title: HIV mono-infection is associated with an impaired anti-hepatitis C virus activity of natural killer cells.
abstract: OBJECTIVE
  Hepatitis C virus (HCV) infection in HIV(+) patients is associated with faster liver disease progression compared with HCV mono-infection. HIV-associated immune defects are considered to play an important role in this context. Here, we analyzed the effects of HIV infection on natural killer (NK)-cell-mediated anti-HCV activity.
  
  
  METHODS
  NK cell phenotype and interferon gamma (IFN-γ) production, NK cell-mediated inhibition of HCV replication and CD4 T-cell/NK cell interactions were studied in treatment naive HIV (n = 22), and HIV patients under combined antiretroviral therapy (n = 29), compared with healthy controls (n = 20).
  
  
  METHODS
  NK cell-mediated inhibition of HCV replication was analyzed using the HuH7A2HCVreplicon model. IFN-γ production of NK cells as well as interleukin-2 secretion of CD4 T lymphocytes were studied by flow cytometry.
  
  
  RESULTS
  Peripheral blood mononuclear cells from HIV(+) patients displayed a significantly impaired anti-HCV activity, irrespective of combined antiretroviral therapy. This could in part be explained by HIV-associated decline in NK cell numbers. In addition, NK cell IFN-γ production was significantly impaired in HIV infection. Accordingly, we found low frequency of IFN-γ(+) NK cells in HIV(+) patients to be associated with ineffective inhibition of HCV replication. Finally, we show that CD4 T-cell-mediated stimulation of NK cell IFN-γ production was dysregulated in HIV infection with an impaired interleukin-2 response of NK cells.
  
  
  CONCLUSIONS
  HIV infection has a strong suppressive effect on anti-HCV activity of NK cells. This may contribute to low spontaneous clearance rate and accelerated progression of HCV-associated liver disease observed in HIV(+) patients.
authors.affiliation: aDepartment of Internal Medicine I, University of Bonn bGerman Center for Infection Research (DZIF), Bonn, Germany. *Goeser and Glässner contributed equally to the writing of this article. †Benjamin Krämer and Jacob Nattermann shared senior authorship.
authors.forename: Felix
authors.initials: F
authors.lastname: Goeser
authors.forename: Andreas
authors.initials: A
authors.lastname: Glässner
authors.forename: Pavlos
authors.initials: P
authors.lastname: Kokordelis
authors.forename: Franziska
authors.initials: F
authors.lastname: Wolter
authors.forename: Philipp
authors.initials: P
authors.lastname: Lutz
authors.forename: Dominik J
authors.initials: DJ
authors.lastname: Kaczmarek
authors.forename: Carolynne
authors.initials: C
authors.lastname: Schwarze-Zander
authors.forename: Christoph
authors.initials: C
authors.lastname: Boesecke
authors.forename: Christian P
authors.initials: CP
authors.lastname: Strassburg
authors.forename: Jürgen K
authors.initials: JK
authors.lastname: Rockstroh
authors.forename: Ulrich
authors.initials: U
authors.lastname: Spengler
authors.forename: Benjamin
authors.initials: B
authors.lastname: Krämer
authors.forename: Jacob
authors.initials: J
authors.lastname: Nattermann
mesh_terms: D000328:Adult; D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D005260:Female; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology*; D016174:Hepacivirus / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008875:Middle Aged
chemical_list: D044966:Anti-Retroviral Agents; D007376:Interleukin-2; D007371:Interferon-gamma