Improvement in hepatic fibrosis biomarkers associated with chemokine receptor inactivation through mutation or therapeutic blockade
Sherman, K. E., Abdel-Hameed, E., Rouster, S. D., Shata, M. T. M., Blackard, J. T., Safaie, P., Kroner, B., Preiss, L., Horn, P. S., & Kottilil, S. (2019). Improvement in hepatic fibrosis biomarkers associated with chemokine receptor inactivation through mutation or therapeutic blockade. Clinical Infectious Diseases, 68(11), 1911-1918. https://doi.org/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.