Gastroenterology

Gastroenterology

Volume 135, Issue 1, July 2008, Pages 226-233
Gastroenterology

Basic—Liver, Pancreas, and Biliary Tract
Human Immunodeficiency Virus-Related Microbial Translocation and Progression of Hepatitis C

https://doi.org/10.1053/j.gastro.2008.03.022Get rights and content

Background & Aims: Human immunodeficiency virus (HIV)-1 infection has been associated with enhanced microbial translocation, and microbial translocation is a mechanism through which alcohol and some enteric conditions cause liver disease. We hypothesized that HIV promotes liver disease by enhancing microbial translocation. Methods: We studied human cohorts in which hepatitis C virus (HCV) and HIV outcomes were carefully characterized. Results: HIV-related CD4+ lymphocyte depletion was strongly associated with microbial translocation as indicated by elevated levels of circulating lipopolysaccharide (LPS), LPS-binding protein, soluble CD14, and fucose-binding lectin (AAL) reactive to immunoglobulin G specific for the α-galactose epitope and suppressed levels of endotoxin core antibodies (EndoCAb IgM) in HIV-infected subjects compared with the same persons before they had HIV infection and compared with HIV-uninfected subjects. The same measures of microbial translocation were strongly associated with HCV-related liver disease progression (cirrhosis), eg, LPS, odds ratio, 19.0 (P = .002); AAL, odds ratio, 27.8 (P < .0001); in addition, levels of LPS were elevated prior to recognition of cirrhosis. Conclusions: Microbial translocation may be a fundamental mechanism through which HIV accelerates progression of chronic liver disease.

Section snippets

Study Population

For this investigation, subjects were chosen from 3 distinct ongoing cohorts in which liver disease, HIV infection, and HCV infection were carefully evaluated and serum specimens were archived at −80°C. All subjects provided informed consent for testing through a protocol approved by the committees on human research of the Johns Hopkins School of Medicine or Bloomberg School of Public Health.

Prevalent Liver Disease Group and Microbial Translocation Markers

A total of 88 HCV-infected persons had either cirrhosis or end-stage liver disease (17 cases) or clear evidence of minimal liver disease (71 controls). The mean age of subjects was 43.4 years at time of testing: 79.6% were male, 96.6% were African American, mean HCV RNA level was 12,928,360 IU/mL (7.1 log10), and 31.8% were HIV infected (Table 1). The associations of microbial translocation markers with factors such as age, sex, and alcohol use that might affect these markers and/or liver

Discussion

In this study, we confirmed that HIV-related CD4+ lymphocyte depletion was associated with microbial translocation and established a link between HIV-related microbial translocation and the severity of liver disease. These data suggest that microbial translocation may be a novel mechanism by which HIV accelerates liver disease.

The link between HIV and microbial translocation was already made by Brenchley et al.10 We confirm their cross-sectional analyses and extend these observations by finding

References (45)

  • V. Di Martino 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)
  • D.P. Praaningvandalen et al.

    Clearance capacity of rat liver Kupffer, endothelial, and parenchymal cells

    Gastroenterology

    (1981)
  • R. Weber et al.

    Liver-related deaths in persons infected with the human immunodeficiency virus: the D:A:D study

    Arch Intern Med

    (2006)
  • Z. Smit-McBride et al.

    Gastrointestinal T lymphocytes retain high potential for cytokine responses but have severe CD4(+) T-cell depletion at all stages of simian immunodeficiency virus infection compared to peripheral lymphocytes

    J Virol

    (1998)
  • R.S. Veazey et al.

    Gastrointestinal tract as a major site of CD4+ T-cell depletion and viral replication in SIV infection

    Science

    (1998)
  • Z.F. Sun et al.

    Intrarectal transmission, systemic infection, and CD4(+) T-cell depletion in humanized mice infected with HIV-1

    J Exp Med

    (2007)
  • S. Mehandru et al.

    Primary HIV-1 infection is associated with preferential depletion of CD4(+) T lymphocytes from effector sites in the gastrointestinal tract

    J Exp Med

    (2004)
  • M. Guadalupe et al.

    Severe CD4(+) T-cell depletion in gut lymphoid tissue during primary human immunodeficiency virus type 1 infection and substantial delay in restoration following highly active antiretroviral therapy

    J Virol

    (2003)
  • J.M. Brenchley et al.

    Microbial translocation is a cause of systemic immune activation in chronic HIV infection

    Nat Med

    (2006)
  • R.G. Thurman

    Mechanisms of hepatic toxicity IIAlcoholic liver injury involves activation of Kupffer cells by endotoxin

    Am J Physiol Gastrointest Liver Physiol

    (1998)
  • N. Enomoto et al.

    Development of a new, simple rat model of early alcohol-induced liver injury based on sensitization of Kupffer cells

    Hepatology

    (1999)
  • E. Seki et al.

    TLR4 enhances TGF-beta signaling and hepatic fibrosis

    Nat Med

    (2007)
  • Cited by (247)

    • Impact of the gut microbiome on human health and diseases

      2022, Microbiome, Immunity, Digestive Health and Nutrition: Epidemiology, Pathophysiology, Prevention and Treatment
    View all citing articles on Scopus

    Supported by grants 1 R37DA004334, R01 2 DA012568, R01 DA016078, R01 DA013806, T32 AI07291, NCI R01CA120206, and U01CA084951.

    Conflicts of interest: The authors have no financial conflicts of interest to report.

    View full text