Persistent immune activation in chronic HIV infection: Do any interventions work?

AIDS

Volumn 27, Issue 8, 2013, Pages 1199-1208

  Rajasuriar, Reena ^a,b   Khoury, Gabriela ^b,c   Kamarulzaman, Adeeba ^a   French, Martyn A ^d,e   Cameron, Paul U ^b,c,f   Lewin, Sharon R ^b,c,f  

^a UNIVERSITY OF MALAYA   (Malaysia)

^b MONASH UNIVERSITY   (Australia)

^c BURNET INSTITUTE   (Australia)

^d UNIVERSITY OF WESTERN AUSTRALIA   (Australia)

^e ROYAL PERTH HOSPITAL   (Australia)

^f ALFRED HOSPITAL   (Australia)

Author keywords

Chronic immune activation; Combination antiretroviral therapy; HIV; Non AIDS defining illness; T cell activation

Indexed keywords

ALPHA INTERFERON; ATORVASTATIN; CELECOXIB; CHLOROQUINE; HYDROXYCHLOROQUINE; HYDROXYMETHYLGLUTARYL COENZYME A REDUCTASE INHIBITOR; IMMUNOGLOBULIN G; LEFLUNOMIDE; LISINOPRIL; METHOTREXATE; PIRFENIDONE; PRAVASTATIN; PREBIOTIC AGENT; PROBIOTIC AGENT; PYRIDOSTIGMINE; RIBAVIRIN; RIFAXIMIN; SIFALIMUMAB; TERIFLUNOMIDE; TRACE ELEMENT;

COLOSTRUM; CYTOMEGALOVIRUS; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTED PATIENT; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; MIXED INFECTION; PRIORITY JOURNAL; REVIEW;

ANTI-RETROVIRAL AGENTS; CHRONIC DISEASE; CLINICAL TRIALS AS TOPIC; DRUG THERAPY, COMBINATION; HIV INFECTIONS; HIV SEROPOSITIVITY; HUMANS; IMMUNE SYSTEM; LYMPHOCYTE ACTIVATION; T-LYMPHOCYTES;

EID: 84879096060     PISSN: 02699370     EISSN: 14735571     Source Type: Journal    
DOI: 10.1097/QAD.0b013e32835ecb8b     Document Type: Review

References (113)

1. Lewden C, May T, Rosenthal E., Burty C, Bonnet F, Costagliola D., et al. Changes in causes of death among adults infected by HIV between 2000 and 2005: the 'Mortalite 2000 and 2005' surveys (ANRS EN19 and Mortavic). J Acquir Immune Defic Syndr 2008; 48:590-598.
2. Chege D, Sheth PM, Kain T, Kim C.J., Kovacs C., Loutfy M, et al Sigmoid Th17 populations, the HIV latent reservoir, and microbial translocation in men on long-term antiretroviral therapy. AIDS 2011; 25:741-749.
3. French MA, King MS, Tschampa J.M., da Silva BA, Landay AL Serum immune activation markers are persistently increased in patients with HIV infection after 6 years of antiretroviral therapy despite suppression of viral replication and reconsti-tution of CD4+ T cells. J Infect Dis 2009; 200:1212-1215.
4. Piconi S, Trabattoni D, Gori A., Parisotto S, Magni C, Meraviglia P., et al. Immune activation, apoptosis, and Treg activity are associated with persistently reduced CD4+ T-cell counts during antiretroviral therapy. AIDS 2010; 24:1991-2000.
5. Hunt PW, Cao HL, Muzoora C, Ssewanyana I., Bennett J, Emenyonu N, et al Impact of CD8+ T-cell activation on CD4+ T-cell recovery and mortality in HIV-infected Ugandans initiating antiretroviral therapy. AIDS 2011; 25:2123-2131.
6. Sandler NG, Wand H, Roque A., Law M, Nason MC, Nixon D.E., et al. Plasma levels of soluble CD14 independently predict mortality in HIV infection. J Infect Dis 2011; 203:780-790.
7. Tincati C, Bellistri GM, Casana M, Merlini E., Comi L, Bai F, et al CD8+ hyperactivation and senescence correlate with early carotid intima-media thickness in HIV+ patients with no cardiovascular disease. J Acquir Immune Defic Syndr 2009; 51:642-644.
8. Carsenti-Dellamonica H., Vassallo M, Pradier C., Durant J, Harvey-Langton A, Lebrun-Frenay C, et al. LPS may be a predictive factor even in mild forms of HIV-associated neu-rocognitive impairment: sub-analysis of the Neuradapt Study. 18th Conference on Retroviruses and Opportunistic Infections, Boston, 27 Feb to 2 Mar 2011:Paper# 404.
9. Lyons JL, Uno H, Ancuta P., Kamat A, Moore DJ, Singer E.J., et al. Plasma sCD14 is a biomarker associated with impaired neu-rocognitive test performance in attention and learning domains in HIV infection. J Acquir Immune Defic Syndr 2011; 57:371-379.
10. Gazzola L, Ballistri G, Bai F., Savoldi A, Bini T, Marchetti G., et al. Higher CD4+ and CD8+ T-cell activation are associated factors of impaired bone mineral density in HIV infected patients. In: 19th Conference on Retroviruses and Opportunistic Infections, Seattle, Washington; 2012.
11. Appay V, Sauce D. Immune activation and inflammation in HIV-1 infection: causes and consequences. J Pathol 2008; 214:231-241.
12. Deeks SG. HIV infection, inflammation, immunosenescence, and aging. Annu Rev Med 2011; 62:141-155.
13. Brenchley JM, Price DA, Schacker T.W., Asher TE, Silvestri G, Rao S, et al Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12:1365-1371.
14. Jiang W, Lederman MM, Hunt P, Sieg S.F., Haley K., Rodriguez B, et al 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.
15. Mavigner M, Delobel P, Cazabat M., Dubois M, L'Faqihi-Olive FE, Raymond S, et al. HIV-1 residual viremia correlates with persistent T-cell activation in poor immunological responders to combination antiretroviral therapy. PLoS One 2009; 4:e7658.
16. Ostrowski SR, Katzenstein TL, Pedersen B.K., Gerstoft J., Ullum H. Residual viraemia in HIV-1-infected patients with plasma viral load
17. Kovacs A, Al-Harthi L, Christensen S., Mack W, Cohen M, Landay A. CD8(+) T cell activation in women coinfected with human immunodeficiency virus type 1 and hepatitis C virus. J Infect Dis 2008; 197:1402-1407.
18. Pandrea I, Cornell E, Wilson C., Ribeiro RM, Ma D, Kristoff J, et al Coagulation biomarkers predict disease progression in SIV-infected nonhuman primates. Blood 2012; 120:1357-1366.
19. Jacquelin B, Mayau V, Targat B., Liovat AS, Kunkel D, Petitjean G, et al Nonpathogenic SIV infection of African green monkeys induces a strong but rapidly controlled type I IFN response. J Clin Invest 2009; 119:3544-3555.
20. Sedaghat AR, German J, Teslovich T.M., Cofrancesco J Jr, Jie CC, Talbot CC Jr, et al. Chronic CD4+ T-cell activation and depletion in human immunodeficiency virus type 1 infection: type I interferon-mediated disruption of T-cell dynamics. J Virol 2008; 82:1870-1883.
21. Rempel H, Sun B, Calosing C., Pillai SK, Pulliam L. Interferon-alpha drives monocyte gene expression in chronic unsup-pressed HIV-1 infection. AIDS 2010; 24:1415-1423.
22. Fernandez S, Tanaskovic S, Helbig K., Rajasuriar R, Kramski M, Murray J.M., et al. CD4+ T-cell deficiency in HIV patients responding to antiretroviral therapy is associated with increased expression of interferon-stimulated genes in CD4+ T cells. J Infect Dis 2011; 204:1927-1935.
23. Valdez H, Lederman MM Cytokines and cytokine therapies in HIV infection. AIDS Clin Rev 1997; 2:187-228.
24. Biancotto A, Grivel JC, Iglehart S.J., Vanpouille C., Lisco A, Sieg SF, et al Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1. Blood 2007; 109:4272-4279.
25. Herbeuval JP, Hardy AW, Boasso A, Anderson S.A., Dolan MJ, Dy M, et al 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 U S A 2005; 102:13974-13979.
26. Katsikis PD, Wunderlich ES, Smith C.A., Herzenberg LA, Herzenberg LA Fas antigen stimulation induces marked apoptosis of T lymphocytes in human immunodeficiency virus-infected individuals. J Exp Med 1995; 181:2029-2036.
27. Zeng M, Smith AJ, Wietgrefe S.W., Southern PJ, Schacker TW, Reilly CS, et al Cumulative mechanisms of lymphoid tissue fibrosis and T cell depletion in HIV-1 and SIV infections. J Clin Invest 2011; 121:998-1008.
28. Hunt PW, Landay AL, Sinclair E, Martinson J.A., Hatano H., Emu B, 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:e15924.
29. Eggena MP, Barugahare B, Jones N., Okello M, Mutalya S, Kityo C., et al. Depletion of regulatory T cells in HIV infection is associated with immune activation. J Immunol 2005; 174:4407-4414.
30. Cosgrove C, Ussher JE, Rauch A, Gartner K., Kurioka A, Huhn MH, et al Early and nonreversible decrease of CD161++/ MAIT cells in HIV infection. Blood 2012. [Epub ahead of print]
31. Leeansyah E, Ganesh A, Quigley M.F., Sonnerborg A., Andersson J, Hunt PW, et al Activation, exhaustion and persistent decline of the antimicrobial MR1-restricted MAIT cell population in chronic HIV-1 infection. Blood 2012. [Epub ahead of print]
32. Ganesan A, Crum-Cianflone N, Higgins J., Qin J, Rehm C, Metcalf J., et al. High dose atorvastatin decreases cellular markers of immune activation without affecting HIV-1 RNA levels: results of a double-blind randomized placebo controlled clinical trial. J Infect Dis 2011; 203:756-764.
33. De Wit S., Delforge M, Necsoi C.V., Clumeck N. Downregulation of CD38 activation markers by atorvastatin in HIV patients with undetectable viral load. AIDS 2011; 25:1332-1333.
34. Aslangul E, Fellahi S, Assoumou L.K., Bastard JP, Capeau J, Costagliola D. High-sensitivity C-reactive protein levels fall during statin therapy in HIV-infected patients receiving ritonavir-boosted protease inhibitors. AIDS 2011; 25:1128-1131.
35. Fichtenbaum CJ, Yeh TM, Evans S.R., Aberg JA Treatment with pravastatin and fenofibrate improves atherogenic lipid profiles but not inflammatory markers in ACTG 5087. J Clin Lipidol 2010; 4:279-287.
36. Manfredi R, Calza L, Chiodo F. Long-term statin use does not act on the temporal trend of CD4 cell count in patients on virologically effective HAART. AIDS 2006; 20:455-457.
37. Moore RD, Bartlett JG, Gallant JE Association between use of HMG CoA reductase inhibitors and mortality in HIV-infected patients. PLoS One 2011; 6:e21843.
38. Chao C, Xu L, Abrams D.I., Towner WJ, Horberg MA, Leyden WA, et al HMG-CoA reductase inhibitors (statins) use and risk of non-Hodgkin lymphoma in HIV-positive persons. AIDS 2011; 25:1771-1777.
39. Murray SM, Down CM, Boulware D.R., Stauffer WM, Cavert WP, Schacker TW, et al Reduction of immune activation with chloroquine therapy during chronic HIV infection. J Virol 2010; 84:12082-12086.
40. Paton NI, Goodall RL, Dunn D.T., Franzen S., Collaco-Moraes Y, Gazzard BG, et al Effects of hydroxychloroquine on immune activation and disease progression among HIV-infected patients not receiving antiretroviral therapy: a randomized controlled trial. JAMA 2012; 308:353-361.
41. Piconi S, Parisotto S, Rizzardini G., Passerini S, Terzi R, Argenteri B, et al. Hydroxychloroquine drastically reduces immune activation in HIV-infected, antiretroviral therapy-treated immunologic nonresponders. Blood 2011; 118:3263-3272.
42. Kvale D, Ormaasen V, Kran A.M., Johansson CC, Aukrust P, Aandahl EM, et al Immune modulatory effects of cycloox-ygenase type 2 inhibitors in HIV patients on combination antiretroviral treatment. AIDS 2006; 20:813-820.
43. Pettersen FO, Torheim EA, Dahm AEA, Aaberge IS, Lind A, Holm M., et al. An exploratory trial of cyclooxygenase type 2 inhibitor in HIV-1 infection: downregulated immune activation and improved T cell-dependent vaccine responses. J Virol 2011; 85:6557-6566.
44. Read SW, DeGrezia M, Ciccone E.J., DerSimonian R., Higgins J, Adelsberger JW, et al The effect of leflunomide on cycling and activation of T-cells in HIV-1-infected participants. PLoS One 2010; 5:e11937.
45. Floren CH, Chinenye S, Elfstrand L., Hagman C, Ihse I. Colo-Plus, a new product based on bovine colostrum, alleviates HIV-associated diarrhoea. Scand J Gastroenterol 2006; 41:682-686.
46. Anukam KC, Osazuwa EO, Osadolor H.B., Bruce AW, Reid G. Yogurt containing probiotic Lactobacillus rhamnosus GR-1 and L. J Clin Gastroen-terol 2008; 42:239-243.
47. Kaducu FO, Okia SA, Upenytho G, Elfstrand L., Floren CH Effect of bovine colostrum-based food supplement in the treatment of HIV-associated diarrhea in Northern Uganda: a randomized controlled trial. Indian J Gastroenterol 2011; 30:270-276.
48. Fawzi WW, Msamanga GI, Spiegelman D, Wei R., Kapiga S, Villamor E, et al A randomized trial of multivitamin supplements and HIV disease progression and mortality. N Engl J Med 2004; 351:23-32.
49. Kaiser JD, Campa AM, Ondercin J.P., Leoung GS, Pless RF, Baum MK Micronutrient supplementation increases CD4 count in HIV-infected individuals on highly active antiretro-viral therapy: a prospective, double-blinded, placebo-controlled trial. J Acquir Immune Defic Syndr 2006; 42:523-528.
50. Trois L, Cardoso EM, Miura E. Use of probiotics in HIV-infected children: a randomized double-blind controlled study. J Trop Pediatr 2008; 54:19-24.
51. Irvine SL, Hummelen R, Hekmat S, Looman CW, Habbema JD, Reid G. Probiotic yogurt consumption is associated with an increase of CD4 count among people living with HIV/AIDS. J Clin Gastroenterol 2010; 44:e201-e205.
52. Byakwaga H, Kelly M, Purcell D.F., French MA, Amin J, Lewin SR, et al Intensification of antiretroviral therapy with ralte-gravir or addition of hyperimmune bovine colostrum in HIV-infected patients with suboptimal CD4+ T-cell response: a randomized controlled trial. J Infect Dis 2011; 204:1532-1540.
53. Gandhi RT, Zheng L, Bosch RJ, Chan ES, Margolis DM, Read S, et al. The effect of raltegravir intensification on low-level residual viremia in HIV-infected patients on antiretroviral therapy: a randomized controlled trial. PLoS Med 2010; 7:e1000321.
54. Hatano H, Hayes TL, Dahl V, Sinclair E., Lee TH, Hoh R, et al A randomized, controlled trial of raltegravir intensification in antiretroviral-treated, HIV-infected patients with a sub-optimal CD4+ T cell response. J Infect Dis 2011; 203:960-968.
55. Yukl SA, Shergill AK, McQuaid K, Gianella S., Lampiris H, Hare CB, et al Effect of raltegravir-containing intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive adults on suppressive antiretroviral therapy. AIDS 2010; 24:2451-2460.
56. Dahl V, Lee E, Peterson J., Spudich SS, Leppla I, Sinclair E, et al Raltegravir treatment intensification does not alter cerebrosp-inal fluid HIV-1 infection or immunoactivation in subjects on suppressive therapy. J Infect Dis 2011; 204:1936-1945.
57. Chege D, Kovacs C, la Porte C, Ostrowski M, Raboud J., Su D, et al. Effect of raltegravir intensification on HIV proviral DNA in the blood and gut mucosa of men on long-term therapy: a randomized controlled trial. AIDS 2012; 26:167-174.
58. Yilmaz A, Verhofstede C, D'Avolio A, Watson V, Hagberg L., Fuchs D, et al. Treatment intensification has no effect on the HIV-1 central nervous system infection in patients on sup-pressive antiretroviral therapy. J Acquir Immune Defic Syndr 2010; 55:590-596.
59. Buzon MJ, Massanella M, Llibre J.M., Esteve A., Dahl V, Puertas MC, et al HIV-1 replication and immune dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat Med 2010; 16:460-465.
60. Vallejo A, Gutierrez C, Hernandez-Novoa B, Diaz L., Madrid N, Abad-Fernandez M, et al The effect of intensification with raltegravir on the HIV-1 reservoir of latently infected memory CD4 T cells in suppressed patients. AIDS 2012; 26:1885-1894.
61. Gutierrez C, Diaz L, Vallejo A., Hernandez-Novoa B, Abad M, Madrid N., et al. Intensification of antiretroviral therapy with a CCR5 antagonist in patients with chronic HIV-1 infection: effect on T cells latently infected. PLoS One 2011; 6:e27864.
62. Wilkin TJ, Lalama CM, McKinnon J, Gandhi R.T., Lin N., Landay A, et al A pilot trial of adding maraviroc to suppressive antiretroviral therapy for suboptimal CD4+ T-cell recovery despite sustained virologic suppression: ACTG A5256. J Infect Dis 2012; 206:534-542.
63. Cuzin L, Trabelsi S, Delobel P., Barbuat C, Reynes J, Allavena C., et al. Maraviroc intensification of stable antiviral therapy in HIV-1-infected patients with poor immune restoration: MAR-IMUNO-ANRS 145 study. J Acquir Immune Defic Syndr 2012; 61:557-564.
64. Hunt P, Shulman N, Hayes T.L., Dahl V., Funderburg N, Adeyemi O, et al Immunomodulatory effects of MVC intensification in HIV-infected individuals with incomplete CD4+ T cell recovery during suppressive ART. In: 18th Conference on Retroviruses and Opportunistic Infections, Boston, Massachusetts; 2011.
65. Hunt PW, Martin JN, Sinclair E, Epling L., Teague J, Jacobson MA, et al Valganciclovir reduces T cell activation in HIV-infected individuals with incomplete CD4+ T cell recovery on antiretroviral therapy. J Infect Dis 2011; 203:1474-1483.
66. Gonzalez VD, Falconer K, Blom K.G., Reichard O., Morn B, Laursen AL, et al High levels of chronic immune activation in the T-cell compartments of patients coinfected with hepatitis C virus and human immunodeficiency virus type 1 and on highly active antiretroviral therapy are reverted by alpha interferon and ribavirin treatment. J Virol 2009; 83:11407-11411.
67. Negredo E, Clotet B, Puig J., Perez-Alvarez N, Ruiz L, Romeu J., et al. The effect of atorvastatin treatment on HIV-1-infected patients interrupting antiretroviral therapy. AIDS 2006; 20:619-621.
68. Vermeulen JN, Prins JM, Bunnik E, Hack C.E., Jurriaans S., Miedema F, et al Intravenous immunoglobulin (IVIG) treatment for modulation of immune activation in human immunodeficiency virus type 1 infected therapy-naive individuals. AIDS Res Hum Retroviruses 2007; 23:1348-1353.
69. Mellberg T, Gonzalez VD, Lindkvist A, Eden A., Sonnerborg A, Sandberg JK, et al Rebound of residual plasma viremia after initial decrease following addition of intravenous immuno-globulin to effective antiretroviral treatment of HIV. AIDS Res Ther 2011; 8:21.
70. Ho EL, Spudich SS, Lee E, Fuchs D., Sinclair E, Price RW Minocycline fails to modulate cerebrospinal fluid HIV infection or immune activation in chronic untreated HIV-1 infection: results of a pilot study. AIDS Res Ther 2011; 8:17.
71. Lange JM, Gazzard B, Diaz R. Reduced CD4+ T cell decline and immune activation by NR100157: a specific multitar-geted nutritional intervention in HIV-1 positive adults not on antiretroviral therapy (BITE). In: 49th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, California; 2009.
72. Jiamton S, Pepin J, Suttent R., Filteau S, Mahakkanukrauh B, Hanshaoworakul W., et al. A randomized trial of the impact of multiple micronutrient supplementation on mortality among HIV-infected individuals living in Bangkok. AIDS 2003; 17:2461-2469.
73. Kelly P, Katubulushi M, Todd J., Banda R, Yambayamba V, Fwoloshi M., et al. Micronutrient supplementation has limited effects on intestinal infectious disease and mortality in a Zambian population of mixed HIV status: a cluster randomized trial. Am J Clin Nutr 2008; 88:1010-1017.
74. Hummelen R, Changalucha J, Butamanya N.L., Koyama TE, Cook A, Habbema JD, et al Effect of 25 weeks probiotic supplementation on immune function of HIV patients. Gut Microb 2011; 2:80-85.
75. Gori A, Rizzardini G, Van't Land B, Amor KB, van Schaik J, Torti C, et al. Specific prebiotics modulate gut microbiota and immune activation in HAART-naive HIV-infected adults: results of the 'COPA' pilot randomized trial. Mucosal Immunol 2011; 4:554-563.
76. Gandhi RT, Coombs RW, Chan E.S., Bosch RJ, Zheng L, Margolis DM, et al No effect of raltegravir intensification on viral replication markers in the blood of HIV-1-infected patients receiving antiretroviral therapy. J Acquir Immune Defic Syndr 2012; 59:229-235.
77. Eltawil KM, Laryea M, Peltekian K., Molinari M. Rifaximin vs. conventional oral therapy for hepatic encephalopathy: a meta-analysis. World J Gastroenterol 2012; 18:767-777.
78. Pandrea I, Haret-Richter G, Ma D., Ribeiro RM, Nusbaum R, Trichel A, et al Administration of rifaximin and sulfasalazine during acute SIV infection decreases microbial translocation and coagulation marker levels and significantly impacts viral replication. In: 19th Conference on Retrovirology and Opportunistic Infections, Seattle, Washington; 2012.
79. Valdes-Ferrer S.I., Crispin JC, Belaunzaran P.F., Cantu-Brito CG, Sierra-Madero J, Alcocer-Varela J. Acetylcholine-esterase inhibitor pyridostigmine decreases T cell overactivation in patients infected by HIV. AIDS Res Hum Retroviruses 2009; 25:749-755.
80. Navarro-Gonzalez J.F., Mora-Fernandez C, Muros de Fuentes M, Donate-Correa J, Cazana-Perez V, Garcia-Perez J. Effect of phosphate binders on serum inflammatory profile, soluble CD14, and endotoxin levels in hemodialysis patients. Clin J Am Soc Nephrol 2011; 6:2272-2279.
81. Rodriguez-Torres M., Rodriguez-Orengo JF, Rios-Bedoya CF, Fernandez-Carbia A, Salgado-Mercado R, Marxuach-Cuetara AM. Double-blind pilot study of mesalamine vs. placebo for treatment of chronic diarrhea and nonspecific colitis in im-munocompetent HIV patients. Dig Dis Sci 2006; 51:161-167.
82. Baker JV, Huppler Hullsiek K, Prosser R, Duprez D., Grimm R, Rhame F, et al. Angiotensin cenverting enzyme inhibitor (ACE-I) and/or HMG-CoA reductase inhibitor ('statin') treatment as adjunct therapy for persons with HIV infection: a pilot study. In: 19th Conference on Retroviruses and Opportunistic Infections, Seattle, Washington; 2012.
83. Chen K, Wei Y, Sharp G.C., Braley-Mullen H. Inhibition of TGFbeta1 by anti-TGFbeta1 antibody or lisinopril reduces thyroid fibrosis in granulomatous experimental autoimmune thyroiditis. J Immunol 2002; 169:6530-6538.
84. Yao Y, Richman L, Higgs B.W., Morehouse CA, de los Reyes M, Brohawn P, et al. Neutralization of interferon-alpha/beta-inducible genes and downstream effect in a phase I trial of an antiinterferon-alpha monoclonal antibody in systemic lupus erythematosus. Arthritis Rheum 2009; 60:1785-1796.
85. Merrill JT, Wallace DJ, Petri M, Kirou K.A., Yao Y., White WI, et al Safety profile and clinical activity of sifalimumab, a fully human antiinterferon alpha monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study. Ann Rheum Dis 2011; 70:1905-1913.
86. Yao Y, Higgs BW, Richman L, White B., Jallal B. Use of type I interferon-inducible mRNAs as pharmacodynamic markers and potential diagnostic markers in trials with sifalimumab, an anti-IFNalpha antibody, in systemic lupus erythematosus. Arthritis Res Ther 2010; 12 (Suppl 1):S6.
87. d'Ettorre G., Paiardini M, Ceccarelli G., Silvestri G, Vullo V. HIV-associated immune activation: from bench to bedside. AIDS Res Hum Retroviruses 2011; 27:355-364.
88. Beignon AS, McKenna K, Skoberne M., Manches O, DaSilva I, Kavanagh D.G., et al. Endocytosis of HIV-1 activates plasma-cytoid dendritic cells via Toll-like receptor-viral RNA interactions. J Clin Invest 2005; 115:3265-3275.
89. Schmidt B, Ashlock BM, Foster H, Fujimura S.H., Levy JA HIV-infected cells are major inducers of plasmacytoid dendritic cell interferon production, maturation, and migration. Virology 2005; 343:256-266.
90. Martinson JA, Montoya CJ, Usuga X, Ronquillo R., Landay AL, Desai SN Chloroquine modulates HIV-1-induced plasmacy-toid dendritic cell alpha interferon: implication for T-cell activation. Antimicrob Agents Chemother 2010; 54:871-881.
91. Aandahl EM, Aukrust P, Skalhegg B.S., Muller F., Froland SS, Hansson V, et al Protein kinase A type I antagonist restores immune responses of T cells from HIV-infected patients. FASEB J 1998; 12:855-862.
92. Torgersen KM, Vang T, Abrahamsen H., Yaqub S, Tasken K. Molecular mechanisms for protein kinase A-mediated modulation of immune function. Cell Signal 2002; 14:1-9.
93. Brudvik KW, Tasken K. Modulation of T cell immune functions by the prostaglandin E(2) - cAMP pathway in chronic inflammatory states. Br J Pharmacol 2012; 166:411-419.
94. Johansson CC, Bryn T, Aandahl E.M., Areklett MA, Aukrust P, Tasken K, et al Treatment with type-2 selective and nonse-lective cyclooxygenase inhibitors improves T-cell proliferation in HIV-infected patients on highly active antiretroviral therapy. AIDS 2004; 18:951-952.
95. Hossain MM, Margolis DM Inhibition of HIV replication by A77 1726, the active metabolite of leflunomide, in combination with pyrimidine nucleoside reverse transcriptase inhibitors. J Acquir Immune Defic Syndr 2001; 28:199-201.
96. Schlapfer E, Fischer M, Ott P., Speck RF Anti-HIV-1 activity of leflunomide: a comparison with mycophenolic acid and hy-droxyurea. AIDS 2003; 17:1613-1620.
97. Davis JP, Cain GA, Pitts W.J., Magolda RL, Copeland RA The immunosuppressive metabolite of leflunomide is a potent inhibitor of human dihydroorotate dehydrogenase. Biochemistry 1996; 35:1270-1273.
98. Cherwinski HM, Cohn RG, Cheung P, Webster D.J., Xu YZ, Caulfield JP, et al The immunosuppressant leflunomide inhibits lymphocyte proliferation by inhibiting pyrimidine biosynthesis. J Pharmacol Exp Ther 1995; 275:1043-1049.
99. Attili SV, Gulati AK, Singh V.P., Varma DV, Rai M, Sundar S. Diarrhea, CD4 counts and enteric infections in a hospital-based cohort of HIV-infected patients around Varanasi, India. BMC Infect Dis 2006; 6:39.
100. Lazzerini M, Ronfani L. Oral zinc for treating diarrhoea in children. Cochrane Database Syst Rev 2008:CD005436.
101. Plettenberg A, Stoehr A, Stellbrink H.J., Albrecht H., Meigel W. A preparation from bovine colostrum in the treatment of HIV-positive patients with chronic diarrhea. Clin Investig 1993; 71:42-45.
102. Ellis CL, Ma ZM, Mann S.K., Li CS, Wu J, Knight TH, et al Molecular characterization of stool microbiota in HIV-infected subjects by panbacterial and order-level 16S ribo-somal DNA (rDNA) quantification and correlations with immune activation. J Acquir Immune Defic Syndr 2011; 57:363-370.
103. Merlini E, Bai F, Bellistri G.M., Tincati C., d'Arminio Monforte A, Marchetti G. Evidence for polymicrobic flora translocating in peripheral blood of HIV-infected patients with poor immune response to antiretroviral therapy. PLoS One 2011; 6:e18580.
104. Bastard JP, Soulie C, Fellahi S., Haim-Boukobza S, Simon A, Katlama C., et al. Circulating interleukin-6 levels correlate with residual HIV viraemia and markers of immune dysfunction in treatment-controlled HIV-infected patients. Antivir Ther 2012; 17:915-919.
105. Steel A, Cox AE, Shamji M.H., John L., Nelson M, Henderson DC, et al HIV-1 viral replication below 50copies/ml in patients on antiretroviral therapy is not associated with CD8R T-cell activation. Antivir Ther 2007; 12:971-975.
106. Hatano H, Scherzer R, Wu Y., Harvill K, Maka K, Hoh R., et al. A randomized controlled trial assessing the effects of raltegravir intensification on endothelial function in treated HIV infection. J Acquir Immune Defic Syndr 2012; 61:317-325.
107. Westrop SJ, Moyle G, Jackson A., Nelson M, Mandalia S, Imami N. CCR5 antagonism impacts vaccination response and immune profile in HIV-1 infection. Mol Med 2012; 18:1240-1248.
108. Canestri A, Krivine A, Assoumou L., Le Corre M, Rozenberg F, Marcelin A.G., et al. Maraviroc does not affect humoral response to the pandemic influenza A-H1N1v 2009 adjuvanted vaccine in HIV-1-infected patients. AIDS 2010; 24:2887-2889.
109. Markowitz M, Evering T, Figueroa K., Rodriguez M, La Mar M, Garmon D, et al Very early initiation of combination anti-retroviral therapy results in normal levels of markers of immune activation. In: XIX International AIDS Conference, Washington DC, USA; 2012.
110. Hsue PY, Hunt PW, Sinclair E, Bredt B., Franklin A, Killian M, et al Increased carotid intima-media thickness in HIV patients is associated with increased cytomegalovirus-specific T-cell responses. AIDS 2006; 20:2275-2283.
111. Parrinello CM, Sinclair E, Landay A.L., Lurain N., Sharrett AR, Gange SJ, et al Cytomegalovirus immunoglobulin G antibody is associated with subclinical carotid artery disease among HIV-infected women. J Infect Dis 2012; 205:1788-1796.
112. Appay V, Fastenackels S, Katlama C., Ait-Mohand H, Schneider L, Guihot A., et al. Old age and anticytomegalovirus immunity are associated with altered T-cell reconstitution in HIV-1-infected patients. AIDS 2011; 25:1813-1822.
113. Guzman-Fulgencio M., Berenguer J, de Castro IF, Micheloud D, Lopez JC, Cosin J, et al Sustained virological response to interferon-alpha plus ribavirin decreases inflammation and endothelial dysfunction markers in HIV/HCV co-infected patients. J Antimicrob Chemother 2011; 66:645-649.