CYTOKINE RESPONSE ASSOCIATED WITH HEPATITIS C VIRUS CLEARANCE IN HIV COINFECTED PATIENTS INITIATING PEG INTERFERON-? BASED THERAPY.
Main Article Content
hepatitis C virus, HIV, cytokines
Background: Treatment against hepatitis C virus (HCV) infection based on peginterferon-a (pegIFNa) and ribavirin induces important changes on cytokine release and T cell activation.
Objective: Immune response to pegIFNa-ribavirin therapy was explored in patients coinfected by HCV and HIV.
Methods: Concentrations of 25 cytokines and CD8+ T cell activation were monitored in HCV/HIV coinfected patients classified as sustained virological responders (SVR, n=19) and non-responders (NR, n=11).
Results: High pretreatment concentrations of IP-10 (CXCL-10) and MCP-1 (CCL-2) were associated with poor anti-HCV response. PegIFNa-ribavirin therapy increased CD8+ T cell activation and induced significant changes in levels of eleven cytokines related to both Th1 and Th2 responses in SVR (IL-1b, IL-1RA, IL-4, IL-5, IL-6, IL-7, IL-12p40/70, IL-13, IP-10, eotaxin, MCP-1) but only six cytokines in NR (IL-1b, IL-2, IL-5, IL-12p40/70, IL-13, eotaxin). Highest rise in MIP-1b and MCP-1 levels was observed four weeks after anti-HCV treatment initiation in SVR compared to NR (p=0.002 and p=0.03, respectively), whereas a decrease of IL-8 concentration was associated with treatment failure (p= 0.052).
Conclusions: Higher and broader cytokine responses to pegIFNa-ribavirin therapy were observed in SVR patients compared to NR. Changes in IL-8, MIP-1b and MCP-1 serum concentrations may be associated with efficacy of pegIFNa- and ribavirin-based therapies in patients coinfected by HCV and HIV.
2. Larsen C, Chaix ML, Le Strat Y, et al. Gaining greater insight into HCV emergence in HIV-infected men who have sex with men: the HEPAIG Study. PLoS One 2011; 6:e29322.
3. Luz PM, Bruyand M, Ribeiro S, et al. AIDS and non-AIDS severe morbidity associated with hospitalizations among HIV-infected patients in two regions with universal access to care and antiretroviral therapy, France and Brazil, 2000-2008: hospital-based cohort studies. BMC Infect Dis 2014; 21:278.
4. Ingle SM, May MT, Gill MJ, et al. Antiretroviral Therapy Cohort Collaboration. Impact of risk factors for specific causes of death in the first and subsequent years of antiretroviral therapy among HIV-infected patients. Clin Infect Dis 2014; 59:287-297.
5. Thein HH1, Yi Q, Dore GJ, Krahn MD. Natural history of hepatitis C virus infection in HIV-infected individuals and the impact of HIV in the era of highly active antiretroviral therapy: a meta-analysis. AIDS 2008; 22:1979-1991.
6. Danta M, Semmo N, Fabris P, et al. Impact of HIV on host-virus interactions during early hepatitis C virus infection. J Infect Dis 2008; 197:1558–1566.
7. Loko MA, Bani-Sadr F, Winnock M, et al. Impact of HAART exposure and associated lipodystrophy on advanced liver fibrosis in HIV/HCV-coinfected patients. J Viral Hepat 2011; 18:307-314.
8. D’Arminio Monforte A, Cozzi-Lepri A, Castagna A, et al. Risk of developing specific AIDS-defining illnesses in patients coinfected with HIV and hepatitis C virus with or without liver cirrhosis. Clin Infect Dis 2009; 49:612-622.
9. Davies A, Singh KP, Shubber Z, et al. Treatment outcomes of treatment-naïve Hepatitis C patients co-infected with HIV: a systematic review and meta-analysis of observational cohorts. PLoS One 2013; 8:e55373.
10. Ford N, Kirby C, Singh K, et al. Chronic hepatitis C treatment outcomes in low- and middle-income countries: a systematic review and meta-analysis. Bulletin of the World Health Organization 2012; 90:540–550.
11. European Association for Study of Liver. EASL Clinical Practice Guidelines: management of hepatitis C virus infection. J Hepatol 2014; 60:392-420.
12. Cacciarelli TV, Martinez OM, Gish RG, et al. Immunoregulatory cytokines in chronic hepatitis C virus infection: pre- and posttreatment with interferon alfa. Hepatology 1996; 24: 6-9.
13. Heim MH. Interferons and hepatitis C virus. Swiss Med Wkly 2012; 142: w13586.
14. Tokumoto Y, Hiasa Y, Uesugi K, et al. Ribavirin regulates hepatitis C virus replication through enhancing interferon-stimulated genes and interleukin 8. J Infect Dis 2012; 205: 1121-1130.
15. Rigopoulou EI, Abbott WG, Williams R, Naoumov NV. Direct evidence for immunomodulatory properties of ribavirin on T-cell reactivity to hepatitis C virus. Antiviral Res 2007; 75:36-42.
16. Brenndörfer ED, Brass A, Karthe J, et al. Cleavage of the T cell protein tyrosine phosphatase by the hepatitis C virus nonstructural 3/4A protease induces a Th1 to Th2 shift reversible by ribavirin therapy. J Immunol 2014; 192: 1671-1680.
17. Falconer K, Askarieh G, Weis N, et al. IP-10 predicts the first phase decline of HCV RNA and overall viral response to therapy in patients co-infected with chronic hepatitis C virus infection and HIV. Scand J Infect Dis 2010; 42:896-901.
18. Zeremski M, Markatou M, Brown QB, et al. Interferon gamma-inducible protein 10: a predictive marker of successful treatment response in hepatitis C virus/HIV-coinfected patients. J Acquir Immune Defic Syndr 2007; 45:262-268.
19. Thomson EC, Fleming VM, Main J, et al. Predicting spontaneous clearance of acute hepatitis C virus in a large cohort of HIV-1-infected men. Gut 2011; 60: 837-845.
20. Brockman MA, Kwon DS, Tighe DP, et al. IL-10 is up-regulated in multiple cell types during viremic HIV infection and reversibly inhibits virus-specific T cells. Blood 2009; 114:346-356.
21. Porichis F, Hart MG, Zupkosky J, et al. Differential impact of PD-1 and/or interleukin-10 blockade on HIV-1-specific CD4 T cell and antigen-presenting cell functions. J Virol 2014; 88:2508-2518.
22. Grabmeier-Pfistershammer K, Steinberger P, Rieger A, et al. Identification of PD-1 as a unique marker for failing immune reconstitution in HIV-1-infected patients on treatment. J Acquir Immune Defic Syndr 2011; 56:118-124.
23. Spitsin S, Tustin NB, Riedel E, et al. Programmed death 1 receptor changes ex vivo in HIV-infected adults following initiation of highly active antiretroviral therapy. Clin Vaccine Immunol 2012; 19: 752-756.
24. Cockerham LR1, Jain V, Sinclair E, et al. Programmed death-1 expression on CD4? and CD8? T cells in treated and untreated HIV disease. AIDS 2014; 28:1749-1758.
25. Rubbo PA, Van de Perre P, Tuaillon E. The long way toward understanding host and viral determinants of therapeutic success in HCV infection. Hepatol Int 2012; 6:436–440.
26. Tuaillon E, Al Tabaa Y, Baillat V, et al. Close association of CD8+/CD38 bright with HIV-1 replication and complex relationship with CD4+ T-cell count. Cytometry B Clin Cytom 2009; 76: 249-260.
27. Djoba Siawaya JF, Roberts T, Babb C, et al. An evaluation of commercial fluorescent bead-based luminex cytokine assays. PloS ONE 2008; 3: e2535.
28. Dupuy AM, Kuster N, Lizard G, et al. Performance evaluation of human cytokines profiles obtained by various multiplexed-based technologies underlines a need for standardization. Clin Chem Lab Med 2013; 51: 1385-1393.
29. Askarieh G, Alsio A, Pugnale P, et al. Systemic and intrahepatic interferon-gamma-inducible protein 10kDa predicts the first-phase decline in hepatitis C virus RNA and overall viral response to therapy in chronic hepatitis C. Hepathology 2010; 51:1523-1530.
30. Sarasin-Filipowicz M, Oakeley EJ, et al. Interferon signaling and treatment outcome in chronic hepatitis C. Proc Natl Acad Sci U S A 2008; 105:7034-7039.
31. Feld JJ, Nanda S, Huang Y, et al. Hepatic gene expression during treatment with peginterferon and ribavirin: identifying molecular pathways for treatment response. Hepathology 2007; 46: 1548-1563.
32. Dill MT, Duong FH, Vogt JE, et al. Interferon-induced gene expression is a stronger predictor of treatment response than IL28B genotype in patients with hepatitis C. Gastroenterology 2011; 140: 1021-1031.
33. Chen L, Borozan I, Feld J, et al. Hepatic gene expression discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Gastroenterology 2005; 128:1437-1444.
34. Micheloud D, Salcedo M, Banares R, et al. Serum levels of fibrosis biomarkers measured early after liver transplantation are associated with severe hepatitis C virus recurrence. Transpl Infect Dis 2009; 11:183-188.
35. Mühlbauer M, Bosserhoff AK, Hartmann A, et al. A novel MCP-1 gene polymorphism is associated with hepatic MCP-1 expression and severity of HCV-related liver disease. Gastroenterology 2003; 125: 1085-1093.
36. El-Bassiouni NE, Mahmoud OM, El Ahwani EG, Ibrahim RA, El Bassiouny AE. Monocyte adhesion molecules expression in patients with chronic hepatitis C liver disease. Mediterr J Hematol Infect Dis. 2013; 5(1): e2013054.
37. Gu B, Ye B, Mao WL, Ye JL. Monocyte chemotactic protein-1 as possible prognostic markers of the efficacy of antiviral treatment in chronic hepatitis C. Hepatogastroenterology 2014; 61: 55-58.
38. Heydtmann M, Adams DH. Chemokines in the immunopathogenesis of hepatitis C infection. Hepatology 2009; 49:676-688.
39. Tuyama AC, Hong F, Saiman Y, et al. Human immunodeficiency virus (HIV)-1 infects human hepatic stellate cells and promotes collagen I and monocyte chemoattractant protein-1 expression: implications for the pathogenesis of HIV/hepatitis C virus-induced liver fibrosis. Hepatology 2010; 52:612-22.
40. Hong F, Bansal MB. HIV gp120(X4) promotes hepatic stellate cell activation, fibrogenesis, and proliferation: a potential mechanism for rapid fibrosis progression in HIV/HCV coinfected patients. Hepathology 2009; 51:676-688.
41. Weiss JM, Nath A, Major EO, Berman JW. HIV-1 Tat induces monocyte chemoattractant protein-1-mediated monocyte transmigration across a model of the human blood-brain barrier and up-regulates CCR5 expression on human monocytes. J Immunol 1999; 163:2953-2959.
42. Kim BO, Liu Y, Zhou BY, He JJ. Induction of C chemokine XCL1 (lymphotactin/single C motif-1 alpha/activation-induced, T cell-derived and chemokine-related cytokine) expression by HIV-1 Tat protein. J Immunol 2004; 172:1888-1895.
43. Gu L, Tseng S, Horner RM, et al. Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1. Nature 2000; 404:407–411.
44. Ansari AW, Heiken H, Meyer-Olson D, Schmidt RE. CCL2: a potential prognostic marker and target of anti-inflammatory strategy in HIV/AIDS pathogenesis. Eur J Immunol 2011; 41:3412-3418.
45. Zhang Y, Guo D, Zhao Y, et al. The effect of cytokine profiles on the viral response to re-treatment in antiviral-experienced patients with chronic hepatitis C virus infection. Antiviral Res 2011; 92: 247-254.
46. Florholmen J, Kristiansen MG, Steigen SE, et al. A rapid chemokine response of macrophage inflammatory protein (MIP)-1?, MIP-1? and the regulated on activation, normal T expressed and secreted chemokine is associated with a sustained virological response in the treatment of chronic hepatitis C. Clin Microbiol Infect 2011; 17: 204-209.
47. Shimoda K, Begum NA, Shibuta K, et al. Interleukin-8 and hIRH (SDF1-alpha/PBSF) mRNA expression and histological activity index in patients with chronic hepatitis C. Hepatology 1998; 28:108-115
48. Mahmood S, Sho M, Yasuhara Y, et al. Clinical significance of intrahepatic interleukin-8 in chronic hepatitis C patients. Hepatol Res 2002; 24:413-419.
49. Asselah T, Bièche I, Laurendeau I, et al. Liver gene expression signature of mild fibrosis in patients with chronic hepatitis C. Gastroenterology 2005; 129:2064-2075.
50. Polyak SJ, Khabar KS, Paschal DM, et al. Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. J Virol 2001; 75:6095-6106.
51. Akbar H, Idrees M, Butt S, et al. High baseline interleukine-8 level is an independent risk factor for the achievement of sustained virological response in chronic HCV patients. Infect. Genet Evol 2011; 11:1301–1305.