5
  • Douglas F. Nixon
    • 5
    • 6
  • Robert Grant
    • 5
    • 6
  • Jean-francois Poulin
    • 5
  • Joseph M. Mccune
    • 5
    • 6
  • Karam Mounzer
    • 2
  • Luis J. Montaner
    • 2
    • 7
  1. 1.The Wistar InstitutePhiladelphia
  2. 2.Philadelphia Field Initiating Group for HIV-1 TrialsPhiladelphia
  3. 3.Division of Infectious DiseasesUniversity of PennsylvaniaPhiladelphia
  4. 4.Center for Clinical Epidemiology and BiostatisticsUniversity of PennsylvaniaPhiladelphia
  5. 5.The Gladstone Institute of Virology and ImmunologyUniversity of CaliforniaSan Francisco
  6. 6.Department of MedicineUniversity of CaliforniaSan Francisco
  7. 7.the Wistar InstitutePhiladelphia

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