Improvement in Hepatic Fibrosis Biomarkers Associated With Chemokine Receptor Inactivation Through Mutation or Therapeutic Blockade

Clin Infect Dis. 2019 May 17;68(11):1911-1918. doi: 10.1093/cid/ciy807.


Background: The C-C chemokine receptor Type 5 (CCR5) is a key receptor for human immunodeficiency virus type 1 (HIV-1) entry into T-cells and a variant allele, CCR5 delta-32, is associated with decreased viral replication and disease progression. Active HIV-1 replication is highly associated with accelerated rates of hepatic fibrosis. We postulated that CCR5 plays a role in the development of hepatic fibrosis and evaluated the longitudinal effect of natural or drug-induced CCR5 mutation and blockade on biomarkers of liver fibrosis in HIV-1 patients.

Methods: To accomplish this goal, we examined 2 distinct cohorts. First, we evaluated fibrosis markers in the Multicenter Hemophilia Cohort Studies (MHCS), which included subjects with HIV and hepatitis C virus (HCV) coinfection with the CCR5 delta-32 allele. We also evaluated an HIV-1 infected cohort that was treated with a dual CCR5/CCR2 antagonist, cenicriviroc. The enhanced liver fibrosis (ELF) index was validated against liver histology obtained from HCV/HIV and HCV patients and demonstrated strong correlation with fibrosis stage.

Results: In both the MHCS patients and patients treated with cenicriviroc, CCR5 mutation or blockade was associated with a significant decrease in the ELF index. Among the patients with the delta-32 allele, the ELF index rate significantly decreased in sequential samples as compared to CCR5 wild-type patients (P = .043). This was not observed in control subjects treated with efavirenz nor with a lower dose of 100 mg cenicriviroc.

Conclusion: These findings suggest that hepatic fibrosis in HIV-1 infected patients can be modulated by the mutation of CCR5 and/or use of CCR5/CCR2 blockade agents.

Clinical trials registration: NCT01338883.

Keywords: CCR2; CCR5; HIV; cenicriviroc; fibrosis.

Publication types

  • Clinical Trial, Phase II
  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Alleles
  • Biomarkers / analysis
  • CCR5 Receptor Antagonists / therapeutic use
  • Child
  • Child, Preschool
  • Cohort Studies
  • Coinfection / complications
  • Coinfection / virology
  • Double-Blind Method
  • HIV Infections / complications*
  • HIV Infections / drug therapy
  • HIV-1
  • Hepacivirus
  • Hepatitis C / complications*
  • Humans
  • Imidazoles / therapeutic use*
  • Liver Cirrhosis / drug therapy*
  • Liver Cirrhosis / immunology*
  • Liver Cirrhosis / virology
  • Male
  • Middle Aged
  • Mutation
  • Observational Studies as Topic
  • Receptors, CCR5 / genetics*
  • Sulfoxides
  • Young Adult


  • Biomarkers
  • CCR5 Receptor Antagonists
  • CCR5 protein, human
  • Imidazoles
  • Receptors, CCR5
  • Sulfoxides
  • cenicriviroc

Associated data