Acute and chronic immune biomarker changes during interferon/ribavirin treatment in HIV/HCV co‐infected patients

Abstract

Chronic viral infections lead to persistent immune activation, which is alleviated by eradicating or suppressing the infection. To understand the effects of interferon treatment on immune system activation by chronic infections, we evaluated kinetic patterns of a broad spectrum of serum biomarkers during HCV treatment in HIV/HCV co-infected patients. HCV viral load and 50 biomarkers were analyzed at baseline and 27 time points during pegylated interferon and ribavirin (IFN/RBV) treatment of 12 HIV/HCV co-infected patients. We evaluated biomarker changes from baseline for each time point, and biomarker correlations with clinical parameters, treatment response and liver histopathology. IL-1α, IL-12p40, IL-1RA, IP-10, MIG, MIP-1α/1β, HGF, sCD40L, TRAIL and leptin increased in the first day. IL-12p70, IL-17A, IL-10, GROα, IL-8, MCP-3, IL-4, and M-CSF peaked later during week 1. IL-1α, HGF, IP-10, MIP-1α, TRAIL, sCD40L, IL-10, IL-12p70, MCP-3, FGFb, ENA-78, TGFβ, IL-2, IFNγ, IL-6, IL-15, IL-7, and PDGF-BB decreased below baseline over the course of treatment. Higher BMI, baseline HCV viral load and leptin levels were associated with lack of sustained virological response. ENA-78 was associated with sustained viral response. Positive correlations were found between liver inflammation and baseline CD4 count, sVCAM, and HGF; fibrosis stage and HGF; liver steatosis, BMI and leptin. Our findings suggest IFN/RBV treatment initially increases levels of several biomarkers, but eventually leads to a decline in many immune markers. These findings shed light on the relationship between IFN treatment and immune activation by chronic viral infections, such as HCV.

Hepatitis C virus‐induced myeloid‐derived suppressor cells regulate T‐cell differentiation and function via the signal transducer and activator of transcription 3 pathway

“…Although dysregulated myelopoiesis by inflammatory cytokines, such as IL‐6, IL‐10, TGF‐ β and prostaglandin E 2 that are up‐regulated during chronic HCV infection, may partially explain the expansion of MDSCs, the molecular nature of this process is unclear. Previous studies have shown that increased expression of arginase 1, nitric oxide synthase or reactive oxygen species is the primary mechanism by which MDSCs promote immunosuppression during chronic HCV infection .…”

PDGF signaling pathway in hepatic fibrosis pathogenesis and therapeutics

“…Blocking PDGF signaling inhibits HSC proliferation and ameliorates liver fibrogenesis ( 12 ). Clinical studies have additionally confirmed that excessive activation of PDGF and its downstream molecules appears to be associated with the extent of necroinflammation and fibrosis in patients with hepatic damage ( 13 – 15 ). Therefore, the PDGF signaling pathway serves important roles in the development and prognosis of hepatic fibrosis.…”

Plasma Inflammatory Biomarkers Associated with Advanced Liver Fibrosis in HIV–HCV-Coinfected Individuals

“…In some studies, IFN-γ was negatively correlated with liver fibrosis [ 33 ], while IFN-γ was also found to have proinflammatory effects that can aggravate disease progression and organ dysfunction [ 30 ], and an increased production of IFN-γ is observed among cirrhotic patients [ 34 ]. Soluble IL-10 was higher in HIV–HCV-coinfected patients than in HIV-negative persons [ 27 ], but could be reduced following peg-interferon plus ribavirin (PR) treatment for HCV [ 35 ]. GM-CSF was higher in HIV patients than in healthy control subjects [ 31 ], and may promote liver damage and liver fibrosis [ 36 ].…”