Prognostic, clinical and therapeutic importance of RANTES-CCR5 axis in hepatitis A infection: A multi-approach study.

Fulminant hepatic failure (FHF) is a lethal manifestation of hepatitis A virus (HAV) infection, whose underlying mechanisms are poorly understood. We aimed to evaluate the importance of the modulation of RANTES-CCR5 signalling axis and its immunomodulatory effects in directing hepatitis A disease pathogenesis using an in-silico, in-vitro and patient cohort based approach.In-silico interaction studies were performed using computation approaches with suitable software. Differential expression of relevant cytokines and immune cell markers were studied using qRT-PCR, ELISA and flow-cytometry-based methods. In HepG2 cell line, we studied inflammatory responses and susceptibility to HAV infection following RANTES stimulation and antibody blockade of CCR5.The HAV-VP3 region exhibited high interaction in CCR5: HAV complexes. RANTES levels were significantly increased in FHF cases. A reduced monocyte and T-cell activation was observed in FHF cases. RANTES expression inversely correlated with viremia but positively correlated with pro-inflammatory responses. Hyper Th1-biased immune responses, marked by high IL-12/IL-10 ratio were observed in FHF cases, which were also characterized by upregulated TNF-α expression and reduced IFN-γ expression. In-vitro, RANTES was protective against HAV infection, but resulted in upregulated TNF-α expression. Although viral load increased upon regulation of inflammatory responses by CCR5 blocking, it was still significantly lower compared to control HAV-infected cells.Our study suggests the importance of RANTES-CCR5 signalling and linked-immunomodulation in HAV disease pathogenesis, as well as highlights the utility of CCR5 antagonists as a risk-reduction strategy in FHF patients. Our findings therefore have important implications for the management of high-risk HAV infections. This article is protected by copyright. All rights reserved.