• 1
    Barre-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, et al. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science 1983; 220: 868871.
  • 2
    Siliciano JD, Siliciano RF. Latency and viral persistence in HIV-1 infection. J Clin Invest 2000; 106: 823825.
  • 3
    Veazey RS, Mansfield KG, Tham IC, Carville AC, Shvetz DE, Forand AE, et al. Dynamics of CCR5 expression by CD4+ T cells in lymphoid tissues during simian immunodeficiency virus infection. J Virol 2000; 74: 1100111007.
  • 4
    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: 769776.
  • 5
    Brenchley JM, Schacker TW, Ruff LE, Price DA, Taylor JH, Beilman GJ, et al. CD4+ T cell depletion during all stages of HIV disease occurs predominantly in the gastrointestinal tract. J Exp Med 2004; 200: 749759.
  • 6
    Veazey RS, DeMaria M, Chalifoux LV, Shvetz DE, Pauley DR, Knight HL, et al. Gastrointestinal tract as a major site of CD4+ T cell depletion and viral replication in SIV infection. Science 1998; 280: 427431.
  • 7
    Mattapallil JJ, Smit-McBride Z, McChesney M, Dandekar S. Intestinal intraepithelial lymphocytes are primed for gamma interferon and MIP-1β expression and display antiviral cytotoxic activity despite severe CD4+ T cell depletion in primary simian immunodeficiency virus infection. J Virol 1998; 72: 64216429.
  • 8
    Groux H, Torpier G, Monte D, Mouton Y, Capron A, Ameisen JC. Activation-induced death by apoptosis in CD4+ T cells from human immunodeficiency virus-infected asymptomatic individuals. J Exp Med 1992; 175: 331340.
  • 9
    Meyaard L, Otto SA, Jonker RR, Mijnster MJ, Keet RP, Miedema F. Programmed death of T cells in HIV-1 infection. Science 1992; 257: 217219.
  • 10
    Gougeon ML, Montagnier L. Apoptosis in AIDS. Science 1993; 260: 12691270.
  • 11
    Finkel TH, Tudor-Williams G, Banda NK, Cotton MF, Curiel T, Monks C, et al. Apoptosis occurs predominantly in bystander cells and not in productively infected cells of HIV- and SIV-infected lymph nodes. Nat Med 1995; 1: 129134.
  • 12
    Weiss L, Haeffner-Cavaillon N, Laude M, Gilquin J, Kazatchkine MD. HIV infection is associated with the spontaneous production of interleukin-1 (IL-1) in vivo and with an abnormal release of IL-1α in vitro. AIDS 1989; 3: 695699.
  • 13
    Molina JM, Scadden DT, Byrn R, Dinarello CA, Groopman JE. Production of tumor necrosis factor alpha and interleukin 1 beta by monocytic cells infected with human immunodeficiency virus. J Clin Invest 1989; 84: 733737.
  • 14
    Emilie D, Peuchmaur M, Maillot MC, Crevon MC, Brousse N, Delfraissy JF, et al. Production of interleukins in human immunodeficiency virus-1-replicating lymph nodes. J Clin Invest 1990; 86: 148159.
  • 15
    Birx DL, Redfield RR, Tencer K, Fowler A, Burke DS, Tosato G. Induction of interleukin-6 during human immunodeficiency virus infection. Blood 1990; 76: 23032310.
  • 16
    Lafeuillade A, Poizot-Martin I, Quilichini R, Gastaut JA, Kaplanski S, Farnarier C, et al. Increased interleukin-6 production is associated with disease progression in HIV infection. AIDS 1991; 5: 11391140.
  • 17
    Canque B, Rosenzwajg M, Gey A, Tartour E, Fridman WH, Gluckman JC. Macrophage inflammatory protein-1α is induced by human immunodeficiency virus infection of monocyte-derived macrophages. Blood 1996; 87: 20112019.
  • 18
    Cotter RL, Zheng J, Che M, Niemann D, Liu Y, He J, et al. Regulation of human immunodeficiency virus type 1 infection, β-chemokine production, and CCR5 expression in CD40L-stimulated macrophages: immune control of viral entry. J Virol 2001; 75: 43084320.
  • 19
    Giorgi JV, Liu Z, Hultin LE, Cumberland WG, Hennessey K, Detels R. Elevated levels of CD38+CD8+ T cells in HIV infection add to the prognostic value of low CD4+ T cell levels: results of 6 years of follow-up. The Los Angeles Center, Multicenter AIDS Cohort Study. J Acqu Immune Defic Syndr 1993; 6: 904912.
  • 20
    Liu Z, Cumberland WG, Hultin LE, Kaplan AH, Detels R, Giorgi JV. CD8+ T-lymphocyte activation in HIV-1 disease reflects an aspect of pathogenesis distinct from viral burden and immunodeficiency. J Acqu Immune Defic Syndr Hum Retrovirol 1998; 18: 332340.
  • 21
    Giorgi JV, Hultin LE, McKeating JA, Johnson TD, Owens B, Jacobson LP, et al. Shorter survival in advanced human immunodeficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis 1999; 179: 859870.
  • 22
    Hazenberg MD, Otto SA, van Benthem BH, Roos MT, Coutinho RA, Lange JM, et al. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS 2003; 17: 18811888.
  • 23
    Deeks SG, Kitchen CM, Liu L, Guo H, Gascon R, Narvaez AB, et al. Immune activation set point during early HIV infection predicts subsequent CD4+ T cell changes independent of viral load. Blood 2004; 104: 942947.
  • 24
    Wilson CM, Ellenberg JH, Douglas SD, Moscicki AB, Holland CA. CD8+CD38+ T cells but not HIV type 1 RNA viral load predict CD4+ T cell loss in a predominantly minority female HIV+ adolescent population. AIDS Res Hum Retroviruses 2004; 20: 263269.
  • 25
    Silvestri G, Sodora DL, Koup RA, Paiardini M, O'Neil SP, McClure HM, et al. Nonpathogenic SIV infection of sooty mangabeys is characterized by limited bystander immunopathology despite chronic high-level viremia. Immunity 2003; 18: 441452.
  • 26
    Leligdowicz A, Yindom LM, Onyango C, Sarge-Njie R, Alabi A, Cotten M, et al. Robust Gag-specific T cell responses characterize viremia control in HIV-2 infection. J Clin Invest 2007; 117: 30673074.
  • 27
    Sousa AE, Carneiro J, Meier-Schellersheim M, Grossman Z, Victorino RM. CD4 T cell depletion is linked directly to immune activation in the pathogenesis of HIV-1 and HIV-2 but only indirectly to the viral load. J Immunol 2002; 169: 34003406.
  • 28
    Anzala AO, Simonsen JN, Kimani J, Ball TB, Nagelkerke NJ, Rutherford J, et al. Acute sexually transmitted infections increase human immunodeficiency virus type 1 plasma viremia, increase plasma type 2 cytokines, and decrease CD4 cell counts. J Infect Dis 2000; 182: 459466.
  • 29
    Villinger F, Rowe T, Parekh BS, Green TA, Mayne AE, Grimm B, et al. Chronic immune stimulation accelerates SIV-induced disease progression. J Med Primatol 2001; 30: 254259.
  • 30
    Betts MR, Ambrozak DR, Douek DC, Bonhoeffer S, Brenchley JM, Casazza JP, et al. Analysis of total human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T cell responses: relationship to viral load in untreated HIV infection. J Virol 2001; 75: 1198311991.
  • 31
    Papagno L, Appay V, Sutton J, Rostron T, Gillespie GM, Ogg GS, et al. Comparison between HIV- and CMV-specific T cell responses in long-term HIV infected donors. Clin Exp Immunol 2002; 130: 509517.
  • 32
    Douek DC, Brenchley JM, Betts MR, Ambrozak DR, Hill BJ, Okamoto Y, et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 2002; 417: 9598.
  • 33
    Merrill JE, Koyanagi Y, Chen IS. Interleukin-1 and tumor necrosis factor alpha can be induced from mononuclear phagocytes by human immunodeficiency virus type 1 binding to the CD4 receptor. J Virol 1989; 63: 44044408.
  • 34
    Rieckmann P, Poli G, Fox CH, Kehrl JH, Fauci AS. Recombinant gp120 specifically enhances tumor necrosis factor-alpha production and Ig secretion in B lymphocytes from HIV-infected individuals but not from seronegative donors. J Immunol 1991; 147: 29222927.
  • 35
    Lee C, Liu QH, Tomkowicz B, Yi Y, Freedman BD, Collman RG. Macrophage activation through CCR5- and CXCR4-mediated gp120-elicited signaling pathways. J Leukoc Biol 2003; 74: 676682.
  • 36
    Wang JK, Kiyokawa E, Verdin E, Trono D. The Nef protein of HIV-1 associates with rafts and primes T cells for activation. Proc Natl Acad Sci USA 2000; 97: 394399.
  • 37
    Simmons A, Aluvihare V, McMichael A. Nef triggers a transcriptional program in T cells imitating single-signal T cell activation and inducing HIV virulence mediators. Immunity 2001; 14: 763777.
  • 38
    Swingler S, Mann A, Jacque J, Brichacek B, Sasseville VG, Williams K, et al. HIV-1 Nef mediates lymphocyte chemotaxis and activation by infected macrophages. Nat Med 1999; 5: 103997.
  • 39
    Dunn HS, Haney DJ, Ghanekar SA, Stepick-Biek P, Lewis DB, Maecker HT. Dynamics of CD4 and CD8 T cell responses to cytomegalovirus in healthy human donors. J Infect Dis 2002; 186: 1522.
  • 40
    Papagno L, Spina CA, Marchant A, Salio M, Rufer N, Little S, et al. Immune activation and CD8+ T cell differentiation towards senescence in HIV-1 infection. PLoS Biol 2004; 2: E20.
  • 41
    Doisne JM, Urrutia A, Lacabaratz-Porret C, Goujard C, Meyer L, Chaix ML, et al. CD8+ T cells specific for EBV, cytomegalovirus, and influenza virus are activated during primary HIV infection. J Immunol 2004; 173: 24102418.
  • 42
    Brenchley JM, Price DA, Schacker TW, Asher TE, Silvestri G, Rao S, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12: 13651371.
  • 43
    Brenchley JM, Price DA, Douek DC. HIV disease: fallout from a mucosal catastrophe? Nat Immunol 2006; 7: 235239.
  • 44
    Kawakami K, Scheidereit C, Roeder RG. Identification and purification of a human immunoglobulin-enhancer-binding protein (NF-κB) that activates transcription from a human immunodeficiency virus type 1 promoter in vitro. Proc Natl Acad Sci USA 1988; 85: 47004704.
  • 45
    Decrion AZ, Dichamp I, Varin A, Herbein G. HIV and inflammation. Curr HIV Res 2005; 3: 243259.
  • 46
    Stockmann M, Schmitz H, Fromm M, Schmidt W, Pauli G, Scholz P, et al. Mechanisms of epithelial barrier impairment in HIV infection. Ann NY Acad Sci 2000; 915: 293303.
  • 47
    Ferreira C, Barthlott T, Garcia S, Zamoyska R, Stockinger B. Differential survival of naive CD4 and CD8 T cells. J Immunol 2000; 165: 36893694.
  • 48
    Homann D, Teyton L, Oldstone MB. Differential regulation of antiviral T cell immunity results in stable CD8+ but declining CD4+ T cell memory. Nat Med 2001; 7: 913919.
  • 49
    Foulds KE, Zenewicz LA, Shedlock DJ, Jiang J, Troy AE, Shen H. Cutting edge: CD4 and CD8 T cells are intrinsically different in their proliferative responses. J Immunol 2002; 168: 15281532.
  • 50
    Haase AT, Henry K, Zupancic M, Sedgewick G, Faust RA, Melroe H, et al. Quantitative image analysis of HIV-1 infection in lymphoid tissue. Science 1996; 274: 985989.
  • 51
    Lassen K, Han Y, Zhou Y, Siliciano J, Siliciano RF. The multifactorial nature of HIV-1 latency. Trends Mol Med 2004; 10: 525531.
  • 52
    Effros RB, Pawelec G. Replicative senescence of T cells: does the Hayflick limit lead to immune exhaustion? Immunol Today 1997; 18: 450454.
  • 53
    Maini MK, Soares MV, Zilch CF, Akbar AN, Beverley PC. Virus-induced CD8+ T cell clonal expansion is associated with telomerase up-regulation and telomere length preservation: a mechanism for rescue from replicative senescence. J Immunol 1999; 162: 45214526.
  • 54
    Hathcock KS, Kaech SM, Ahmed R, Hodes RJ. Induction of telomerase activity and maintenance of telomere length in virus-specific effector and memory CD8+ T cells. J Immunol 2003; 170: 147152.
  • 55
    Roth A, Yssel H, Pene J, Chavez EA, Schertzer M, Lansdorp PM, et al. Telomerase levels control the lifespan of human T lymphocytes. Blood 2003; 102: 849857.
  • 56
    Plunkett FJ, Soares MV, Annels N, Hislop A, Ivory K, Lowdell M, et al. The flow cytometric analysis of telomere length in antigen-specific CD8+ T cells during acute Epstein–Barr virus infection. Blood 2001; 97: 700707.
  • 57
    Plunkett FJ, Franzese O, Finney HM, Fletcher JM, Belaramani LL, Salmon M, et al. The loss of telomerase activity in highly differentiated CD8+CD28CD27 T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol 2007; 178: 77107719.
  • 58
    Hakim FT, Memon SA, Cepeda R, Jones EC, Chow CK, Kasten-Sportes C, et al. Age-dependent incidence, time course, and consequences of thymic renewal in adults. J Clin Invest 2005; 115: 930939.
  • 59
    George AJ, Ritter MA. Thymic involution with ageing: obsolescence or good housekeeping? Immunol Today 1996; 17: 267272.
  • 60
    Aspinall R, Andrew D. Thymic involution in aging. J Clin Immunol 2000; 20: 250256.
  • 61
    Mackall CL, Fleisher TA, Brown MR, Andrich MP, Chen CC, Feuerstein IM, et al. Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy. N Engl J Med 1995; 332: 143149.
  • 62
    Mackall CL, Gress RE. Thymic aging and T cell regeneration. Immunol Rev 1997; 160: 91102.
  • 63
    Engelhardt M, Kumar R, Albanell J, Pettengell R, Han W, Moore MA. Telomerase regulation, cell cycle, and telomere stability in primitive haematopoietic cells. Blood 1997; 90: 182193.
  • 64
    Hakim FT, Cepeda R, Kaimei S, Mackall CL, McAtee N, Zujewski J, et al. Constraints on CD4 recovery postchemotherapy in adults: thymic insufficiency and apoptotic decline of expanded peripheral CD4 cells. Blood 1997; 90: 37893798.
  • 65
    Rufer N, Brummendorf TH, Kolvraa S, Bischoff C, Christensen K, Wadsworth L, et al. Telomere fluorescence measurements in granulocytes and T lymphocyte subsets point to a high turnover of haematopoietic stem cells and memory T cells in early childhood. J Exp Med 1999; 190: 157167.
  • 66
    Notaro R, Cimmino A, Tabarini D, Rotoli B, Luzzatto L. In vivo telomere dynamics of human haematopoietic stem cells. Proc Natl Acad Sci USA 1997; 94: 1378213785.
  • 67
    Gamadia LE, van Leeuwen EM, Remmerswaal EB, Yong SL, Surachno S, Wertheim-van Dillen PM, et al. The size and phenotype of virus-specific T cell populations is determined by repetitive antigenic stimulation and environmental cytokines. J Immunol 2004; 172: 61076114.
  • 68
    Brenchley JM, Karandikar NJ, Betts MR, Ambrozak DR, Hill BJ, Crotty LE, et al. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood 2003; 101: 27112720.
  • 69
    Betts MR, Nason MC, West SM, De Rosa SC, Migueles SA, Abraham J, et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 2006; 107: 47814789.
  • 70
    Migueles SA, Laborico AC, Shupert WL, Sabbaghian MS, Rabin R, Hallahan CW, et al. HIV-specific CD8+ T cell proliferation is coupled to perforin expression and is maintained in nonprogressors. Nat Immunol 2002; 3: 10611068.
  • 71
    Alexander-Miller MA, Leggatt GR, Berzofsky JA. Selective expansion of high- or low-avidity cytotoxic T lymphocytes and efficacy for adoptive immunotherapy. Proc Natl Acad Sci USA 1996; 93: 41024107.
  • 72
    Sedlik C, Dadaglio G, Saron MF, Deriaud E, Rojas M, Casal SI, et al. In vivo induction of a high-avidity, high-frequency cytotoxic T-lymphocyte response is associated with antiviral protective immunity. J Virol 2000; 74: 57695775.
  • 73
    Almeida JR, Price DA, Papagno L, Arkoub ZA, Sauce D, Bornstein E, et al. Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. J Exp Med 2007; 204: 24732485.
  • 74
    Day CL, Kaufmann DE, Kiepiela P, Brown JA, Moodley ES, Reddy S, et al. PD-1 expression on HIV-specific T cells is associated with T cell exhaustion and disease progression. Nature 2006; 443: 350354.
  • 75
    Trautmann L, Janbazian L, Chomont N, Said EA, Gimmig S, Bessette B, et al. Up-regulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction. Nat Med 2006; 12: 11981202.
  • 76
    Sauce D, Almeida JR, Larsen M, Haro L, Autran B, Freeman GJ, et al. PD-1 expression on human CD8 T cells depends on both state of differentiation and activation status. AIDS 2007; 21: 20052013.
  • 77
    Marandin A, Katz A, Oksenhendler E, Tulliez M, Picard F, Vainchenker W, et al. Loss of primitive haematopoietic progenitors in patients with human immunodeficiency virus infection. Blood 1996; 88: 45684578.
  • 78
    Jenkins M, Hanley MB, Moreno MB, Wieder E, McCune JM. Human immunodeficiency virus-1 infection interrupts thymopoiesis and multilineage haematopoiesis in vivo. Blood 1998; 91: 26722678.
  • 79
    Moses A, Nelson J, Bagby GC Jr. The influence of human immunodeficiency virus-1 on haematopoiesis. Blood 1998; 91: 14791495.
  • 80
    Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 1998; 396: 690695.
  • 81
    Schnittman SM, Denning SM, Greenhouse JJ, Justement JS, Baseler M, Kurtzberg J, et al. Evidence for susceptibility of intrathymic T cell precursors and their progeny carrying T cell antigen receptor phenotypes TCRαβ+ and TCRγδ+ to human immunodeficiency virus infection: a mechanism for CD4+ (T4) lymphocyte depletion. Proc Natl Acad Sci USA 1990; 87: 77277731.
  • 82
    Stanley SK, McCune JM, Kaneshima H, Justement JS, Sullivan M, Boone E, et al. Human immunodeficiency virus infection of the human thymus and disruption of the thymic microenvironment in the SCID-hu mouse. J Exp Med 1993; 178: 11511163.
  • 83
    Kalayjian RC, Landay A, Pollard RB, Taub DD, Gross BH, Francis IR, et al. Age-related immune dysfunction in health and in human immunodeficiency virus (HIV) disease: association of age and HIV infection with naive CD8+ cell depletion, reduced expression of CD28 on CD8+ cells, and reduced thymic volumes. J Infect Dis 2003; 187: 19241933.
  • 84
    Sempowski GD, Hale LP, Sundy JS, Massey JM, Koup RA, Douek DC, et al. Leukemia inhibitory factor, oncostatin M, IL-6, and stem cell factor mRNA expression in human thymus increases with age and is associated with thymic atrophy. J Immunol 2000; 164: 21802187.
  • 85
    Linton PJ, Dorshkind K. Age-related changes in lymphocyte development and function. Nat Immunol 2004; 5: 133139.
  • 86
    Schacker TW, Nguyen PL, Beilman GJ, Wolinsky S, Larson M, Reilly C, et al. Collagen deposition in HIV-1 infected lymphatic tissues and T cell homeostasis. J Clin Invest 2002; 110: 11331139.
  • 87
    Schacker TW, Reilly C, Beilman GJ, Taylor J, Skarda D, Krason D, et al. Amount of lymphatic tissue fibrosis in HIV infection predicts magnitude of HAART-associated change in peripheral CD4 cell count. AIDS 2005; 19: 21692171.
  • 88
    Appay V, Zaunders JJ, Papagno L, Sutton J, Jaramillo A, Waters A, et al. Characterization of CD4+ CTLs ex vivo. J Immunol 2002; 168: 59545958.
  • 89
    Effros RB, Allsopp R, Chiu CP, Hausner MA, Hirji K, Wang L, et al. Shortened telomeres in the expanded CD28-CD8+ cell subset in HIV disease implicate replicative senescence in HIV pathogenesis. AIDS 1996; 10: F1722.
  • 90
    Wolthers KC, Bea G, Wisman A, Otto SA, de Roda Husman AM, Schaft N, et al. T cell telomere length in HIV-1 infection: no evidence for increased CD4+ T cell turnover. Science 1996; 274: 15431547.
  • 91
    Clerici M, Stocks NI, Zajac RA, Boswell RN, Lucey DR, Via CS, et al. Detection of three distinct patterns of T helper cell dysfunction in asymptomatic, human immunodeficiency virus-seropositive patients. Independence of CD4+ cell numbers and clinical staging. J Clin Invest 1989; 84: 18921899.
  • 92
    Fan J, Bass HZ, and Fahey JL. Elevated IFNγ and decreased IL-2 gene expression are associated with HIV infection. J Immunol 1993; 151: 50315040.
  • 93
    Appay V, Rowland-Jones SL. Premature ageing of the immune system: the cause of AIDS? Trends Immunol 2002; 23: 580585.
  • 94
    Wang EC, Moss PA, Frodsham P, Lehner PJ, Bell JI, Borysiewicz LK. CD8highCD57+ T lymphocytes in normal, healthy individuals are oligoclonal and respond to human cytomegalovirus. J Immunol 1995; 155: 50465056.
  • 95
    Kuijpers TW, Vossen MT, Gent MR, Davin JC, Roos MT, Wertheim-van Dillen PM, et al. Frequencies of circulating cytolytic, CD45RA+CD27, CD8+ T lymphocytes depend on infection with CMV. J Immunol 2003; 170: 43424348.
  • 96
    Fletcher JM, Vukmanovic-Stejic M, Dunne PJ, Birch KE, Cook JE, Jackson SE, et al. Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. J Immunol 2005; 175: 82188225.
  • 97
    Sylwester AW, Mitchell BL, Edgar JB, Taormina C, Pelte C, Ruchti F, et al. Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. J Exp Med 2005; 202: 673685.
  • 98
    Webster A, Phillips AN, Lee CA, Janossy G, Kernoff PB, Griffiths PD. Cytomegalovirus (CMV) infection, CD4+ lymphocyte counts and the development of AIDS in HIV-1-infected haemophiliac patients. Clin Exp Immunol 1992; 88: 69.
  • 99
    Pawelec G, Effros RB, Caruso C, Remarque E, Barnett Y, Solana R. T cells and aging (update, February 1999). Front Biosci 1999; 4: D216269.
  • 100
    Roberts-Thomson IC, Whittingham S, Youngchaiyud U, Mackay IR. Ageing, immune response, and mortality. Lancet 1974; 2: 368370.
  • 101
    Wayne SJ, Rhyne RL, Garry PJ, Goodwin JS. Cell-mediated immunity as a predictor of morbidity and mortality in subjects over 60. J Gerontol 1990; 45: M4548.
  • 102
    Scutellari PN, Orzincolo C, Guarnelli EM. [Periodontal disease in patients with HIV infection. Radiographic study]. Radiol Med (Torino) 1996; 92: 562568.
  • 103
    Arpadi SM, Horlick M, Thornton J, Cuff PA, Wang J, Kotler DP. Bone mineral content is lower in prepubertal HIV-infected children. J Acqu Immune Defic Syndr 2002; 29: 450454.
  • 104
    Teichmann J, Stephan E, Discher T, Lange U, Federlin K, Stracke H, et al. Changes in calciotropic hormones and biochemical markers of bone metabolism in patients with human immunodeficiency virus infection. Metabolism 2000; 49: 11341139.
  • 105
    Amorosa V, Tebas P. Bone disease and HIV infection. Clin Infect Dis 2006; 42: 108114.
  • 106
    Hsue PY, Lo JC, Franklin A, Bolger AF, Martin JN, Deeks SG, et al. Progression of atherosclerosis as assessed by carotid intima-media thickness in patients with HIV infection. Circulation 2004; 109: 16031608.
  • 107
    McArthur JC, Hoover DR, Bacellar H, Miller EN, Cohen BA, Becker JT, et al. Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study. Neurology 1993; 43: 22452252.
  • 108
    Valcour VG, Shikuma CM, Watters MR, Sacktor NC. Cognitive impairment in older HIV-1-seropositive individuals: prevalence and potential mechanisms. AIDS 2004; 18(suppl 1): S7986.
  • 109
    Valcour V, Paul R. HIV infection and dementia in older adults. Clin Infect Dis 2006; 42: 14491454.
  • 110
    Desquilbet L, Jacobson LP, Fried LP, Phair JP, Jamieson BD, Holloway M, et al. HIV-1 infection is associated with an earlier occurence of a phenotype related to frailty. AIDS 2007; (in press).
  • 111
    Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C, Gottdiener J, et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 2001; 56: M146156.
  • 112
    Chung HY, Kim HJ, Kim JW, Yu BP. The inflammation hypothesis of aging: molecular modulation by calorie restriction. Ann NY Acad Sci 2001; 928: 327335.
  • 113
    Bruunsgaard H, Pedersen M, Pedersen BK. Aging and proinflammatory cytokines. Curr Opin Haematol 2001; 8: 131136.
  • 114
    Cohen HJ, Pieper CF, Harris T, Rao KM, Currie MS. The association of plasma IL-6 levels with functional disability in community-dwelling elderly. J Gerontol A Biol Sci Med Sci 1997; 52: M201208.
  • 115
    Ferrucci L, Harris TB, Guralnik JM, Tracy RP, Corti MC, Cohen HJ, et al. Serum IL-6 level and the development of disability in older persons. J Am Geriatr Soc 1999; 47: 639646.
  • 116
    Ershler WB, Keller ET. Age-associated increased interleukin-6 gene expression, late-life diseases, and frailty. Annu Rev Med 2000; 51: 245270.
  • 117
    Weaver JD, Huang MH, Albert M, Harris T, Rowe JW, Seeman TE. Interleukin-6 and risk of cognitive decline: MacArthur studies of successful aging. Neurology 2002; 59: 371378.
  • 118
    Bruunsgaard H, Skinhoj P, Pedersen AN, Schroll M, Pedersen BK. Ageing, tumour necrosis factor-alpha (TNFα) and atherosclerosis. Clin Exp Immunol 2000; 121: 255260.
  • 119
    Dinarello CA. Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process. Am J Clin Nutr 2006; 83: 447455S.
  • 120
    Merrill JE. Tumor necrosis factor alpha, interleukin 1 and related cytokines in brain development: normal and pathological. Dev Neurosci 1992; 14: 110.
  • 121
    Griffin WS, Mrak RE. Interleukin-1 in the genesis and progression of and risk for development of neuronal degeneration in Alzheimer's disease. J Leukoc Biol 2002; 72: 233238.
  • 122
    Chao CC, Hu S, Ehrlich L, Peterson PK. Interleukin-1 and tumor necrosis factor-alpha synergistically mediate neurotoxicity: involvement of nitric oxide and of N-methyl-D-aspartate receptors. Brain Behav Immun 1995; 9: 355365.
  • 123
    McCann SM, Licinio J, Wong ML, Yu WH, Karanth S, Rettorri V. The nitric oxide hypothesis of aging. Exp Gerontol 1998; 33: 813826.
  • 124
    Conti A, Miscusi M, Cardali S, Germano A, Suzuki H, Cuzzocrea S, et al. Nitric oxide in the injured spinal cord: synthases cross-talk, oxidative stress and inflammation. Brain Res Rev 2007; 54: 205218.
  • 125
    Ginaldi L, De Martinis M, Monti D, Franceschi C. Chronic antigenic load and apoptosis in immunosenescence. Trends Immunol 2005; 26: 7984.
  • 126
    Franceschi C, Valensin S, Fagnoni F, Barbi C, Bonafe M. Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load. Exp Gerontol 1999; 34: 911921.
  • 127
    Dyer WB, Ogg GS, Demoitie MA, Jin X, Geczy AF, Rowland-Jones SL, et al. 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 1999; 73: 436443.
  • 128
    Darby SC, Ewart DW, Giangrande PL, Spooner RJ, Rizza CR. Importance of age at infection with HIV-1 for survival and development of AIDS in UK haemophilia population. UK Haemophilia Centre Directors' Organisation. Lancet 1996; 347: 15731579.
  • 129
    Cohen Stuart J, Hamann D, Borleffs J, Roos M, Miedema F, Boucher C, et al. Reconstitution of naive T cells during antiretroviral treatment of HIV-infected adults is dependent on age. AIDS 2002; 16: 22632266.
  • 130
    Stoll M, Schmidt RE. Immune restoration inflammatory syndromes: apparently paradoxical clinical events after the initiation of HAART. Curr HIV/AIDS Rep 2004; 1: 122127.
  • 131
    Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science 1997; 277: 112116.
  • 132
    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 1998; 351: 16821686.
  • 133
    Lederman MM, Connick E, Landay A, Kuritzkes DR, Spritzler J, St Clair M, et al. 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 1998; 178: 7079.
  • 134
    Ogg GS, Jin X, Bonhoeffer S, Moss P, Nowak MA, Monard S, et al. Decay kinetics of human immunodeficiency virus-specific effector cytotoxic T lymphocytes after combination antiretroviral therapy. J Virol 1999; 73: 797800.
  • 135
    Kalams SA, Goulder PJ, Shea AK, Jones NG, Trocha AK, Ogg GS, et al. Levels of human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte effector and memory responses decline after suppression of viremia with highly active antiretroviral therapy. J Virol 1999; 73: 67216728.
  • 136
    Pitcher CJ, Quittner C, Peterson DM, Connors M, Koup RA, Maino VC, et al. HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression [see comments]. Nat Med 1999; 5: 518525.
  • 137
    Rizzardi GP, Harari A, Capiluppi B, Tambussi G, Ellefsen K, Ciuffreda D, et al. Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy. J Clin Invest 2002; 109: 681688.
  • 138
    Lederman MM, Smeaton L, Smith KY, Rodriguez B, Pu M, Wang H, et al. Cyclosporin A provides no sustained immunologic benefit to persons with chronic HIV-1 infection starting suppressive antiretroviral therapy: results of a randomized, controlled trial of the AIDS Clinical Trials Group A5138. J Infect Dis 2006; 194: 16771685.
  • 139
    Czeslick E, Struppert A, Simm A, Sablotzki A. E5564 (Eritoran) inhibits lipopolysaccharide-induced cytokine production in human blood monocytes. Inflamm Res 2006; 55: 511515.
  • 140
    Savov JD, Brass DM, Lawson BL, McElvania-Tekippe E, Walker JK, Schwartz DA. Toll-like receptor 4 antagonist (E5564) prevents the chronic airway response to inhaled lipopolysaccharide. Am J Physiol Lung Cell Mol Physiol 2005; 289: L329337.
  • 141
    Connolly NC, Riddler SA, Rinaldo CR. Proinflammatory cytokines in HIV disease—a review and rationale for new therapeutic approaches. AIDS Rev 2005; 7: 168180.
  • 142
    Messaoudi I, Warner J, Fischer M, Park B, Hill B, Mattison J, et al. Delay of T cell senescence by caloric restriction in aged long-lived nonhuman primates. Proc Natl Acad Sci USA 2006; 103: 1944819453.
  • 143
    Kovacs JA, Vogel S, Albert JM, Falloon J, Davey RT Jr, Walker RE, et al. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiency virus. N Engl J Med 1996; 335: 13501356.
  • 144
    Aspinall R, Andrew D. Thymic atrophy in the mouse is a soluble problem of the thymic environment. Vaccine 2000; 18: 16291637.
  • 145
    Andrew D, Aspinall R. Age-associated thymic atrophy is linked to a decline in IL-7 production. Exp Gerontol 2002; 37: 455463.
  • 146
    Kelley KW, Arkins S, Minshall C, Liu Q, Dantzer R. Growth hormone, growth factors and haematopoiesis. Horm Res 1996; 45: 3845.
  • 147
    Burgess W, Liu Q, Zhou J, Tang Q, Ozawa A, VanHoy R, et al. The immune–endocrine loop during aging: role of growth hormone and insulin-like growth factor-I. Neuroimmunomodulation 1999; 6: 5668.
  • 148
    Napolitano LA, Lo JC, Gotway MB, Mulligan K, Barbour JD, Schmidt D, et al. Increased thymic mass and circulating naive CD4 T cells in HIV-1-infected adults treated with growth hormone. AIDS 2002; 16: 11031111.
  • 149
    Schindler M, Munch J, Kutsch O, Li H, Santiago ML, Bibollet-Ruche F, et al. Nef-mediated suppression of T cell activation was lost in a lentiviral lineage that gave rise to HIV-1. Cell 2006; 125: 10551067.