title: HIV increases HCV replication in a TGF-beta1-dependent manner.
abstract: OBJECTIVE
  Human immunodeficiency virus (HIV) coinfection increases hepatitis C virus (HCV)-related progression of hepatic fibrosis, increases HCV persistence, and decreases response rates to interferon-based anti-HCV therapy. It has remained unclear how HIV, a nonhepatotropic virus, accelerates the progression of liver disease by HCV.
  
  
  METHODS
  We explored the possibility that circulating HIV and/or its proteins contribute to the pathogenesis of HCV through engagement of extracellular coreceptors on hepatocytes.
  
  
  RESULTS
  In this study, we found that inactivated HIV or gp120 increases HCV replication and enhances HCV-regulated transforming growth factor (TGF)-beta1 expression in both a replicon and an infectious model of HCV. This proviral effect of HIV and gp120 on HCV replication is neutralized by antibodies to CCR5 or CXCR4. However, HIV and gp120 did not alter type I interferon-mediated signaling in these HCV models, indicating that HIV regulates HCV replication through an alternative mechanism. Interestingly, we found that human TGF-beta1 also enhanced HCV replication. The effect of HIV on HCV replication was blocked by a neutralizing antibody to TGF-beta1, indicating that its effects on HCV replication are TGF-beta1 dependent.
  
  
  CONCLUSIONS
  These results suggest a novel mechanism by which HIV not only enhances HCV replication but also contributes to progression of hepatic fibrosis.
authors.affiliation: Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Wenyu
authors.initials: W
authors.lastname: Lin
authors.forename: Ethan M
authors.initials: EM
authors.lastname: Weinberg
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Tai
authors.forename: Lee F
authors.initials: LF
authors.lastname: Peng
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.forename: Kyung-Ah
authors.initials: KA
authors.lastname: Kim
authors.forename: Sun Suk
authors.initials: SS
authors.lastname: Kim
authors.forename: Carolina B
authors.initials: CB
authors.lastname: Borges
authors.forename: Run-Xuan
authors.initials: RX
authors.lastname: Shao
authors.forename: Raymond T
authors.initials: RT
authors.lastname: Chung
mesh_terms: D000906:Antibodies; D045744:Cell Line, Tumor; D005355:Fibrosis; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism*; D016174:Hepacivirus / Q000235:genetics / Q000254:growth & development / Q000378:metabolism* / Q000472:pathogenicity; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology / Q000821:virology*; D006801:Humans; D016898:Interferon-alpha / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D019713:Receptors, CCR5 / Q000276:immunology / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000276:immunology / Q000378:metabolism*; D014779:Virus Replication
chemical_list: D000906:Antibodies; D015699:HIV Envelope Protein gp120; D016898:Interferon-alpha; D012367:RNA, Viral; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; C514793:gp120 protein, Human immunodeficiency virus 1