Ribavirin inhibits DNA, RNA, and protein synthesis in PHA‐stimulated human peripheral blood mononuclear cells: Possible explanation for therapeutic efficacy in patients with chronic HCV infection

Abstract

The treatment of choice for patients infected chronically with HCV is the combination of IFN-alpha and ribavirin. Monotherapy with ribavirin leads to a clinical and histological improvement, but its exact mechanism of action is unknown. Therefore, the effect of ribavirin on synthesis of inflammatory cytokines and on apoptosis in stimulated peripheral blood mononuclear cells (PBMCs) was investigated. PBMCs were isolated from the blood of HCV infected patients and from healthy volunteers. The effect of ribavirin on IFN-gamma and IL-1beta release in the supernatant of unstimulated and phytohemagglutinin (PHA) stimulated PBMCs was investigated by enzyme linked immunosorbent assay (ELISA). The effect on total DNA, RNA, and protein synthesis was analyzed by measurement of 3H-thymidine, 3H-uridine and 3H-leucine incorporation into cellular macromolecules. Ribavirin led to a dose-dependent decrease of the IFN-gamma but an increase of IL-1beta release into the supernatant of PHA-stimulated PBMCs. At the same time, a dose-dependent decrease of total DNA, RNA, and protein synthesis in cultures of PHA-stimulated PBMCs was demonstrated. These effects could be compensated by the addition of equimolar amounts of guanosine. The rate of apoptotic CD45+ and CD14+ cells in PBMCs cultures increased in a dose-dependent manner. Our data suggest that ribavirin administration to chronically HCV-infected patients could lead to a decrease of the synthesis of proinflammatory cytokines (e.g., IFN-gamma) by an inhibition of total DNA-, RNA-, and protein-synthesis and by induction of apoptosis in the cells of the inflammatory infiltrate. Furthermore, ribavirin could influence the synthesis of viral particles in the hepatocytes.

Assessment of immunological, haematological and biochemical status after sofosbuvir-based combination therapy in HCV Egyptian patients from Menoufia Province

“…It is obvious that immune cells abnormalities were more frequent among HCV Egyptian patients receiving peg-IFNα-2a. Consistent with the current results, upon RBV administration, the rate of apoptotic CD14 + and CD45 + cells in PBMCs in vitro cultures were increased in a dose-dependent way (Meier et al, 2003). RBV administration induced STAT-1 DNA binding which may be rendered to the consequence of an enhanced STAT-1 tyrosine phosphorylation, enhanced STAT-1 synthetic rate, or an indirect effect caused by minimizing the expression of upstream STAT inhibitors (like STAT inhibitor II) (Zhang et al, 2003).…”

“…Previous studies enumerated many adverse effects of peg-IFN α and/or RBV treatment on the immune status SOF chronically infected HCV patients (Arizcorreta et al, 2006;Kondo et al, 2013;Meier et al, 2003;Werner et al, 2014). DAAs were initially utilized in addition to peg-IFN α plus RBV, which amended SVR rates but at the expense of further restricting patient eligibility and incrementing the range of side effects.…”

Preservation of immune function and anti-hepatitis C virus (HCV) immune responses after liver transplantation in HIV–HCV coinfected patients (ANRS-HC08 “THEVIC” trial)

“…IFN-a is known to mediate anti-inflammatory effects [28] and inhibit leukocyte proliferation while modulating both T helper type 1 (Th1) and type 2 immune responses. RBV reduces liver inflammation and proliferation and to some extent the production of IFN-c by Th1 lymphocytes [29]. During previous studies by our group [30] and others [31], PegIFN-a/RBV were shown to exert a significant negative impact on HIV and/or CMV but not on HCV-specific Th1 immune responses.…”

Impact of Alpha Interferon and Ribavirin on the Function of Maturing Dendritic Cells

“…A number of studies have reported that ribavirin has diverse effects on the cytokines produced by peripheral blood mononuclear cells stimulated with nonspecific mitogens (22,24,32,34). The results of these studies suggest that ribavirin enhances the production of some cytokines and inhibits the production of others.…”