All Title Author
Keywords Abstract

PLOS ONE  2014 

HIV Infection of Hepatocytes Results in a Modest Increase in Hepatitis C Virus Expression In Vitro

DOI: 10.1371/journal.pone.0083728

Full-Text   Cite this paper   Add to My Lib


Previous studies demonstrate that soluble HIV proteins impact both hepatocyte function and HCV replication in vitro. It has also been reported that HIV can productively infect hepatocytes. We therefore investigated the impact of HIV infection of hepatocytes on HCV expression. The Huh7.5JFH1 cell line that constitutively expresses infectious HCV was infected with the lab-adapted strains HIVNL4-3 or HIVYK-JRCSF. HCV expression was quantified via HCV core antigen ELISA, Western blot, and strand-specific real-time PCR for positive-sense and negative-sense HCV RNA. After HIVNL4-3 infection of Huh7.5JFH1 cells, positive-sense and negative-sense HCV RNA levels were elevated compared to HIV uninfected cells. Increased HCV RNA synthesis was also observed after infection of Huh7.5JFH1 cells with HIVYK-JRCSF. HIV-induced HCV core production was decreased in the presence of the anti-HIV drugs AZT, T20, and raltegravir, although these medications had a minimal effect on HCV expression in the absence of HIV. HCV core, NS3, and NS5A protein expression were increased after HIV infection of Huh7.5JFH1 cells. Chemically inactivated HIV had a minimal effect on HCV expression in Huh7.5JFH1 cells suggesting that ongoing viral replication was critical. These data demonstrate that HIV induces HCV RNA synthesis and protein production in vitro and complement previous in vivo reports that HCV RNA levels are elevated in individuals with HIV/HCV co-infection compared to those with HCV mono-infection. These findings suggest that HIV suppression may be a critical factor in controlling liver disease, particularly if the underlying liver disease is not treated.


[1]  Tedaldi E, Baker R, Moorman A, Alzola C, Furhrer J, et al. (2003) Influence of coinfection with hepatitis C virus on morbidity and mortality due to human immunodeficiency virus infection in the era of highly active antiretroviral therapy. Clinical Infectious Diseases 36: 363–367. doi: 10.1086/345953
[2]  Bica I, McGovern B, Dhar R, Stone D, McGowan K, et al. (2001) Increasing mortality due to end-stage liver disease in patients with human immunodeficiency virus infection. Clinical Infectious Diseases 32: 492–497. doi: 10.1086/318501
[3]  Kim AY, Chung R (2009) Coinfection with HIV-1 and HCV - a one-two punch. Gastroenterology 137: 795–814. doi: 10.1053/j.gastro.2009.06.040
[4]  Rotman Y, Liang T (2009) Coinfection with hepatitis C virus and human immunodeficiency virus: virological, immunological, and clinical outcomes. Journal of Virology 83: 7366–7374. doi: 10.1128/jvi.00191-09
[5]  Keaveny AP, Karasik M (1998) Hepatobiliary and pancreatic infections in AIDS: Part one. AIDS Patient Care and STDs 12: 347–357. doi: 10.1089/apc.1998.12.347
[6]  Kahn J, Walker B (1998) Acute human immunodeficiency virus type 1 infection. New England Journal of Medicine 339: 33–39. doi: 10.1056/nejm199807023390107
[7]  Bonacini M (1992) Hepatobiliary complications in patients with human immunodeficiency virus infection. American Journal of Medicine 92: 404–411. doi: 10.1016/0002-9343(92)90271-c
[8]  Ingiliz P, Valantin MA, Duvivier C, Medja F, Dominguez S, et al. (2009) Liver damage underlying unexplained transaminase elevation in human immunodeficiency virus-1 mono-infected patients on antiretroviral therapy. Hepatology 49: 436–442. doi: 10.1002/hep.22665
[9]  Sterling R, Wilson M, Sanyal A, Luketic V, Stravitz R, et al. (2004) Impact of highly active antiretroviral therapy on the spectrum of liver disease in HCV-HIV coinfection. Clinical Gastroenterology and Hepatology 2: 432–439. doi: 10.1016/s1542-3565(04)00129-6
[10]  Mata-Marin JA, Gaytan-Martinez JE, Grados-Chavarria BH, Fuentes-Allen JL, Arroyo-Anduiza CI, et al. (2009) Correlation between HIV viral and aminotransferases as liver damage markers in HIV infected naive patients: a concordance cross-sectional study. Virology Journal 6: 181. doi: 10.1186/1743-422x-6-181
[11]  Chen YJ, Tsai HC, Cheng MF, Lee SS, Chen Y (2010) Primary human immunodeficiency virus infection presenting as elevated aminotransferases. Journal of Microbiology, Immunology, and Infection 43: 175–179. doi: 10.1016/s1684-1182(10)60028-x
[12]  Blackard JT, Welge JA, Taylor LE, Mayer KE, Klein RS, et al. (2011) HIV mono-infection is associated with FIB-4 - a noninvasive index of liver fibrosis - in women. Clinical Infectious Diseases 52: 674–680. doi: 10.1093/cid/ciq199
[13]  Mendeni M, Focà E, Gotti D, Ladisa N, Angarano G, et al. (2011) Evaluation of liver fibrosis: concordance analysis between noninvasive scores (APRI and FIB-4) evolution and predictors in a cohort of HIV-infected patients without hepatitis C and B infection. Clinical Infectious Diseases 52: 1164–1173. doi: 10.1093/cid/cir071
[14]  Price JC, Seaberg EC, Badri S, Witt MD, D'Acunto K, et al. (2012) HIV monoinfection is associated with increased aspartate aminotransferase-to-platelet ratio index, a surrogate marker for hepatic fibrosis. Journal of Infectious Diseases 205: 1005–1013. doi: 10.1093/infdis/jir885
[15]  Towner WJ, Xu L, Leyden WA, Horberg MA, Chao CR, et al. (2012) The effect of HIV infection, immunodeficiency, and antiretroviral therapy on the risk of hepatic dysfunction. Journal of Acquired Immune Deficiency Syndromes 60: 321–327. doi: 10.1097/qai.0b013e31824e9ef2
[16]  Thomas DL, Rich JD, Schuman P, Smith DK, Astemborski JA, et al. (2001) Multicenter evaluation of hepatitis C RNA levels among female injection drug users. Journal of Infectious Diseases 183: 973–976. doi: 10.1086/319256
[17]  Blackard JT, Sherman K (2008) HCV/HIV co-infection: time to re-evaluate the role of HIV in the liver? Journal of Viral Hepatitis 15: 323–330. doi: 10.1111/j.1365-2893.2008.00970.x
[18]  Bansal M, Blackard J (2012) Effects of HIV on liver cell populations; Sherman K, editor. New York: Springer Science+Business Media
[19]  Cao YZ, Dieterich D, Thomas PA, Huang YX, Mirabile M, et al. (1992) Identification and quantitation of HIV-1 in the liver of patients with AIDS. AIDS 6: 65–70. doi: 10.1097/00002030-199201000-00008
[20]  Housset C, Lamas E, Brechot C (1990) Detection of HIV1 RNA and p24 antigen in HIV-1-infected human liver. Research in Virology 141: 153–159. doi: 10.1016/0923-2516(90)90017-d
[21]  Jiang TJ, Zhao M, Zhao JM, Zhou GD, Pan D, et al. (2005) Immunohistochemical evidence for HIV-1 infection in the liver of HIV-infected patients. Zhonghua Shi Yan He Lin Chuang Bing Du Xue Za Zhi 19: 152–154.
[22]  Hoda SA, White JE, Gerber M (1991) Immunohistochemical studies of human immunodeficiency virus-1 in liver tissues of patients with AIDS. Modern Pathology 4: 578–581.
[23]  Lang ZW, Dao WB, Zhang FJ, Shi XH, Ma ZC, et al. (2005) A pathological study on liver tissues of patients with HIV infection. Zhonghua Gan Zang Bing Za Zhi 13: 930–932.
[24]  Xiao P, Usami O, Suzuki Y, Ling H, Shimizu N, et al. (2008) Characterization of a CD4-independent clinical HIV-1 that can efficiently infect human hepatocytes through chemokine (C-X-C motif) receptor 4. AIDS 22: 1749–1757. doi: 10.1097/qad.0b013e328308937c
[25]  Fromentin R, Tardif MR, Tremblay M (2010) Human hepatoma cells transmit surface bound HIV-1 to CD4+ T cells through an ICAM-1/LFA-1-dependent mechanism. Virology 398: 168–175. doi: 10.1016/j.virol.2009.12.008
[26]  Iser DM, Warner N, Revill PA, Solomon A, Wightman F, et al. (2010) Coinfection of hepatic cell lines with human immunodeficiency virus and hepatitis B virus leads to an increase in intracellular hepatitis B surface antigen. Journal of Virology 84: 5860–5867. doi: 10.1128/jvi.02594-09
[27]  Kong L, Cardona Maya W, Moreno-Fernandez ME, Ma G SM, Sherman KE, et al. (2012) Low-level HIV infection of hepatocytes. Virology Journal 9: 157. doi: 10.1186/1743-422x-9-157
[28]  Cai Z, Zhang C, Chang KS, Jiang J, Ahn BC, et al. (2005) Robust production of infectious hepatitis C virus (HCV) from stably HCV cDNA-transfected human hepatoma cells. Journal of Virology 79: 13963–13973. doi: 10.1128/jvi.79.22.13963-13973.2005
[29]  Platt EJ, Wehrly K, Kuhmann SE, Chesebro B, Kabat D (1998) Effects of CCR5 and CD4 cell surface concentrations on infections by macrophage tropic isolates of human immunodeficiency virus type 1. Journal of Virology 72: 2855–2864.
[30]  Adachi A, Gendelman H, Koenig S, Folks T, Willey R, et al. (1986) Production of acquired immunodeficiency syndrome-associated retrovirus in human and nonhuman cells transfected with an infectious molecular clone. Journal of Virology 59: 284–291.
[31]  Haltiner M, Kempe T, Tjian R (1985) A novel strategy for constructing clustered point mutations. Nucleic Acids Research 13: 1015–1025. doi: 10.1093/nar/13.3.1015
[32]  Rossio JL, Esser MT, Suryanarayana K, Schneider DK, Bess JW Jr, et al. (1998) Inactivation of human immunodeficiency virus type 1 infectivity with preservation of conformational and functional integrity of virion surface proteins. Journal of Virology 72: 7992–8001.
[33]  Blackard JT, Smeaton L, Hiasa Y, Horiike N, Onji M, et al. (2005) Detection of hepatitis C virus (HCV) in serum and peripheral blood mononuclear cells of HCV-monoinfected and HIV/HCV-coinfected persons. Journal of Infectious Diseases 192: 258–265. doi: 10.1086/430949
[34]  Cao YZ, Friedman-Kein AE, Huang YX, Li XL, Mirabile M, et al. (1990) CD4-independent, productive human immunodeficiency virus type 1 infection of hepatoma cell lines in vitro. Journal of Virology 64: 2553–2559.
[35]  Jia Y, Wei L, Jiang D, Wang J, Cong X, et al. (2007) Antiviral action of interferon-alpha against hepatitis C virus replicon and its modulation by interferon-gamma and interleukin-8. Journal of Gastroenterology and Hepatology 22: 1278–1285. doi: 10.1111/j.1440-1746.2007.04957.x
[36]  Polyak SJ, Khabar KS, Rezeiq M, Gretch D (2001) Elevated levels of interleukin-8 in serum are associated with hepatitis C infection and resistance to interferon therapy. Journal of Virology 75: 6209–6211. doi: 10.1128/jvi.75.13.6209-6211.2001
[37]  Polyak SJ, Khabar KS, Paschal DM, Ezelle HJ, Duverlie G, et al. (2001) Hepatitis C virus nonstructural 5A protein induces interleukin-8, leading to partial inhibition of the interferon-induced antiviral response. Journal of Virology 75: 6095–6106. doi: 10.1128/jvi.75.13.6095-6106.2001
[38]  Balasubramanian A, Ganju R, Groopman J (2003) HCV and HIV envelope proteins collaboratively mediate IL-8 secretion through activation of p38 MAP kinase and SHP2 in hepatocytes. Journal of Biological Chemistry 278: 35755–35766. doi: 10.1074/jbc.m302889200
[39]  Lin W, Choe W, Hiasa Y, Kamegaya Y, Blackard J, et al. (2005) Hepatitis C virus expression suppresses interferon signaling by degrading STAT1. Gastroenterology 128: 1034–1041. doi: 10.1053/j.gastro.2005.02.006
[40]  Lin W, Kim SS, Yeung E, Kamegaya Y, Blackard JT, et al. (2006) Hepatitis C virus core protein blocks interferon signaling by interaction with the STAT1 SH2 domain. Journal of Virology 80: 9226–9235. doi: 10.1128/jvi.00459-06
[41]  Balasubramanian A, Ganju RK, Groopman JE (2006) Signal transducer and activator of transcription factor 1 mediates apoptosis induced by hepatitis C virus and HIV envelope proteins in hepatocytes. Journal of Infectious Diseases 194: 670–681. doi: 10.1086/505708
[42]  Munshi N, Balasubramanian A, Koziel M, Ganju R, Groopman J (2003) Hepatitis C and human immunodeficiency virus envelope proteins cooperatively induce hepatocytic apoptosis via an innocent bystander mechanism. Journal of Infectious Diseases 188: 1192–1204. doi: 10.1086/378643
[43]  Balasubramanian A, Koziel M, Groopman J, Ganju R (2005) Molecular mechanism of hepatic injury in coinfection with hepatitis C virus and HIV. Clinical Infectious Diseases 41: S32–S37. doi: 10.1086/429493
[44]  Babu CK, Suwansrinon K, Bren GD, Badley AD, Rizza S (2009) HIV induces TRAIL sensitivity in hepatocytes. PLoS One 4: e4623. doi: 10.1371/journal.pone.0004623
[45]  Lin W, Weinberg EM, Tai AW, Peng LF, Brockman MA, et al. (2008) HIV increases HCV replication in a TGF-beta1-dependent manner. Gastroenterology 164: 803–811. doi: 10.1053/j.gastro.2008.01.005
[46]  Zhang X, Daucher M, Baeza J, Kim CW, Russell R, et al. (2012) Human immunodeficiency virus enhances hepatitis C virus replication by differential regulation of IFN and TGF family genes. Journal of Medical Virology 84: 1344–1352. doi: 10.1002/jmv.23315
[47]  Yokozaki S, Takamatsu J, Nakano I, Katano Y, Toyoda H, et al. (2000) Immunological dynamics in hemophiliac patients infected with hepatitis C and human immunodeficiency virus: influence of antiretroviral therapy. Blood 96: 4293–4299.
[48]  Sherman KE, Andreatta C, O'Brien J, Gutierrez A, Harris R (1996) Hepatitis C in human immunodeficiency virus-coinfected patients: increased variability in the hypervariable envelope coding domain. Hepatology 23: 688–694. doi: 10.1002/hep.510230405
[49]  Beld M, Penning M, Lukashov V, McMorrow M, Roos M, et al. (1998) Evidence that both HIV and HIV-induced immunodeficiency enhance HCV replication among HCV seroconverters. Virology 244: 504–512. doi: 10.1006/viro.1998.9130


comments powered by Disqus