The split personality of regulatory T cells in HIV infection

Blood

Volumn 121, Issue 1, 2013, Pages 29-37

  Chevalier, Mathieu F ^a,b   Weiss, Laurence ^a,b,c  

^a INSTITUT PASTEUR   (France)

^b UNIVERSITÉ PARIS DESCARTES   (France)

^c HÔPITAL EUROPÉEN GEORGES POMPIDOU   (France)

Author keywords

[No Author keywords available]

Indexed keywords

ANTI HUMAN IMMUNODEFICIENCY VIRUS AGENT; CD39 ANTIGEN; CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; HLA DR ANTIGEN; INTERLEUKIN 2 RECEPTOR ALPHA; RECOMBINANT INTERLEUKIN 2; T LYMPHOCYTE RECEPTOR; TRANSCRIPTION FACTOR FOXP3;

CD4+ CD25+ T LYMPHOCYTE; CD4+ T LYMPHOCYTE; CELL FUNCTION; DISEASE COURSE; HIGHLY ACTIVE ANTIRETROVIRAL THERAPY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME; IMMUNOMODULATION; INFECTION; NONHUMAN; PATHOGENESIS; PHENOTYPE; PRIORITY JOURNAL; REGULATORY T LYMPHOCYTE; REVIEW; T LYMPHOCYTE ACTIVATION; VIRUS INHIBITION; VIRUS LOAD; VIRUS REPLICATION;

EID: 84872093577     PISSN: 00064971     EISSN: 15280020     Source Type: Journal    
DOI: 10.1182/blood-2012-07-409755     Document Type: Review

References (101)

1. Bentwich Z, Kalinkovich A,Weisman Z, Grossman Z. Immune activation in the context of HIV infection. Clin Exp Immunol. 1998;111(1):1-2.
2. Hazenberg MD, Otto SA, van Benthem BH, et al. Persistent immune activation in HIV-1 infection is associated with progression to AIDS. AIDS. 2003;17(13):1881-1888.
3. 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(1):11-23.
4. Rosenberg ES, Billingsley JM, Caliendo AM, et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science. 1997;278(5342):1447-1450.
5. Soghoian DZ, Jessen H, Flanders M, et al. HIV-specific cytolytic CD4 T cell responses during acute HIV infection predict disease outcome. Sci Transl Med. 2012;4(123):123ra125.
6. 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.
7. Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science. 2003;299(5609):1057-1061.
8. Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol. 2003;4(4):330-336.
9. Seddiki N, Santner-Nanan B, Martinson J, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med. 2006;203(7):1693-1700.
10. Read S, Malmstrom V, Powrie F. Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med. 2000;192(2):295-302.
11. McHugh RS, Whitters MJ, Piccirillo CA, et al. CD4(+)CD25(+) immunoregulatory T cells: gene expression analysis reveals a functional role for the glucocorticoid-induced TNF receptor. Immunity. 2002;16(2):311-323.
12. Miyara M, Gorochov G, Ehrenstein M, Musset L, Sakaguchi S, Amoura Z. Human FoxP3+ regulatory T cells in systemic autoimmune diseases. Autoimmun Rev. 2011;10(12):744-755.
13. Belkaid Y, Tarbell K. Regulatory T cells in the control of host-microorganism interactions (*). Annu Rev Immunol. 2009;27:551-589.
14. Belkaid Y, Rouse BT. Natural regulatory T cells in infectious disease. Nat Immunol. 2005;6(4):353-360.
15. Schulze Zur Wiesch J, Thomssen A, Hartjen P, et al. Comprehensive analysis of frequency and phenotype of T regulatory cells in HIV infection: CD39 expression of FoxP3+ T regulatory cells correlates with progressive disease. J Virol. 2011;85(3):1287-1297.
16. Antons AK, Wang R, Oswald-Richter K, et al. Naive precursors of human regulatory T cells require FoxP3 for suppression and are susceptible to HIV infection. J Immunol. 2008;180(2):764-773.
17. Oswald-Richter K, Grill SM, Shariat N, et al. HIV infection of naturally occurring and genetically reprogrammed human regulatory T-cells. PLoS Biol. 2004;2(7):E198.
18. Zaunders JJ, Ip S, Munier ML, et al. Infection of CD127+ (interleukin-7 receptor+) CD4+ cells and overexpression of CTLA-4 are linked to loss of antigen-specific CD4 T cells during primary human immunodeficiency virus type 1 infection. J Virol. 2006;80(20):10162-10172.
19. Moreno-Fernandez ME, Zapata W, Blackard JT, Franchini G, Chougnet CA. Human regulatory T cells are targets for human immunodeficiency Virus (HIV) infection, and their susceptibility differs depending on the HIV type 1 strain. J Virol. 2009;83(24):12925-12933.
20. .Weiss L, Piketty C, Assoumou L, et al. Relationship between regulatory T cells and immune activation in human immunodeficiency virus-infected patients interrupting antiretroviral therapy. PLoS One. 2010;5(7):e11659.
21. Holmes D, Knudsen G, Mackey-Cushman S, Su L. FoxP3 enhances HIV-1 gene expression by modulating NFkappaB occupancy at the long terminal repeat in human T cells. J Biol Chem. 2007;282(22):15973-15980.
22. Grant C, Oh U, Fugo K, et al. Foxp3 represses retroviral transcription by targeting both NF-kappaB and CREB pathways. PLoS Pathog. 2006;2(4):e33.
23. Selliah N, Zhang M, White S, et al. FOXP3 inhibits HIV-1 infection of CD4 T-cells via inhibition of LTR transcriptional activity. Virology. 2008;381(2):161-167.
24. Bandera A, Ferrario G, Saresella M, et al. CD4+ T cell depletion, immune activation and increased production of regulatory T cells in the thymus of HIV-infected individuals. PLoS One. 2010;5(5):e10788.
25. Fritzsching B, Oberle N, Eberhardt N, et al. In contrast to effector T cells, CD4+CD25+FoxP3+ regulatory T cells are highly susceptible to CD95 ligand- but not to TCR-mediated cell death. J Immunol. 2005;175(1):32-36.
26. Nilsson J, Boasso A, Velilla PA, et al. HIV-1- driven regulatory T-cell accumulation in lymphoid tissues is associated with disease progression in HIV/AIDS. Blood. 2006;108(12):3808-3817.
27. Ji J, Cloyd MW. HIV-1 binding to CD4 on CD4+CD25+ regulatory T cells enhances their suppressive function and induces them to home to, and accumulate in, peripheral and mucosal lymphoid tissues: an additional mechanism of immunosuppression. Int Immunol. 2009;21(3):283-294.
28. Becker C, Taube C, Bopp T, et al. Protection from graft-versus-host disease by HIV-1 envelope protein gp120-mediated activation of human CD4+CD25+ regulatory T cells. Blood. 2009;114(6):1263-1269.
29. Hsieh SM, Chen MY, Pan SC, Hung CC, Chang SC. Aberrant induction of regulatory activity of CD4+CD25+ T cells by dendritic cells in HIV-infected persons with amebic liver abscess. J Acquir Immune Defic Syndr. 2007;44(1):6-13.
30. Carbonneil C, Donkova-Petrini V, Aouba A, Weiss L. Defective dendritic cell function in HIV-infected patients receiving effective highly active antiretroviral therapy: neutralization of IL-10 production and depletion of CD4+CD25+ T cells restore high levels of HIV-specific CD4+ T cell responses induced by dendritic cells generated in the presence of IFN-alpha. J Immunol. 2004;172(12):7832-7840.
31. Krathwohl MD, Schacker TW, Anderson JL. Abnormal presence of semimature dendritic cells that induce regulatory T cells in HIV-infected subjects. J Infect Dis. 2006;193(4):494-504.
32. Manches O, Munn D, Fallahi A, et al. HIV-activated human plasmacytoid DCs induce Tregs through an indoleamine 2,3-dioxygenase-dependent mechanism. J Clin Invest. 2008; 118(10):3431-3439.
33. .Wang R, Kozhaya L, Mercer F, Khaitan A, Fujii H, Unutmaz D. Expression of GARP selectively identifies activated human FOXP3+ regulatory T cells. Proc Natl Acad Sci U S A. 2009;106(32):13439-13444.
34. Simonetta F, Lecuroux C, Girault I, et al. Early and long-lasting alteration of effector CD45RAFoxp3high regulatory T-cell homeostasis during HIV infection. J Infect Dis. 2012;205(10):1510-1519.
35. Angin M, Kwon DS, Streeck H, et al. Preserved function of regulatory T cells in chronic HIV-1 infection despite decreased numbers in blood and tissue. J Infect Dis. 2012;205(10):1495-1500.
36. Bi X, Suzuki Y, Gatanaga H, Oka S. High frequency and proliferation of CD4+ FOXP3+ Treg in HIV-1-infected patients with low CD4 counts. Eur J Immunol. 2009;39(1):301-309.
37. Suchard MS, Mayne E, Green VA, et al. FOXP3 expression is upregulated in CD4T cells in progressive HIV-1 infection and is a marker of disease severity. PLoS One. 2010;5(7):e11762.
38. Weiss L, Donkova-Petrini V, Caccavelli L, Balbo M, Carbonneil C, Levy Y. Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients. Blood. 2004;104(10):3249-3256.
39. Tsunemi S, Iwasaki T, Imado T, et al. Relationship of CD4+CD25+ regulatory T cells to immune status in HIV-infected patients. AIDS. 2005;19(9):879-886.
40. Jiao Y, Fu J, Xing S, et al. The decrease of regulatory T cells correlates with excessive activation and apoptosis of CD8+ T cells in HIV-1-infected typical progressors, but not in long-term nonprogressors. Immunology. 2009;128(Suppl 1):e366-e375.
41. Epple HJ, Loddenkemper C, Kunkel D, et al. Mucosal but not peripheral FOXP3+ regulatory T cells are highly increased in untreated HIV infection and normalize after suppressive HAART. Blood. 2006;108(9):3072-3078.
42. Montes M, Sanchez C, Lewis DE, et al. Normalization of FoxP3(+) regulatory T cells in response to effective antiretroviral therapy. J Infect Dis. 2011;203(4):496-499.
43. Lim A, Tan D, Price P, et al. Proportions of circulating T cells with a regulatory cell phenotype increase with HIV-associated immune activation and remain high on antiretroviral therapy. AIDS. 2007;21(12):1525-1534.
44. Hunt PW, Landay AL, Sinclair E, et al. A low T regulatory cell response may contribute to both viral control and generalized immune activation in HIV controllers. PLoS One. 2011;6(1):e15924.
45. Nikolova M, Carriere M, Jenabian MA, et al. CD39/adenosine pathway is involved in AIDS progression. PLoS Pathog. 2011;7(7):e1002110.
46. Ndhlovu LC, Loo CP, Spotts G, Nixon DF, Hecht FM. FOXP3 expressing CD127lo CD4+ T cells inversely correlate with CD38+ CD8+ T cell activation levels in primary HIV-1 infection. J Leukocyte Biol. 2008;83(2):254-262.
47. Eggena MP, Barugahare B, Jones N, et al. Depletion of regulatory T cells in HIV infection is associated with immune activation. J Immunol. 2005; 174(7):4407-4414.
48. Kared H, Lelievre JD, Donkova-Petrini V, et al. HIV-specific regulatory T cells are associated with higher CD4 cell counts in primary infection. AIDS. 2008;22(18):2451-2460.
49. Foxall RB, Albuquerque AS, Soares RS, et al. Memory and naive-like regulatory CD4+ T cells expand during HIV-2 infection in direct association with CD4+ T-cell depletion irrespectively of viremia. AIDS. 2011;25(16):1961-1970.
50. Andersson J, Boasso A, Nilsson J, et al. The prevalence of regulatory T cells in lymphoid tissue is correlated with viral load in HIV-infected patients. J Immunol. 2005;174(6):3143-3147.
51. 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(4):381-385.
52. Chase AJ, Yang HC, Zhang H, Blankson JN, Siliciano RF. Preservation of FoxP3+ regulatory T cells in the peripheral blood of human immunodeficiency virus type 1-infected elite suppressors correlates with low CD4+ T-cell activation. J Virol. 2008;82(17):8307-8315.
53. Vieira PL, Christensen JR, Minaee S, et al. IL-10- secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells. J Immunol. 2004;172(10):5986-5993.
54. Xing S, Fu J, Zhang Z, et al. Increased turnover of FoxP3high regulatory T cells is associated with hyperactivation and disease progression of chronic HIV-1 infection. J Acquir Immune Defic Syndr. 2010;54(5):455-462.
55. Piconi S, Trabattoni D, Gori A, et al. Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy. AIDS. 2010;24(13):1991-2000.
56. Grabar S, Selinger-Leneman H, Abgrall S, Pialoux G, Weiss L, Costagliola D. Prevalence and comparative characteristics of long-term nonprogressors and HIV controller patients in the French Hospital Database on HIV. AIDS. 2009;23(9):1163-1169.
57. Shaw JM, Hunt PW, Critchfield JW, et al. Increased frequency of regulatory T cells accompanies increased immune activation in rectal mucosae of HIV-positive noncontrollers. J Virol. 2011;85(21):11422-11434.
58. Abrams D, Levy Y, Losso MH, et al. Interleukin-2 therapy in patients with HIV infection. N Engl J Med. 2009;361(16):1548-1559.
59. Weiss L, Letimier FA, Carriere M, et al. In vivo expansion of naive and activated CD4+CD25+FOXP3+ regulatory T cell populations in interleukin-2-treated HIV patients. Proc Natl Acad Sci U S A. 2010;107(23):10632-10637.
60. Levy Y, Sereti I, Tambussi G, et al. Effects of rhIL-7 on T cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo controlled, multicenter study. Clin Infect Dis. 2012;55(2):291-300.
61. Macatangay BJ, Szajnik ME, Whiteside TL, Riddler SA, Rinaldo CR. Regulatory T cell suppression of Gag-specific CD8 T cell polyfunctional response after therapeutic vaccination of HIV-1- infected patients on ART. PLoS One. 2010;5(3):e9852.
62. Kinter A, McNally J, Riggin L, Jackson R, Roby G, Fauci AS. Suppression of HIV-specific T cell activity by lymph node CD25+ regulatory T cells from HIV-infected individuals. Proc Natl Acad Sci U S A. 2007;104(9):3390-3395.
63. Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol. 2008;214(2):231-241.
64. Sehrawat S, Rouse BT. Tregs and infections: on the potential value of modifying their function. J Leukocyte Biol. 2011;90(6):1079-1087.
65. Prendergast A, Prado JG, Kang YH, et al. HIV-1 infection is characterized by profound depletion of CD161+ Th17 cells and gradual decline in regulatory T cells. AIDS. 2010;24(4):491-502.
66. Del Pozo-Balado Mdel M, Leal M, Mendez- Lagares G, Pacheco YM. CD4(+)CD25(+/hi)CD127(lo) phenotype does not accurately identify regulatory T cells in all populations of HIV-infected persons. J Infect Dis. 2010;201(3):331-335.
67. 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(2):183-191.
68. Hunt PW, Brenchley J, Sinclair E, et al. 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(1):126-133.
69. Petitjean G, Chevalier MF, Tibaoui F, et al. Level of double negative T cells, which produce TGFbeta and IL-10, predicts CD8 T-cell activation in primary HIV-1 infection. AIDS. 2012;26(2):139-148.
70. Brenchley JM, Price DA, Schacker TW, et al. Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006;12(12):1365-1371.
71. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annu Rev Immunol. 2009;27:485-517.
72. Dandekar S, George MD, Baumler AJ. Th17 cells, HIV and the gut mucosal barrier. Curr Opin HIV AIDS. 2010;5(2):173-178.
73. Bettelli E, Carrier Y, Gao W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells. Nature. 2006;441(7090):235-238.
74. Favre D, Mold J, Hunt PW, et al. Tryptophan catabolism by indoleamine 2,3-dioxygenase 1 alters the balance of TH17 to regulatory T cells in HIV disease. Sci Transl Med. 2010;2(32):32ra36.
75. Card CM, McLaren PJ, Wachihi C, Kimani J, Plummer FA, Fowke KR. Decreased immune activation in resistance to HIV-1 infection is associated with an elevated frequency of CD4(+)CD25(+)FOXP3(+) regulatory T cells. J Infect Dis. 2009;199(9):1318-1322.
76. Legrand FA, Nixon DF, Loo CP, et al. Strong HIV- 1-specific T cell responses in HIV-1-exposed uninfected infants and neonates revealed after regulatory T cell removal. PLoS One. 2006;1:e102.
77. Antonelli LR, Mahnke Y, Hodge JN, et al. Elevated frequencies of highly activated CD4+ T cells in HIV+ patients developing immune reconstitution inflammatory syndrome. Blood. 2010; 116(19):3818-3827.
78. Seddiki N, Sasson SC, Santner-Nanan B, et al. Proliferation of weakly suppressive regulatory CD4+ T cells is associated with over-active CD4+ T-cell responses in HIV-positive patients with mycobacterial immune restoration disease. Eur J Immunol. 2009;39(2):391-403.
79. Yamaguchi T, Wing JB, Sakaguchi S. Two modes of immune suppression by Foxp3(+) regulatory T cells under inflammatory or non-inflammatory conditions. Semin Immunol. 2011;23(6):424-430.
80. Angin M, King M, Altfeld M, Walker BD, Wucherpfennig KW, Addo MM. Identification of HIV-1-specific regulatory T-cells using HLA class II tetramers. AIDS. 2012;26(16):2112-2115.
81. Kinter AL, Hennessey M, Bell A, et al. CD25(+)CD4(+) regulatory T cells from the peripheral blood of asymptomatic HIV-infected individuals regulate CD4(+) and CD8(+) HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status. J Exp Med. 2004;200(3):331-343.
82. Kwon DS, Angin M, Hongo T, et al. CD4+ CD25+ regulatory T cells impair HIV-1-specific CD4 T cell responses by upregulating interleukin-10 production in monocytes. J Virol. 2012;86(12):6586-6594.
83. Aandahl EM, Michaelsson J, Moretto WJ, Hecht FM, Nixon DF. Human CD4+ CD25+ regulatory T cells control T-cell responses to human immunodeficiency virus and cytomegalovirus antigens. J Virol. 2004;78(5):2454-2459.
84. Angin M, Streeck H, Wen F, et al. Regulatory T cell frequencies do not correlate with breadth or magnitude of HIV-1-specific T cell responses. AIDS Res Hum Retroviruses. 2012;28(8):749-751.
85. Owen RE, Heitman JW, Hirschkorn DF, et al. HIV+ elite controllers have low HIV-specific T-cell activation yet maintain strong, polyfunctional T-cell responses. AIDS. 2010;24(8):1095-1105.
86. Hryniewicz A, Boasso A, Edghill-Smith Y, et al. CTLA-4 blockade decreases TGF-beta, IDO, and viral RNA expression in tissues of SIVmac251-infected macaques. Blood. 2006;108(12):3834-3842.
87. Cecchinato V, Tryniszewska E, Ma ZM, et al. Immune activation driven by CTLA-4 blockade augments viral replication at mucosal sites in simian immunodeficiency virus infection. J Immunol. 2008;180(8):5439-5447.
88. Corse E, Allison JP. Cutting edge: ctla-4 on effector T cells inhibits in trans. J Immunol. 2012;189(3):1123-1127.
89. Pandrea I, Gaufin T, Brenchley JM, et al. Cutting edge: experimentally induced immune activation in natural hosts of simian immunodeficiency virus induces significant increases in viral replication and CD4+ T cell depletion. J Immunol. 2008;181(10):6687-6691.
90. Thorborn G, Pomeroy L, Isohanni H, Perry M, Peters B, Vyakarnam A. Increased sensitivity of CD4+ T-effector cells to CD4+CD25+ Treg suppression compensates for reduced Treg number in asymptomatic HIV-1 infection. PLoS One. 2010;5(2):e9254.
91. Thorborn GS, Pomeroy L, Ishohanni H, Peters BS, Vyakarnam A. Elevated effector cell sensitivity to Treg-cell suppression that is not associated with reduced Th17-cell expression distinguishes HIV+ asymptomatic subjects from progressors. Eur J Immunol. 2012;42(1):138-146.
92. Sáez-Cirión A, Pancino G, Sinet M, Venet A, Lambotte O. HIV controllers: how do they tame the virus? Trends Immunol. 2007;28(12):532-540.
93. Elahi S, Dinges WL, Lejarcegui N, et al. Protective HIV-specific CD8+ T cells evade Treg cell suppression. Nat Med. 2011;17(8):989-995.
94. Wang F,Wan L, Zhang C, Zheng X, Li J, Chen ZK. Tim-3-Galectin-9 pathway involves the suppression induced by CD4+CD25+ regulatory T cells. Immunobiology. 2009;214(5):342-349.
95. Borsellino G, Kleinewietfeld M, Di Mitri D, et al. Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood. 2007;110(4):1225-1232.
96. Presicce P, Orsborn K, King E, Pratt J, Fichtenbaum CJ, Chougnet CA. Frequency of circulating regulatory T cells increases during chronic HIV infection and is largely controlled by highly active antiretroviral therapy. PLoS One. 2011;6(12):e28118.
97. Moreno-Fernandez ME, Rueda CM, Rusie LK, Chougnet CA. Regulatory T cells control HIV replication in activated T cells through a cAMP-dependent mechanism. Blood. 2011;117(20):5372-5380.
98. Gabrilovich DI, Nagaraj S. Myeloid-derived suppressor cells as regulators of the immune system. Nat Rev Immunol. 2009;9(3):162-174.
99. Vollbrecht T, Stirner R, Tufman A, et al. Chronic progressive HIV-1 infection is associated with elevated levels of myeloid-derived suppressor cells. AIDS. 2012;26(12):F31-F37.
100. Lim A, French MA, Price P. CD4+ and CD8+ T cells expressing FoxP3 in HIV-infected patients are phenotypically distinct and influenced by disease severity and antiretroviral therapy. J Acquir Immune Defic Syndr. 2009;51(3):248-257.
101. Deeks SG, Phillips AN. HIV infection, antiretroviral treatment, ageing, and non-AIDS related morbidity. BMJ. 2009;338:a3172.