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Hepatitis C virus drives increased type I interferon-associated impairments associated with fibrosis severity in antiretroviral treatment-treated HIV-1hepatitis C virus-coinfected individuals
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"Our comprehensive study showed that a highly homogeneous untreated HCV coinfection with mild-to-moderate fibrosis induced a type-I IFN signature associated with increased inflammation in HIV-1-infected individuals."
Understanding the Relative Contributions of IDU and HCV on Systemic Immune Activation...... .....HCV should be aggressively treated in current IDUs even more if HIV and/or HCV positive....http://www.natap.org/2016/CROI/croi_233.htm
AIDS: 1 June 2017 - Griesbeck, Morganea; Valantin, Marc-Antoineb,c; Lacombe, Karinec,d; Samri-Hassimi, Assiaa; Bottero, Juliec,d; Blanc, Catherinee; Sbihi, Zineba; Zoorob, Rimaa; Katlama, Christineb,c; Guiguet, Margueritec; Altfeld, Marcusf; Autran, Brigittea,g; on behalf of the HepACT-VIH study group
Background: Viral coinfections might contribute to the increased immune activation and inflammation that persist in antiretroviral treatment (ART)-treated HIV-1 patients. We investigated whether the hepatitis C virus (HCV) coinfection contributes to such alterations by impairing the plasmacytoid dendritic cell (pDC) IFNα/TLR7 pathway in a highly homogeneous group of ART-treated HIV-1-HCV-coinfected patients.
Methods: Twenty-nine HIV-1-infected patients with fully suppressive ART were included, 15 of whom being HCV-coinfected with mild-to-moderate fibrosis and matched for their HIV-1 disease, and 13 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 interferon (IFN)-associated cytokines [interferon gamma-induced protein 10 (IP-10), MIP-1β, IL-8 and IFN-inducible T-cell alpha chemoattractant) were observed in HIV-1-HCV-coinfected than in HIV-1-monoinfected patients (P = 0.0007, 0.028, 0.028 and 0.035, respectively). The pDCs and T cells displayed a more exhausted (LAG-3+ and CD57+, respectively) phenotype. The pDC IFNα pathway (defined by phosphorylated STAT1 expression) was constitutively activated in all patients, irrespective of HCV coinfection. Expression of interferon-stimulated genes (ISGs) EI2AK2, ISG15, Mx1 and IFI44 was increased in pDCs from HIV-1-HCV-coinfected individuals and was correlated with fibrosis score (Fibroscan, www.echosens.com, Paris, France and aspartate-aminotransferase/platelet-ratio index score, P = 0.026 and 0.019, respectively). Plasma levels of IP-10, STAT1 expression in pDCs and Mx1 mRNA levels in pDCs decreased after interferon-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 interferon-free anti-HCV treatment in those patients.
Understanding whether HCV coinfection increases the systemic immune activation and/or inflammation in HIV-1-infected patients with suppressive ART should help elucidate challenging issues for treating HIV-1 patients with HCV coinfection. To test such hypothesis, we designed a highly homogeneous study that includes only HIV-1-infected patients on suppressive ART, half of them being HCV coinfected and matched for HIV-1 disease and personal characteristics with the HCV-negative HIV-1-monoinfected patients. We investigated whether the HCV coinfection caused by a single genotype and moderate fibrosis drives an increase in parameters of inflammation and cellular immune activation in HIV-1-infected patients under suppressive ART by analyzing the pDC IFNα/TLR7 pathway and expression of activation markers and ISGs.
Our comprehensive study showed that a highly homogeneous untreated HCV coinfection with mild-to-moderate fibrosis induced a type-I IFN signature associated with increased inflammation in HIV-1-infected individuals. The most prominent markers of this signature were an increased expression of IP-10 and some ISGs, including Mx1 in pDCs. The ISG expression score correlated with the levels of liver fibrosis, whereas both IP-10 plasma and Mx1 mRNA levels in pDCs decreased after an interferon-free DAA treatment. Overall, this first extensive ex-vivo study of pDC numbers, activation, phosphorylation, transcription and function of key IFN pathway molecules without further in-vitro stimulation suggest that HCV genotype-1 replication heightens activation of type-I IFN signaling and aggravates immune alterations in HCV-HIV-1 coinfection, even in the context of minimal fibrosis.
Many controversies persist regarding the question of whether HCV coinfection increases T-cell activation or inflammation induced by HIV-1. Indeed, HCV is known to activate the liver type-I IFN pathway despite controversies at the systemic level [25,28,36], whereas chronic activation of the innate rather than adaptive immune system has been associated with increased morbimortality in ART-treated HIV-1 infection [37]. Our results add to the previously reported higher plasma levels of IP-10 and inflammatory cytokines in coinfected patients [38], by showing their association with increased exhaustion of peripheral blood pDCs and CD8+ T cells but not with increased immune activation of T cells, DCs or monocytes. Of note, the CD38+HLADR+CD8+ T-cell percentages were lower in all our study groups than in other studies, consistently with their profound HIV-1 suppression [9]. We also found blood pDC absolute counts to be correlated with CD57+CD8+ T-cell percentages in these ART-treated HCV-HIV-1-coinfected patients. Interestingly, both parameters had been correlated to ART duration irrespective of virus coinfection [39-41]. Indeed, in an effort to attenuate potential confounding factors in T-cell activation and inflammation, our study was restricted to patients under suppressive ART with normalized CD4+ cell counts, coinfected by a single HCV genotype and with mild fibrosis, all matched for sex and for their CD4+/CD8+ ratio and CD4+ nadir known to interfere with immune activation [41,42]. These highly homogeneous patient study groups differ from the various settings of co-HCV-HIV-1-infected patients with very different HIV-1 disease status or liver disease stages in whom previous studies had reported increased T-cell activation [7-9]. The typical ISG signature, with increased mRNA levels of IFI44, EI2AK2/PKR, ISG15, Mx1 and of STAT1 found in coinfected compared with monoinfected patients appeared to be limited to pDCs. Our study was not designed to study other minor populations. Therefore, we cannot exclude that another minor population display similar signature. These ISGs display antiviral activity against a broad spectrum of viruses including HCV and HIV-1 [43]. Our results also add IFI44, EI2AK2/PKR to previous results showing that increased ISG15 and MX1 expressions predict a sustained virological response to interferon-based anti-HCV treatment [44]. Though still preliminary, our results suggest Mx1 mRNA expression decreases in pDCs after HCV clearance with antiviral treatment, thus complementing reports of IFI44 and/or ISG15 downregulation after interferon-free DAA treatment in HCV monoinfection [45,46]. HCV clearance is also associated with decreased IP-10 plasma levels that are partially upregulated by type-I IFN [47]. Moreover, strong ISGs expression in HCV-HIV-1 coinfection had suggested unresponsiveness to standard PegIFN + ribavirin therapy [48], but the liver and peripheral blood IFN pathway had not been compared after Peg-IFNα failure in HCV-infected patients to normal levels [25,26,28,49]. In the context of interferon-free DAA treatments, clinical practice guidelines no longer differentiate between HCV-HIV-1 coinfection and HCV monoinfection and recommend to treat only patients with significant fibrosis [50,51]. Excessive inflammation favors HCV-mediated liver damage and faster progression to fibrosis in HIV-1-HCV coinfection compared with either HIV-1 or HCV monoinfection [52,53]. To avoid heterogeneity and the inflammatory disorders linked to severe liver disease, we biased our recruitment strategy toward male sex, HCV genotype 1 and minimal fibrosis. Our results suggest that pDCs ISGs levels are linked to HCV disease severity and that HCV-HIV-1 coinfection with minimal fibrosis could benefit from an earlier interferon-free DAA treatment.
Altogether, this study shows that HCV-HIV-1 coinfection, even with minimal fibrosis, aggravates the HIV-related immune activation and inflammation, particularly the pDC type-I interferon signaling, in relation to HCV replication and provides a rationale for treating early HCV-HIV-1 coinfection even with mild fibrosis.

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