HIV infection is associated with higher levels of monocyte chemoattractant protein-1 and eotaxin among people with recent hepatitis C virus infection

François M J Lamoury, Behzad Hajarizadeh, Elizabeth Keoshkerian, Jordan J Feld, Janaki Amin, Suzy Teutsch, Gail V Matthews, Margaret Hellard, Gregory J Dore, Andrew R Lloyd, Tanya L Applegate, Jason Grebely, ATAHC Study Group, François M J Lamoury, Behzad Hajarizadeh, Elizabeth Keoshkerian, Jordan J Feld, Janaki Amin, Suzy Teutsch, Gail V Matthews, Margaret Hellard, Gregory J Dore, Andrew R Lloyd, Tanya L Applegate, Jason Grebely, ATAHC Study Group

Abstract

Background: Human immunodeficiency virus (HIV) infection leads to more rapid progression of hepatitis C virus (HCV)-related liver fibrosis, which could be linked to differences in the severity of liver inflammation among HIV/HCV co-infected individuals compared to HCV mono-infected individuals. This study assessed the association of HIV co-infection with pro-inflammatory and pro-fibrogenic cytokines and chemokines during recent HCV infection.

Methods: Participants from the ATAHC study, a prospective cohort of recent HCV infection, with detectable HCV RNA at the time of acute HCV detection were included. Concentrations of 27 plasma cytokines and chemokines were measured by multiplex immunoassays and compared between those with, and without, HIV co-infection.

Results: Out of 117 individuals with recent HCV infection included in analysis, 73 had HCV mono-infection and 44 had HIV/HCV co-infection. Individuals with HIV/HCV co-infection had significantly higher mean levels of eotaxin (1.79 vs. 1.62 log pg/mL; P < 0.001), monocyte chemotactic protein 1 (MCP-1; 2.10 vs. 1.98 log pg/mL; P < 0.001), and interferon-gamma inducible protein-10 (IP-10; 3.11 vs. 2.98 log pg/mL; P = 0.013). Linear regression analyses adjusting for age, alanine transaminase (ALT), HCV RNA levels, and assay run, higher eotaxin levels were independently associated with HIV/HCV co-infection (adjusted β: 0.12; 95%CI: 0.01, 0.24; P = 0.039). Higher MCP-1 levels were also independently associated with HIV/HCV co-infection in adjusted analysis (adjusted β: 0.11; 95%CI: 0.03, 0.18; P = 0.009).

Conclusions: During recent HCV, those with HIV/HCV co-infection had a stronger pro-fibrogenic mediator profile compared to those with HCV mono-infection. These findings may provide a potential explanation for accelerated liver fibrosis in HIV/HCV co-infection.

Trial registration: Australian Trial in Acute Hepatitis C (ATAHC) study was registered with ClinicalTrials.gov registry on September 11, 2005. NCT00192569 .

Keywords: Acute infection; Chemokines; Co-infection; Cytokines; HCV.

Figures

Fig. 1
Fig. 1
Distribution of MCP-1 (a), eotaxin (b) and IP-10 (c) plasma levels among ATAHC participants with detected HCV RNA at acute HCV detection, by HIV status. Horizontal lines represent the mean

References

    1. Di Martino V, Rufat P, Boyer N, Renard P, Degos F, Martinot-Peignoux M, et al. The influence of human immunodeficiency virus coinfection on chronic hepatitis C in injection drug users: a long-term retrospective cohort study. Hepatology. 2001;34(6):1193–1199. doi: 10.1053/jhep.2001.29201.
    1. Goedert JJ, Eyster ME, Lederman MM, Mandalaki T, De Moerloose P, White GC, 2nd, et al. End-stage liver disease in persons with hemophilia and transfusion-associated infections. Blood. 2002;100(5):1584–1589.
    1. Kirk GD, Mehta SH, Astemborski J, Galai N, Washington J, Higgins Y, et al. HIV, age, and the severity of hepatitis C virus-related liver disease: a cohort study. Ann Intern Med. 2013;158(9):658–666. doi: 10.7326/0003-4819-158-9-201305070-00604.
    1. Thein HH, 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(15):1979–1991. doi: 10.1097/QAD.0b013e32830e6d51.
    1. Macías J, Berenguer J, Japón MA, Girón JA, Rivero A, López-Cortés LF, et al. Fast fibrosis progression between repeated liver biopsies in patients coinfected with human immunodeficiency virus/hepatitis C virus. Hepatology. 2009;50(4):1056–1063. doi: 10.1002/hep.23136.
    1. Lin W, Weinberg EM, Chung RT. Pathogenesis of Accelerated Fibrosis in HIV/HCV Co-infection. J Infect Dis. 2013;207(suppl 1):S13–S18. doi: 10.1093/infdis/jis926.
    1. Benhamou Y, Bochet M, Di Martino V, Charlotte F, Azria F, Coutellier A, et al. Liver fibrosis progression in human immunodeficiency virus and hepatitis C virus coinfected patients. The Multivirc Group. Hepatology. 1999;30(4):1054–1058. doi: 10.1002/hep.510300409.
    1. Monto A, Kakar S, Dove LM, Bostrom A, Miller EL, Wright TL. Contributions to hepatic fibrosis in HIV-HCV coinfected and HCV monoinfected patients. Am J Gastroenterol. 2006;101(7):1509–1515. doi: 10.1111/j.1572-0241.2006.00613.x.
    1. Kushner LE, Wendelboe AM, Lazzeroni LC, Chary A, Winters MA, Osinusi A, et al. Immune biomarker differences and changes comparing HCV mono-infected, HIV/HCV co-infected, and HCV spontaneously cleared patients. PLoS One. 2013;8(4):e60387. doi: 10.1371/journal.pone.0060387.
    1. Zeremski M, Dimova RB, Makeyeva J, Sipley JD, Jacobson IM, Rennert H, et al. IL28B polymorphism, pretreatment CXCL10, and HCV RNA levels predict treatment response in racially diverse HIV/HCV coinfected and HCV monoinfected patients. J Acquir Immune Defic Syndr. 2013;63(1):9–16. doi: 10.1097/QAI.0b013e31828323c1.
    1. Kuntzen T, Tural C, Li B, Feldmann G, Kupfer B, Nischalke HD, et al. Intrahepatic mRNA expression in hepatitis C virus and HIV/hepatitis C virus co-infection: infiltrating cells, cytokines, and influence of HAART. AIDS. 2008;22(2):203–210. doi: 10.1097/QAD.0b013e3282f3553b.
    1. Grebely J, Feld JJ, Applegate T, Matthews GV, Hellard M, Sherker A, et al. Plasma interferon-gamma-inducible protein-10 (IP-10) levels during acute hepatitis C virus infection. Hepatology. 2013;57(6):2124–2134. doi: 10.1002/hep.26263.
    1. Dore GJ, Hellard M, Matthews GV, Grebely J, Haber PS, Petoumenos K, et al. Effective treatment of injecting drug users with recently acquired hepatitis C virus infection. Gastroenterology. 2010;138(1):123–135. doi: 10.1053/j.gastro.2009.09.019.
    1. O’Connor KA, Holguin A, Hansen MK, Maier SF, Watkins LR. A method for measuring multiple cytokines from small samples. Brain Behav Immun. 2004;18(3):274–280. doi: 10.1016/j.bbi.2003.09.009.
    1. Heijmans-Antonissen C, Wesseldijk F, Munnikes RJ, Huygen FJ, van der Meijden P, Hop WC, et al. Multiplex bead array assay for detection of 25 soluble cytokines in blister fluid of patients with complex regional pain syndrome type 1. Mediat Inflamm. 2006;2006(1):28398.
    1. Stacey AR, Norris PJ, Qin L, Haygreen EA, Taylor E, Heitman J, et al. Induction of a Striking Systemic Cytokine Cascade prior to Peak Viremia in Acute Human Immunodeficiency Virus Type 1 Infection, in Contrast to More Modest and Delayed Responses in Acute Hepatitis B and C Virus Infections. J Virol. 2009;83(8):3719–3733. doi: 10.1128/JVI.01844-08.
    1. Perneger TV. What’s wrong with Bonferroni adjustments. BMJ. 1998;316(7139):1236–8. .
    1. Rothman KJ. No Adjustments Are Needed for Multiple Comparisons. Epidemiology. 1990;1(1):43–46. doi: 10.1097/00001648-199001000-00010.
    1. Savitz DA, Olshan AF. Multiple Comparisons and Related Issues in the Interpretation of Epidemiologic Data. Am J Epidemiol. 1995;142(9):904–908.
    1. Thompson JR. Invited Commentary: Re: ‘Multiple Comparisons and Related Issues in the Interpretation of Epidemiologic Data”. Am J Epidemiol. 1998;147(9):801–806. doi: 10.1093/oxfordjournals.aje.a009530.
    1. Baeck C, Wehr A, Karlmark KR, Heymann F, Vucur M, Gassler N, et al. Pharmacological inhibition of the chemokine CCL2 (MCP-1) diminishes liver macrophage infiltration and steatohepatitis in chronic hepatic injury. Gut. 2012;61(3):416–426. doi: 10.1136/gutjnl-2011-300304.
    1. Fisher NC, Neil DA, Williams A, Adams DH. Serum concentrations and peripheral secretion of the beta chemokines monocyte chemoattractant protein 1 and macrophage inflammatory protein 1alpha in alcoholic liver disease. Gut. 1999;45(3):416–420. doi: 10.1136/gut.45.3.416.
    1. Weiss L, Si-Mohamed A, Giral P, Castiel P, Ledur A, Blondin C, et al. Plasma levels of monocyte chemoattractant protein-1 but not those of macrophage inhibitory protein-1alpha and RANTES correlate with virus load in human immunodeficiency virus infection. J Infect Dis. 1997;176(6):1621–1624. doi: 10.1086/517341.
    1. Tacke F. Functional role of intrahepatic monocyte subsets for the progression of liver inflammation and liver fibrosis in vivo. Fibrogenesis Tissue Repair. 2012;5(Suppl 1):S27. doi: 10.1186/1755-1536-5-S1-S27.
    1. Seki E, de Minicis S, Inokuchi S, Taura K, Miyai K, van Rooijen N, et al. CCR2 promotes hepatic fibrosis in mice. Hepatology. 2009;50(1):185–197. doi: 10.1002/hep.22952.
    1. Marra F, DeFranco R, Grappone C, Milani S, Pastacaldi S, Pinzani M, et al. Increased expression of monocyte chemotactic protein-1 during active hepatic fibrogenesis: correlation with monocyte infiltration. Am J Pathol. 1998;152(2):423–430.
    1. Zimmermann HW, Seidler S, Nattermann J, Gassler N, Hellerbrand C, Zernecke A, et al. Functional Contribution of Elevated Circulating and Hepatic Non-Classical CD14 < sup > +</sup > CD16 < sup > +</sup > Monocytes to Inflammation and Human Liver Fibrosis. PLoS ONE. 2010;5(6):e11049. doi: 10.1371/journal.pone.0011049.
    1. Marsillach J, Bertran N, Camps J, Ferré N, Riu F, Tous M, et al. The role of circulating monocyte chemoattractant protein-1 as a marker of hepatic inflammation in patients with chronic liver disease. Clin Biochem. 2005;38(12):1138–1140. doi: 10.1016/j.clinbiochem.2005.09.006.
    1. Mühlbauer M, Bosserhoff AK, Hartmann A, Thasler WE, Weiss TS, Herfarth H, 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(4):1085–1093. doi: 10.1016/S0016-5085(03)01213-7.
    1. Farci P, Wollenberg K, Diaz G, Engle RE, Lai ME, Klenerman P, et al. Profibrogenic chemokines and viral evolution predict rapid progression of hepatitis C to cirrhosis. Proc Natl Acad Sci. 2012;109(36):14562–14567. doi: 10.1073/pnas.1210592109.
    1. Tuyama AC, Hong F, Saiman Y, Wang C, Ozkok D, Mosoian A, 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(2):612–622. doi: 10.1002/hep.23679.
    1. Mitchell C, Couton D, Couty J-P, Anson M, Crain A-M, Bizet V, et al. Dual Role of CCR2 in the Constitution and the Resolution of Liver Fibrosis in Mice. Am J Pathol. 2009;174(5):1766–1775. doi: 10.2353/ajpath.2009.080632.
    1. Parker R, Walters M, Ertl L, Ebsworth K, Tan J, McMahon J, et al. Therapeutic use of a clinical stage CCR2 inhibitor, CCX872, in obesity-associated steatohepatitis. Lancet. 2014;383:S78. doi: 10.1016/S0140-6736(14)60341-X.
    1. Gathe J, Cade J, De Jesus E, et al. Week-24 primary analysis of cenicriviroc vs efavirenz, in combination with emtricitabine/tenofovir, in treatment-naive HIV-1+ adults with CCR5-tropic virus. Atlanta: The 20th Conference on Retroviruses and Opportunistic Infections; 2013.
    1. Feinberg J, Thompson M, Cade J, et al. Final week 48 analysis of cenicriviroc compared to efavirenz in combination with emtricitabine/tenofovir in treatment-naïve HIV-1-infected adults with CCR5-tropic virus. Brussels: The 14th EACS; 2013.
    1. Hong F, Chou H, Friedman SL. Significant anti-fibrotic activity of cenicriviroc, a dual CCR2/CCR5 antagonist in a rat model of thioacetamide-induced liver fibrosis and cirrhosis. Hepatology. 2013;58(6):1381A.
    1. Broide D, Sriramarao P. Eosinophil trafficking to sites of allergic inflammation. Immunol Rev. 2001;179(1):163–172. doi: 10.1034/j.1600-065X.2001.790116.x.
    1. Lampinen M, Carlson M, Håkansson LD, Venge P. Cytokine-regulated accumulation of eosinophils in inflammatory disease. Allergy. 2004;59(8):793–805. doi: 10.1111/j.1398-9995.2004.00469.x.
    1. Pham B-N, Bernuau J, Durand F, Sauvanet A, Degott C, Prin L, et al. Eotaxin expression and eosinophil infiltrate in the liver of patients with drug-induced liver disease. J Hepatol. 2001;34(4):537–547. doi: 10.1016/S0168-8278(00)00057-X.
    1. Yoneda S, Umemura T, Joshita S, Ichijo T, Matsumoto A, Yoshizawa K, et al. Serum chemokine levels are associated with the outcome of pegylated interferon and ribavirin therapy in patients with chronic hepatitis C. Hepatol Res. 2011;41(6):587–593. doi: 10.1111/j.1872-034X.2011.00802.x.
    1. Osburn WO, Levine JS, Chattergoon MA, Thomas DL, Cox AL. Anti-inflammatory cytokines, pro-fibrogenic chemokines and persistence of acute HCV infection. J Viral Hepat. 2013;20(6):404–413. doi: 10.1111/jvh.12052.
    1. Tacke F, Trautwein C, Yagmur E, Hellerbrand C, Wiest R, Brenner DA, et al. Up-regulated eotaxin plasma levels in chronic liver disease patients indicate hepatic inflammation, advanced fibrosis and adverse clinical course. J Gastroenterol Hepatol. 2007;22(8):1256–1264. doi: 10.1111/j.1440-1746.2006.04621.x.

Source: PubMed

Sponsorer och medarbetare

Medicinska tillstånd

Läkemedelsinterventioner

3
Prenumerera