HCV drives increased type I IFN-associated impairments associated to fibrosis severity in ART-treated HIV-1-HCV coinfected individuals.

BACKGROUND: Viral coinfections might contribute to the increased immune activation and inflammation that persist in ART-treated HIV-1 patients. We investigated whether the HCV co-infection contributes to such alterations by impairing the pDC IFNα/TLR7 pathway in a highly homogeneous group of ART-treated HIV-1-HCV co-infected patients.

METHODS: Twenty nine HIV-1-infected patients with fully suppressive ART were included, fifteen of whom being HCV co-infected with mild to moderate fibrosis and matched for their HIV-1 disease, and thirteen control healthy donors. Cellular activation, plasma levels of inflammatory cytokines and pDC transcriptome associated with IFNα/TLR7 pathway were characterized.

RESULTS: Higher plasma levels of type-I IFN-associated cytokines (IP-10, MIP-1β, IL-8, ITAC) were observed in HIV-1-HCV co-infected than in HIV-1 mono-infected patients (p=0.0007, p = 0.028, p = 0.028 and p = 0.035 respectively). The pDCs and T cells displayed a more exhausted (LAG-3+ and CD57+) phenotype. The pDC IFNα pathway (defined by phosphorylated STAT1 expression) was constitutively activated in all patients, irrespective of HCV co-infection. Expression of IFN-stimulated genes (ISGs) EI2AK2, ISG15, Mx1 and IFI44 was increased in pDCs from HIV-1-HCV co-infected individuals and was correlated with fibrosis score (Fibroscan and APRI score, p = 0.026 and p = 0.019, respectively). Plasma levels of IP-10, STAT1 expression in pDCs and Mx1 mRNA levels in pDCs decreased after IFN-free anti-HCV treatment.

CONCLUSION: HCV replication appears to drive increases in type-I IFN-associated inflammation and ISGs expression in pDCs, in association with fibrosis severity in ART-treated HIV-1-infected patients with mild to moderate fibrosis. Preliminary results indicate reduction of these alterations with earlier IFN-free anti-HCV treatment in those patients.