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Telatin, Valentina (2018) Immunological restoration in chronic HCV-infected patients treated with different antiviral therapies. [Ph.D. thesis]

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Abstract (english)

SUMMARY OF THE STUDY

The World Health Organization (WHO) estimates that approximately 3% of the global population is chronically infected with Hepatitis C Virus (HCV) and that approximately 3-4 million new cases of hepatitis C occur each year worldwide. While African countries have the highest prevalence of HCV infection (up to 26%) in the world, however, HCV infection represents a global health challenge from which no country, rich or poor, is spared. The acute phase of HCV infection is asymptomatic in the majority of infected individuals (75-80%), and except few cases of acute hepatitis C followed by viral clearance, in approximately 80% of patients the virus establishes a chronic infection and, among these patients, about 20% develop cirrhosis with possible degeneration in hepatocellular carcinoma (HCC) in 1-5% of cases. At present, although numerous candidates have been pursued, there is no vaccine available to prevent HCV infection and, even if antiviral drugs are the choice of treatment, HCV infection indeed represents a major health problem worldwide.
New generation of highly effective interferon-free, direct acting antivirals (DAAs) therapies have been recently introduced in the clinical practice promising to cure HCV and to overcome the issues related to interferon-based therapies. DAAs have revolutionized the care of HCV-infected individuals due to their dramatically high cure rate, above 90%. Nonetheless, recent reports describe the presence of occult HCV infection in some patients, and the occurrence and recurrence of HCC, despite sustained virological response (SVR) after treatment with DAAs (Koutsoudakis G.et al., 2017; Elamarsy S. et al., 2017; Vukotic R. et al., 2017; Reig M. et al., 2016). In addition, the emergence of drug resistance and suboptimal activity of DAA-based therapies against different HCV genotypes have been observed, causing treatment failure and hampering the control of HCV spread globally (Pawlotsky J.M.et al., 2016; Gimeno-Ballester V. et al., 2017). For all these reasons, and considering also that a previous HCV cleared infection does not ensure prevention from re-infection, at present it is unclear if HCV eradication worldwide will be achieved with DAAs therapies alone or with the combination with immunotherapies.
Mechanisms regulating viral clearance or establishment of chronic infection and disease progression have been clarified only partially and several questions are still open (Manns M.P. et al., 2017). During HCV chronic infection, HCV-specific CD8+ T lymphocytes are present in the liver, but these cells are not able to control the replication of HCV, because they have lost their antiviral effector functions, such as cytokine production, proliferation and cytolytic activity. Recent hypothesis is that the loss of function of T lymphocytes may be due to both the liver microenvironment and other cell populations such as CD4+ regulatory T cells (Tregs) or myeloid-derived suppressor cells (MDSCs) exerting inhibitory functions and favoring viral escape and disease progression. MDSCs have been well described in multiple severe human diseases such as cancer, autoimmune diseases, and infections but little is known on their role in HCV infection.
A hallmark feature of persistent HCV infection is chronic immune activation and dysfunction of several types of immune cells, including naïve and memory CD4+ and CD8+ T cells, which have been linked to perturbation of anti-viral and anti-tumoral immune responses. Besides, HCV may exert direct effects on B and T lymphocytes and accelerate T cell immune senescence, as the presence and replication of HCV in these cells has been reported, contributing to viral persistence and impairing overall immune responses and vaccination against other infectious agents. Therefore, the global dysregulation of the immune system caused by HCV infection, in addition to affect HCV clearance itself, may be deleterious in terms of response to other infectious agents and tumor onset.
In this context, how DAA treatments influences immune responses and immune activation, and whether effective inhibition of HCV replication by DAAs restores defective innate and adaptive immune responses in HCV chronically infected patients are unclear and require further investigation. Recent evidence indicate that, in patients with SVR after interferon-free DAA treatments, HCV clearance was associated with improved blood HCV specific immunity (Spaan M. et al., 2016; Serti E. et al., 2015; Larrubia J.R. et al., 2015; Burchill M.A. et al., 2015). However, contradictory results have been reported for MDSCs and other recent studies indicate that DAA-induced HCV clearance does not completely restore the altered cytokines profile in T lymphocytes and CD4+ Treg cells frequency and activation status (Hengst J. et al., 2016; Langhans B. et al., 2017), implying that HCV cure does not lead to complete immune reconstitution and that regulatory cells may play a role in progression of liver disease even long-term after HCV cure. This issue is of crucial interest in the development of strategies aimed at eradicating HCV infection. Indeed, the incomplete reconstitution of HCV-specific and non-specific immune responses even after DAAs treatment may lead to the occult HCV infection and the development of HCC despite SVR (Koutsoudakis G. et al., 2017; Elamarsy S. et al., 2017; Vukotic R. et al., 2017; Reig M. et al., 2016).
To gain further insights into the activity of DAAs on the immune dysfunction, the main objective of this study is to evaluate the capacity of DAA treatments of restoring immune functions, focusing on features of cellular responses known to be affected by HCV infection and/or to be crucial for the effectiveness of adaptive immune responses, such as: 1) the evaluation of the presence, frequency and function of suppressive regulatory cells, including MDSCs. I have focused my attention on M-MDSCs as other reports already showed an increase of this monocytical population in patients infected by HCV, while the effects of HCV antiviral DAA-based treatments on frequency and phenotypes of these cells remain unknown; 2) the phenotype of different CD4+ and CD8+ T cell subpopulations, including evaluation of chronic immune activation, exhaustion, and differentiation, and the presence of Treg, that in other contexts have been shown to be affected by chronic immune activation (Maue A.C. et al., 2009; Papagno L. et al., 2004; Sforza F. et al., 2014); and 3) some metabolic properties of different CD4+ and CD8+ T cell subpopulations. T cell metabolism drives lymphocyte functionality, and may be affected by chronic infections (Dimeloe S. et al., 2016). However, no data are available for HCV infection.
Finally, since in the last years several studies demonstrated the regulatory role of microRNAs (miRNAs) in gene expression and their implication in HCV replication and in MDSCs expansion, I have also analysed the expression profile of miRNA-122, miRNA-196b, miRNA-21 and miRNA-29a (known to play a role in HCV replication and in the expansion of myeloid progenitors) as possible biological markers in peripheral blood of selected HCV infected patients under different therapies or untreated.
For the purpose of this study I have enrolled a total of 262 HCV-chronically infected patients, grouped in: 1) untreated (n=75); 2) during different pharmacological therapies (n=70) (IFN-based n=10, and IFN-free n=60); 3) with cleared infection after the end of pharmacological therapy (n=115) (IFN-based n=38, and IFN-free n=77); 4) patients who have spontaneously cleared HCV infection (n=2) and 5) healthy controls (n=47).
The main results of the study demonstrates that M-MDSCs are deeply altered by HCV infection both quantitatively and qualitatively, and that this is part of a more general phenomenon of HCV-induced immune dysregulation involving also CD4+ and CD8+ T cell subsets. In addition, the results indicate that DAA-based therapy only partially, and slowly, restores these phenomena.

Abstract (italian)

RIASSUNTO

L'Organizzazione mondiale della sanità (OMS) stima che circa il 3% della popolazione mondiale sia cronicamente infettata dal virus dell'epatite C (HCV) e che ogni anno nel mondo si verifichino circa 3-4 milioni di nuovi casi di epatite C. Mentre i paesi africani hanno la più alta prevalenza di infezione da HCV (fino al 26%) nel mondo, tuttavia, l'infezione da HCV rappresenta una sfida sanitaria globale dalla quale nessun paese, ricco o povero, è risparmiato. La fase acuta dell'infezione da HCV è asintomatica nella maggior parte dei soggetti infetti (75-80%) e, tranne alcuni casi di epatite C acuta seguita da clearance virale, in circa l'80% dei pazienti il virus determina un'infezione cronica e, tra questi pazienti, circa il 20% sviluppa cirrosi con possibile degenerazione nell’epatocarcinoma (HCC) nell'1-5% dei casi. Allo stato attuale, sebbene siano stati perseguiti numerosi candidati, non esiste un vaccino disponibile per prevenire l'infezione e, anche se i farmaci antivirali rappresentano la miglior scelta, l'infezione da HCV rappresenta davvero un grave problema in tutto il mondo.
La nuova generazione di terapie anti-antivirali ad azione diretta, senza interferone (DAAs) è stata recentemente introdotta nella pratica clinica che promette di curare l'HCV e di superare i problemi relativi alle terapie basate sull'interferone. I DAAs hanno rivoluzionato la cura degli individui con infezione da HCV a causa del loro tasso di guarigione estremamente alto, superiore al 90%. Nondimeno, rapporti recenti descrivono la presenza di infezione occulta da HCV in alcuni pazienti e l'insorgenza e la recidiva di HCC, nonostante la risposta virologica sostenuta (SVR) dopo il trattamento con DAA (Koutsoudakis G.et al., 2017; Elamarsy S. et al. , 2017; Vukotic R. et al., 2017; Reig M. et al., 2016). Inoltre, è stata osservata l'insorgenza della resistenza ai farmaci e dell'attività sub-ottimale delle terapie basate su DAA contro diversi genotipi dell'HCV, causando fallimento del trattamento e ostacolando il controllo dell'HCV diffuso a livello globale (Pawlotsky JMet al., 2016; Gimeno-Ballester V. et al., 2017). Per tutti questi motivi, e considerando anche che una precedente guarigione dall'HCV non garantisce la prevenzione dalla re-infezione, al momento non è chiaro se l'eradicazione dell'HCV a livello mondiale sarà raggiunta con le terapie DAAs da sole o con l'associazione con le immunoterapie.
Meccanismi che regolano la clearance virale o l'instaurarsi di infezioni croniche e la progressione della malattia sono stati chiariti solo in parte e molte domande sono ancora aperte (Manns M.P. et al., 2017). Durante l'infezione cronica da HCV, i linfociti T CD8 + HCV specifici sono presenti nel fegato, ma queste cellule non sono in grado di controllare la replicazione dell'HCV, poiché hanno perso le loro funzioni antivirali, come la produzione di citochine, la proliferazione e l'attività citolitica. L'ipotesi recente è che la perdita di funzione dei linfociti T possa essere dovuta sia al microambiente epatico che ad altre popolazioni cellulari come le cellule T regolatorie CD4 + (Tregs) o le cellule soppressorie derivate da mieloidi (MDSCs) che esercitano funzioni inibitorie e favoriscono la fuga e la malattia virali progressione. Le MDSCs sono state ben descritte in molte malattie umane gravi come il cancro, le malattie autoimmuni e le infezioni, ma si sa poco sul loro ruolo nell'infezione da HCV.
Una caratteristica distintiva dell'infezione persistente da HCV, è l'attivazione e la disfunzione immunitaria cronica di diversi tipi di cellule immunitarie, comprese le cellule naïve e CD4 + e CD8 + di memoria, che sono state collegate alla perturbazione delle risposte immunitarie anti-virali e anti-tumorali. Inoltre, l'HCV può esercitare effetti diretti sui linfociti B e T e accelerare la senescenza immunitaria delle cellule T, poiché è stata segnalata la presenza e la replicazione del virus in queste cellule, contribuendo alla persistenza virale e compromettendo le risposte immunitarie e la vaccinazione contro altri agenti infettivi. Pertanto, la disregolazione del sistema immunitario causata dall'infezione da HCV, oltre a influire sulla stessa eradicazione del virus, può essere deleterio in termini di risposta ad altri agenti infettivi e insorgenza di tumore.
In questo contesto, sono andata a valutare se i trattamenti con DAA influenzano le risposte immunitarie e l'attivazione immunitaria; e se l'effettiva inibizione della replicazione dell'HCV da parte dei DAA ripristina le risposte immunitarie innate e adattive nei pazienti con infezione cronica da HCV. Recenti lavori indicano che, in pazienti con SVR dopo trattamenti con DAA, la clearance dell'HCV era associata a una migliore immunità specifica per HCV (Spaan M. et al., 2016; Serti E. et al., 2015; Larrubia JR et al. , 2015; Burchill MA et al., 2015). Tuttavia, sono stati riportati risultati contraddittori per MDSCs. Altri recenti studi indicano che la clearance dell'HCV indotta da DAA non ripristina completamente il profilo alterato delle citochine nei linfociti T e nella frequenza delle cellule CD4+ Treg e nello stato di attivazione (Hengst J. et al., 2016; Langhans B. et al., 2017), il che implica che la cura dell'HCV non porta a un completo ripristino immunitario e che le cellule regolatrici possono svolgere un ruolo nella progressione della malattia epatica anche a lungo termine dopo la cura. Questo problema è di fondamentale interesse nello sviluppo di strategie volte a eradicare l'infezione da HCV. In effetti, la ricostituzione incompleta delle risposte immunitarie specifiche e non specifiche dell'HCV anche dopo il trattamento con DAA può portare a un'infezione occulta da HCV e allo sviluppo di HCC nonostante SVR (Koutsoudakis G. et al., 2017; Elamarsy S. Per ottenere ulteriori informazioni sull'attività dei DAA nella disfunzione immunitaria, l'obiettivo principale di questo studio è valutare la capacità dei trattamenti DAA di ripristinare le funzioni immunitarie, concentrandosi sulle caratteristiche delle risposte cellulari note per essere affette da infezione da HCV e/o essere cruciali per l'efficacia delle risposte immunitarie adattive, come ad esempio: 1) la valutazione della presenza, della frequenza e della funzione delle cellule regolatorie soppressive, comprese le MDSCs. Ho focalizzato la mia attenzione su M-MDSCs poiché altri studi mostravano già un aumento di questa popolazione monocitica in pazienti infetti da HCV, mentre gli effetti dei trattamenti antivirali basati su DAA su antivirali su frequenza e fenotipi di queste cellule rimangono sconosciuti; 2) il fenotipo di diverse sottopopolazioni di cellule T CD4+ e CD8+, compresa la valutazione dell'attivazione cronica, dell'exhaustion, della differenziazione e la presenza di Treg. (Maue AC et al ., 2009; Papagno L. et al., 2004; Sforza F. et al., 2014); e 3) alcune proprietà metaboliche di diverse sottopopolazioni di cellule T CD4+ e CD8+. Il metabolismo delle cellule T guida la funzionalità dei linfociti e può essere influenzato da infezioni croniche (Dimeloe S. et al., 2016). Tuttavia, non sono disponibili dati per l'infezione da HCV.et al., 2017; Vukotic R. et al., 2017; Reig M. et al., 2016).
Infine, poiché negli ultimi anni diversi studi hanno dimostrato il ruolo regolatore dei microRNA (miRNA) nell'espressione genica e la loro implicazione nella replicazione dell'HCV e nell'espansione dei MDSC, ho anche analizzato il profilo di espressione di miRNA-122, miRNA-196b, miRNA- 21 e miRNA-29a (noto per svolgere un ruolo nella replicazione dell'HCV e nell'espansione dei progenitori mieloidi) come possibili marcatori biologici nel sangue periferico di pazienti con infezione da HCV selezionati sottoposti a terapie diverse o non trattati.
Ai fini di questo studio, ho arruolato un totale di 262 pazienti con infezione cronica da HCV, raggruppati in: 1) non trattati (n = 75); 2) durante diverse terapie farmacologiche (n = 70) (n = 10 basato su IFN e n = 60 senza IFN); 3) con infezione risolta dopo terapia farmacologica (n = 115) (basato su IFN n = 38 e senza IFN n = 77); 4) pazienti che hanno spontaneamente eliminato l'infezione da HCV (n = 2) e 5) controlli sani (n = 47).
I principali risultati dello studio dimostrano che la frequenza delle M-MDSCs è profondamente alterata dall'infezione sia quantitativamente che qualitativamente e che questo, fa parte di un fenomeno più generale della disregolazione immunitaria indotta da HCV che coinvolge anche i sottogruppi di cellule T CD4+ e CD8+. Inoltre, i risultati indicano che la terapia basata su DAA solo parzialmente, e lentamente, ripristina questa situazione di perturbazione immunitaria.

EPrint type:Ph.D. thesis
Tutor:Caputo, Antonella
Ph.D. course:Ciclo 28 > Scuole 28 > BIOMEDICINA > MEDICINA MOLECOLARE
Data di deposito della tesi:28 February 2018
Anno di Pubblicazione:28 February 2018
Key Words:HCV, MDSC, DAAs therapies, CD4, CD8, Treg
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/17 Malattie infettive
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Molecolare
Codice ID:11183
Depositato il:25 Oct 2018 16:47
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REFERENCES Cerca con Google

1. Accapezzato D., Francavilla S., Paroli M., Casciaro M., Chircu L.V., Cividini A, Mondelli M.U., Barnaba V. (2004) Hepatic expansion of a virus-specific regulatory CD8+ T cell population in chronic hepatitis C virus infection. The journal of Clinical Investigation 113:963–972 Cerca con Google

2. Barth H. (2015) Hepatitis C virus: Is it time to say goodbye yet? Perspectives and challenges for the next decade. World Journal of hepatology 7:725-737 Cerca con Google

3. Bowen D.G. and Walker C.M. (2005) The origin of quasispecies: cause or consequence of chronic hepatitis C viral infection? Journal of hepatology 42:408-417 Cerca con Google

4. Bronte V., Brandau S., Chen S., Colombo M.P., Frey A.B., Greten T.F., Mandruzzato S., Murray P.J., Ochoa A., Ostrand-Rosenberg S., Rodriguez P.C., Sica A. Umansky V., Vonderheide R.H., Gabrilovich D.I. (2016) Recommendations for myeloid-derived suppressor cell nomenclature and characterization standards. Nature Communications 7:12150 Cerca con Google

5. Bukh J. (2016) The history of hepatitis C virus (HCV): Basic research reveals unique features in phylogeny, evolution and the viral life cycle with new perspectives for epidemic control. Journal of hepatology 65:S2-S21 Cerca con Google

6. Burchill M.A., Golden-Mason L., Wind-Rotolo M., Rosen H.R. (2015) Memory re-differentiation and reduced lymphocyte activation in chronic HCV-infected patients receiving direct-acting antivirals. Journal of viral hepatitis 22:983-991 Cerca con Google

7. Cabrera R., Tu Z., Xu Y., Firpi R.J., Rosen H.R., Liu C., Nelson D.R. (2004) An immunomodulatory role for CD4(+)CD25(+) regulatory T lymphocytes in hepatitis C virus infection. Hepatology 40:1062-1071 Cerca con Google

8. Cai W., Qin A., Guo P., Yan D., Hu F., Yang Q., Xu M., Fu Y., Zhou J., Tang X. (2013) Clinical significance and functional studies of myeloid-derived suppressor cells in chronic hepatitis C patients. Journal of clinical immunology 33:798-808 Cerca con Google

9. Cheng J.C., Yeh Y.J., Tseng C.P., Hsu S.D., Chang Y.L., Sakamoto N., Huang H.D. (2012) Let-7b is a novel regulator of hepatitis C virus replication. Cellular and molecular life sciences 69:2621-2633 Cerca con Google

10. Chen S., Zhang Y., Kuzel T.M., Zhang B. (2015) Regulating tumor myeloid-derived suppressor cells by microRNAs. Cancer cell microenvironment 2:637 Cerca con Google

11. Chen X. (2009) MicroRNA signature in liver diseases. World Journal Gastroenterology 15:1665-1672 Cerca con Google

12. Chen Y., Chen J., Wang H., Shi J., Wu K., Liu S., Liu Y., Wu J. (2013) HCV-induced miR-21 contributes to evasion of host immune system by targeting MyD88 and IRAK1. PLoS Pathogens 9:e1003248 Cerca con Google

13. Chiu D.K., Tse A.P., Xu I.M., Di Cui J., Lai R.K., Li L.L., Koh H.Y., Tsang F.H., Wei L.L., Wong C.M., Ng I.O., Wong C.C. (2017) Hypoxia inducible factor HIF-1 promotes myeloid-derived suppressor cells accumulation through ENTPD2/CD39L1 in hepatocellular carcinoma. Nature communications 8:517 Cerca con Google

14. Chung R.T., Gale M., Polyak S.J., Lemon S.M. Liang T.J., Hoofnagle H. (2008) Mechanisms of action of interferon and ribavirin in chronic hepatitis C: Summary of a workshop. Hepatology 47: 306-320 Cerca con Google

15. Condamine T. and Gabrilovich D.I. (2011) Molecular mechanisms regulating myeloid-derived suppressor cell differentiation and function. Trend immunology 32:19-25 Cerca con Google

16. Condamine T., Dominguez G.A., Youn J.I., Kossenkov A.V., Mony S., Alicea-Torres K., Tcyganov E., Hashimoto A., Nefedova Y., Lin C., Partlova S., Garfall A., Vogl D.T., Xu X., Knight S.C., Malietzis G., Lee G.H., Eruslanov E., Albelda S.M., Wang X., Mehta J.L., Bewtra M., Rustgi A., Hockstein N., Witt R., Masters G., Nam B., Smirnov D., Sepulveda M.A., Gabrilovich D.I. (2016) Lectin-type oxidized LDL receptor-1 distinguishes population of human polymorphonuclear myeloid-derived suppressor cells in cancer patients. Science immunology 1:aaf8943 Cerca con Google

17. Damuzzo V., Pinton L., Desantis G., Solito S., Marigo I., Bronte V., Mandruzzato S. (2015) Complexity and challenges in defining myeloid-derived suppressor cells. Cytometry Part B clinical cytometry 88:77-91 Cerca con Google

18. Daw M.A., El-Bouzedi A.A., Ahmed M.O., Dau. A.A. Agnan M.M., Drah A.M. (2016) Geographic integration of hepatitis C virus: A global threat. World Journal Virology 5:170-182. Cerca con Google

19. Delegan L., Neyts J., Vliegen I., Abrignani S., Neddermann P., De Francesco R. (2013) Hepatitis C virus-specific directly acting antiviral drugs. Current topics in microbiology and immunology 369:289-320 Cerca con Google

20. Dimeloe S., Burgener A.V., Grählert J., Hess C. (2016) T-cell metabolism governing activation, proliferation and differentiation; a modular view. Immunology 150:35-44 Cerca con Google

21. Dorhoi A. and Du Plessis N. (2018) Monocytic Myeloid-Derived Suppressor Cells in Chronic Infections. Frontiers in immunology 8:1895 Cerca con Google

22. Duan X., Li S., Li Y., Zeng P., Yang C., Chen L. (2013) The role of microRNA in hepatitis C virus replication. Journal of clinical and translational hepatology 1:125-130 Cerca con Google

23. Elmasry, S., Wadhwa, S., Bang, B.R., Bang B.R., Cook L., Chopra S., Kanel G., Kim B., Harper T., Feng Z., Jerome K.R., Kahn J.A., Saito T. (2017) Detection of occult hepatitis C virus infection in patients who achieved a sustained virologic response to direct-acting antiviral agents for recurrent infection after liver transplantation. Gastroenterology 152:550–553. Cerca con Google

24. Elberry M.H., Darwish NH.E., Mousa S.A. (2017) Hepatitis C virus management: potential impact of nanotechnology Virology journal 14:88 Cerca con Google

25. Enomoto H., Nishikawa H., Ikeda N., Aizawa N., Sakai Y., Yoh K., Takata R., Hasegawa K., Nakano C., Nishimura T., Ishii A., Takashima T., Iwata Y., Iijima H., Nishiguchi S. (2016) Improvement in the Amino Acid Imbalance in Hepatitis C Virus Infected Patients After Viral Eradication by Interferon Treatment. Hepatitis Monthly 16:e35824 Cerca con Google

26. Fallahi P., Ferri C., Ferrari S.M., Corrado A., Sansonno D., Antonelli A. (2012) Cytokines and HCV-related disorders. Clinical and developmental immunology 468107 Cerca con Google

27. Fournier C., Duverlie G, Castelain S. (2013) Are trans-complementation systems suitable for hepatitis C virus life cycle studies? Journal of viral hepatitis 20:225-233 Cerca con Google

28. Friebe P. and Bartenschlager R. (2009) Role of RNA structures in genome terminal sequences of the hepatitis C virus for replication and assembly. Journal of virology 83:11989-11995 Cerca con Google

29. Gabrilovich D.I. and S. Nagaraj. (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nature reviews 9:162-174 Cerca con Google

30. Gabrilovich D.I. (2017) Myeloid-Derived Suppressor Cells. Cancer immunology research 5:3-8 Cerca con Google

31. Gimeno-Ballester V., Buti M., San Miguel R., Riveiro M., Esteban R. (2017) Interferon-free therapies for patients with chronic hepatitis C genotype 3 infection: A systematic review. Journal of viral hepatitis 24:904-916 Cerca con Google

32. Goh C., Narayanan S., Hahn Y. (2013) Myeloid derived suppressor cells: the dark knight or the joker in viral infections? Immunological Reviews 255:210-221 Cerca con Google

33. Goh C., Roggerson K., Lee K., Golden-Mason L., Rosen H.R., Hahn Y.S. (2016) Hepatitis C virus-induced myeloid-derived suppressor cells suppress NK cell IFN-? production by altering cellular metabolism via arginase-1. The journal of immunology 196:2283-2292 Cerca con Google

34. Grandhe S. and Frenette C.T. (2017) Occurrence and Recurrence of Hepatocellular Carcinoma After Successful Direct-Acting Antiviral Therapy for Patients With Chronic Hepatitis C Virus Infection. Gastroenterology & Hepatology 13:421–425 Cerca con Google

35. Guglietta S., Garbuglia A.R., Salichos L., Ruggeri L., Folgori A., Perrone M.P., Camperio C., Mellace V., Maio G., Maio P., Capobianchi M.R., Spada E., Gargano N., Scottà C., Piccolella E., Del Porto P. (2009) Impact of viral selected mutations on T cell mediated immunity in chronically evolving and self-limiting acute HCV infection. Virology 386:398-406 Cerca con Google

36. Gurianova V., Stroy D., Ciccocioppo R., Gasparova I., Petrovic D., Soucek M., Dosenko V., Kruzliak P. (2015) Stress response factors as hub-regulators of microRNA biogenesis: implication to the diseased heart. Cell biochemistry and function 33:509-518 Cerca con Google

37. Haile L.A., Gamrekelashvili J., Manns M.P., Korangy F., Greten T.F. (2010) CD49d is a new marker for distinct myeloid-derived suppressor cell subpopulations in mice. Journal of immunology 185:203-210 Cerca con Google

38. Hajarizadeh B., Grebely J. and Dore G.J. (2013) Epidemiology and natural history of HCV infection. Nature Review Gastroenterology & Hepatology 10:553-562 Cerca con Google

39. Halfon P. and Locarnini S. (2011) Hepatitis C virus resistance to protease inhibitors. Journal of hepatology 55:192-206 Cerca con Google

40. Hamamoto I., Nishimura Y., Okamoto T., Aizaki H., Liu M., Mori Y., Abe T., Suzuki T., Lai M.M., Miyamura T., Moriishi K., Matsuura Y. (2005) Human VAP-B is involved in hepatitis C virus replication through interaction with NS5A and NS5B. Journal of virology 79:13473-13482 Cerca con Google

41. Hammerich L. and Tacke F. (2015) Emerging roles of myeloid derived suppressor cells in hepatica inflammation and fibrosis. World Journal of Gastrointestinal Pathophysiology 6:53-50 Cerca con Google

42. Heim M.H. (2013) 25 years of interferon-based treatment of chronic hepatitis C: an epoch coming to an end. Nature Reviews 13:535-542 Cerca con Google

43. Heim. M.H. and Thiemme R. (2014) Innate and adaptive immune responses in HCV infections. Journal of hepatology 61:14-25 Cerca con Google

44. Hengst J., Falk C.S., Schlaphoff V., Deterding K., Manns M.P., Cornberg M., Wedemeyer H. (2016) Direct-Acting Antiviral-Induced Hepatitis C Virus Clearance Does Not Completely Restore the Altered Cytokine and Chemokine Milieu in Patients With Chronic Hepatitis C. Journal of infectious diseases 214:1965-1974 Cerca con Google

45. Hoechst B., Ormandy L.A., Ballmaier M., Lehner F., Kruger C., Manns M.P., Greten T.F., Korangy F. (2008) A new population of myeloid-derived suppressor cells in hepatocellular carcinoma patients induces CD4+CD25+Foxp3+ T cells. Gastroenterology 135:234-243 Cerca con Google

46. Hoffmann T.W., Gilles D., Abderrahmane B. (2012) MicroRNAs and hepatitis C virus: Toward the end of miR-122 supremacy Virology Journal 9:109 Cerca con Google

47. Horsley-Silva J.L. and Vargas H.E. (2017) New Therapies for Hepatitis C Virus Infection. Gastroenterology and hepatology 13:22-31 Cerca con Google

48. Huang B., Ping-Ying P., Li Q., Sato A.I.,. Levy D. E., Bromberg J., Divino C.M., Chen S.H. Gr-1+CD115+ Immature Myeloid Suppressor Cells Mediate the Development of Tumor-Induced T Regulatory Cells and T-Cell Anergy in Tumor-Bearing Host. Cancer Research 66:1123-1131 Cerca con Google

49. Huang L., , Sineva E.V., Hargittai M.R., Sharma S.D., Suthar M., Raney K.D., Cameron C.E. Purification and characterization of hepatitis C virus non-structural protein 5A expressed in Escherichia coli. (2004) Protein expression and purification 37:144-153 Cerca con Google

50. Huang L., Hwang J., Sharma S.D., Hargittai M.R., Chen Y., Arnold J.J., Raney K.D., Cameron C.E. (2005) Hepatitis C virus nonstructural protein 5A (NS5A) is an RNA-binding protein. Journal of biological chemistry 280:36417-36428 Cerca con Google

51. Jadoon S.A., Ahmed A., Jehangiri A., Ahmad N. (2015) Effect of standard interferon and ribavirin on leukocyte count. Journal of Ayub Medical College Abbottabad 27(2) Cerca con Google

52. Khan A.G., Whidby J., Miller M.T., Scarborough H., Zatorski A.V., Cygan A., Price A.A., Yost S.A., Bohannon C.D., Jacob J., Grakoui A., Marcotrigiano J. (2014) Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2. Nature 509:381-384 Cerca con Google

53. Kim V.N. (2005) MicroRNA Biogenesisis: coordinated cropping and dicing. Nature reviews 9:376-385 Cerca con Google

54. Kotsakis A., Harasymczuk M., Schilling B., Georgoulias V., Argiris A., Whiteside T.L. (2012) Myeloid-derived suppressor cell measurements in fresh and cryopreserved blood samples. Journal Immunology methods 381:14-22 Cerca con Google

55. Koutsoudakis G., Pérez-Del-Pulgar S., Forns X. (2017) Occult Hepatitis C Virus Infection: Are We Digging Too Deep? Gastroenterology 152:472-474 Cerca con Google

56. Kumthip K. and Mannekarn N. (2015) The role of HCV proteins on treatment outcomes. Virology Journal 12:217 Cerca con Google

57. Langhans B., Nischalke H.D., Krämer B., Hausen A., Dold L., van Heteren P., Hüneburg R., Nattermann J., Strassburg C.P., Spengler U. (2017) Increased peripheral CD4+ regulatory T cells persist after successful direct-acting antiviral treatment of chronic hepatitis C. Journal of hepatology 66:888-896 Cerca con Google

58. Larrubia J.R., Moreno-Cubero E., Miquel J., Sanz-de-Villalobos E. (2015) Hepatitis C virus-specific cytotoxic T cell response restoration after treatment-induced hepatitis C virus control. World journal of gastroenterology 21:3480-3491 Cerca con Google

59. Lassmann B., Arumugaswami V., Chew K.W., Lewis M.J. (2013) A new system to measure and compare hepatitis C virus replication capacity using full-length, replication competent viruses. Journal of Virological Methods 194:82-88 Cerca con Google

60. Lauer G.M. (2013) Immune responses to hepatitis C virus (HCV) infection and the prospects for an effective HCV vaccine or immunotherapies. The journal of infectious diseases Suppl 1:S7-S1. Cerca con Google

61. Li L., Zhang J., Diao W., Wang D., Wei Y., Zhang C., Zen Ke (2014) MicroRNA-155 and microRNA-21 promote the expansion of functional myeloid-derived suppressor cells. The journal of immunology 192:1034-1043 Cerca con Google

62. Liu C., Wang Y., Wang C., Feng P., Ko H., Liu Y., Wu Y., Chu Y., Chung F., Lee K., Lin S., Lin H., Wang C., Yu C., Kuo H. (2010) Population alternations of L-arginase and inducible nitric oxide synthase-expressed CD11b+/CD14-/CD15+/CD33+ myeloid-derived suppressor cells and CD8+ T lymphocytes in patients with advanced-stage non-small cell lung cancer. Journal of Cancer Research and Clinical Oncology 136:35-45 Cerca con Google

63. Liu Y., She L., Wang X., Zhang G., Yan Y., Lin C., Zhao Z., Gao Z. (2014) Expansion of myeloid-derived suppressor cells from peripheral blood decrease after 4-week antiviral treatment in patients with chronic hepatitis C. Internal journal of clinical and experimental medicine 7:998-1004 Cerca con Google

64. Manns M.P., Buti M., Gane E., Pawlotsky J.M., Razavi H., Terrault N., Younossi Z. (2017) Hepatitis C virus infection. Nature reviews diseases primers 3:17006 Cerca con Google

65. Mandruzzato S., Solito S., Falisi E., Francescato S., Chiarion-Sileni V., Mocellin S., Zanon A., Rossi C.R., Nitti D., Bronte V., Zanovello P. (2009) IL4Ralpha+ myeloid-derived suppressor cell expansion in cancer patients. The journal of immunology 182:6562-6568 Cerca con Google

66. Mandruzzato S., Brandau S., Britten C.M., Bronte V., Damuzzo V., Gouttefangeas C., Maurer D., Ottensmeier C., van der Burg S.H., Welters M.J., Walter S. (2016) Toward harmonized phenotyping of human myeloid-derived suppressor cells by flow cytometry: results from an interim study. Cancer immunology immunotherapy 65:161-169 Cerca con Google

67. Macdonald A. and Harris M. (2004) Hepatitis C virus NS5A: tales of a promiscuous protein. Journal of general virology 85:2485-2502 Cerca con Google

68. Maue A.C., Yager E.J., Swain S.L., Woodland D.L., Blackman M.A., Haynes L. (2009) T-cell immunosenescence: lessons learned from mouse models of aging. Trends immunology 30:301-305 Cerca con Google

69. Medina-Echeverz J., Eggert T., Han M., Greten T.F. (2015) Hepatic myeloid-derived suppressor cells in cancer. Cancer Immunology immunotherapy 64:931-940 Cerca con Google

70. Messina J.P., Humphreys I., Flaxman A., Brown A., Cooke G.S., Pybus O.G., Barnes E. (2015) Global distribution and prevalence of hepatitis C virus genotypes. Hepatology 61:77-87 Cerca con Google

71. Millrud C.R., Bergenfelz C., Leandersson K. (2017) On the origin of myeloid-derived suppressor cells. Oncotarget 8:3649-3665 Cerca con Google

72. Moradpour D., Penin F., Rice C. (2007) Replication of hepatitis C virus. Nature Reviews 5:453-463 Cerca con Google

73. Moradpour D. and Penin F. (2013) Hepatitis C virus proteins: from structure to function. Current Topics in Microbiology and Immunology 369:113-142 Cerca con Google

74. Neumann-Haefelin C. and Thiemme R. (2013) Adaptive immune responses in hepatitis C virus infection. Current Topics in Microbiology and Immunology 369:243-262 Cerca con Google

75. Ning G., She L., Lu L., Lu Y., Zeng Y., Yan Y., Lin C. (2015) Analysis of monocytic and granulocytic myeloid-derived suppressor cells subsets in patients with hepatitis C virus infection and their clinical significance. BioMed Research International Vol 15 Cerca con Google

76. Nonnenmann J., Stirner R., Roider J., Jung M.C., Schrodl K., Bogner J.R., Draenert R. (2014) Lack of significant elevation of myeloid-derived suppressor cells in peripheral blood of chronically HCV infected individuals. Journal of Virology 88:7678-7682 Cerca con Google

77. Ostrand-Rosenberg S. and Sinha P. (2009) Myeloid-derived suppressor cells: Linking inflammation and cancer. The Journal of Immunology 182:4499-4506 Cerca con Google

78. Pang X., Song H., Zhang Q., Tu Z., Niu J. (2016) Hepatitis C virus regulates the production of monocytic myeloid-derived suppressor cells from peripheral blood mononuclear cells through PI3K pathway and autocrine signaling. Clinical immunology 164:57-64 Cerca con Google

79. Papagno L., Spina C.A., Marchant A., Salio M., Rufer N., Little S., Dong T., Chesney G., Waters A., Easterbrook P., Dunbar P.R., Shepherd D., Cerundolo V., Emery V., Griffiths P., Conlon C., McMichael A.J., Richman D.D., Rowland-Jones S.L., Appay V. (2004) Immune activation and CD8+ T-cell differentiation towards senescence in HIV-1 infection. PLoS biology 2:E20 Cerca con Google

80. Pawlotsky J.M. (2016) Hepatitis C Drugs: Is Next Generation the Last Generation? Gastroenterology 151:587-90 Cerca con Google

81. Pecheur E.I. (2012) Lipoprotein receptors and lipid enzymes in hepatitis C virus entry and early steps of infection. Scientifica 2012:709-853 Cerca con Google

82. Pham T.N., Coffin C.S., Michalak T.I. (2010) Occult hepatitis C virus infection: what does it mean? Liver international 30:502-11 Cerca con Google

83. Pieczenik S.R. and Neustadt J. (2007) Mitochondrial dysfunction and molecular pathways of disease. Experimental and molecular pathology 83:84-92 Cerca con Google

84. Poordad F., Hezode C., Trinh R, Kowdley K., Zeuzem S., Agarwal K., Shiffman M.L., Wedemeyer H., Berg K., Yoshida E.M., Forns X., Lovell S.S., Da-Silva-Tillmann B., Collins C., Campbell A. Podsadecki T., Bernstein B. (2014) ABT-450/r-ombitasvir and dasabuvir with ribavirin for hepatitis c with cirrhosis. The New England journal of medicine 370:1973-1982 Cerca con Google

85. Rajesh S., Sridhar P., Tews B.A., Fénéant L., Cocquerel L., Ward D.G., Berditchevski F., Overduin M. (2012) Structural basis of ligand interactions of the large extracellular domain of tetraspanin CD81. Journal of Virology 86:9606-9616 Cerca con Google

86. Reig M., Torres F., Mariño Z., Forns X., Bruix J. (2016) Reply to "Direct antiviral agents and risk for hepatocellular carcinoma (HCC) early recurrence: Much ado about nothing". Journal of hepatology 65:864-865 Cerca con Google

87. Ren J.P., Zhao J., Dai J., Griffin J.W.D., Wang L., Wu X.Y., Morrison Z.D. Li G.L., Gazzar M., Ning S.B., Moorman J.P., Yao Z.Q. (2016) Hepatitis C virus-induced myeloid-derived suppressor cells regulate T-cell differentiation and function via the signal transducer and activator of transcription 3 pathway. Immunology 148:377-386 Cerca con Google

88. Ren J.P., Wang L., Zhao J., Wang L., Ning S.B., El Gazzar M., Moorman J.P., Yao Z.Q. (2017) Decline of miR-124 in myeloid cells promotes regulatory T-cell development in hepatitis C virus infection. Immunology 150:213-220 Cerca con Google

89. Rodríguez P.C. and Ochoa A.C. (2008) Arginine regulation by myeloid derived suppressor cells and tolerance in cancer: mechanisms and therapeutic perspectives. Immunological review 222:180-191 Cerca con Google

90. Santos J.M.O., Gil da Costa R.M., Medeiros R. (2018) Dysregulation of cellular microRNAs by human oncogenic viruses - Implications for tumorigenesis. Biochimica et Biophisica acta 1861:95-105 Cerca con Google

91. Scagnolari C., Zingarello P., Vecchiet J., Selvaggi C., Racciatti D., Taliani G., Riva E., Pizzigallo E., Anonelli G. (2010) Differential expression of interferon-induced microRNAs in patients with chronic hepatitis C virus infection treated with pegylated interferon alpha Virology Journal 7:311 Cerca con Google

92. Scheel T.K. and Rice C.(2013) Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nature Medicine 19:837 Cerca con Google

93. Serti E., Chepa-Lotrea X., Kim Y.J., Keane M., Fryzek N., Liang T,J., Ghany M., Rehermann B. (2015) Successful Interferon-Free Therapy of Chronic Hepatitis C Virus Infection Normalizes Natural Killer Cell Function. Gastroenterology 149:190-200 Cerca con Google

94. Sedano C.D. and Sarnow P. (2014) Hepatitis C virus subverts liver-specific miR-122 to protect the viral genome from exoribonuclease Xrn2. Cell Host & Microbe 16:257–260 Cerca con Google

95. Shiryaev S.A., Cheltsov A.V., Strongin A.Y. (2012) Probing of exosites leads to novel inhibitor scaffolds of HCV NS3/4A proteinase. Plos one 7:e40029 Cerca con Google

96. Schoggins J.W. and Rice M. (2013) Innate immune responses to hepatitis C virus. Current Topics in Microbiology and Immunology 369:219-242 Cerca con Google

97. Singaravelu R., Desrochers G.F., Srinivasan P., O'Hara S., Lyn R.K., Müller R., Jones D.M., Russell R.S., Pezacki J.P. (2015) Soraphen A: A Probe for Investigating the Role of de Novo Lipogenesis during Viral Infection. ACS infectious diseases 1:130-134 Cerca con Google

98. Spaan M., Janssen H.L.A., Boonstra A. (2012) Immunology of hepatitis C virus infections. Best practice & Research clinical gastroenterology 26:391-400 Cerca con Google

99. Sohn W., Kim J., Kang S.H., Yang S.R., Cho J.Y., Cho H.C., Shim S.G., Paik Y.H. (2015) Serum exosomal microRNAs as novel biomarkers for hepatocellular carcinoma. Experimental and molecular medicine 47:e184 Cerca con Google

100. Solito S., Marigo I., Pinton L., Damuzzo V., Mandruzzato S., Bronte V. (2014) Myeloid-derived suppressor cell heterogeneity in human cancers. Annals of the new york academy of sciences 1319:47-65 Cerca con Google

101. Steinmann E., Brohm C., Kallis S., Bartenschlager R., Pietschmann T.(2008) Efficient trans-encapsidation of hepatitis C virus RNAs into infectious virus-like particles. Journal of Virology 82:7034-7046 Cerca con Google

102. Sforza F., Nicoli F., Gallerani E., Finessi V., Reali E., Cafaro A., Caputo A., Ensoli B., Gavioli R. (2014) HIV-1 Tat affects the programming and functionality of human CD8? T cells by modulating the expression of T-box transcription factors. AIDS 28:1729-1738 Cerca con Google

103. Syed G.H., Amako Y., Siddiqui A. 2010 Hepatitis C virus hijacks host lipid metabolism. Trends in endocrinology and metabolism 21:33-40 Cerca con Google

104. Tacke R.S., Lee H., Goh C., Courtney J., Polyak S.J., Rosen H.R., Hahn Y.S. (2012) Myeloid suppressor cells induced by hepatitis C virus suppress T-cell responses through the production of reactive oxygen species. Hepatology 55:343-353 Cerca con Google

105. Talmadge J.E. and Gabrilovich D.I. (2013) History of myeloid-derived suppressor cells. Nature reviews 13:739-752 Cerca con Google

106. Thiemme R., Binder M., Bartenschlager R. (2012) Failure of innate and adaptive immune responses in controlling hepatitis C virus infection. FEMS Microbiology Review 36:663-683 Cerca con Google

107. Tian J., Rui K., Wang S. (2014) Roles of miRNAs in regulating the differentiation and maturation of myeloid-derived suppressor cells. Medical hypotheses 83: 151-153 Cerca con Google

108. Waring J.F., Dumas E.O., Abel S., Coakley, Coeh D.E., Davis J.W., Podsadecki T., Dutta S. (2016) Serum miR-122 may serve as a biomarker for response to direct acting antivirals: effect of paritaprevir/R with dasabuvir or ombbitasvir on miR-122 in HCV-infected subjects. Journal of Viral Hepatitis 23:96-104 Cerca con Google

109. Welzel T.M., Dultz G., Zeuzem S. (2014) Interferon-free antiviral combination therapies without nucleosidic polymerase inhibitors. Journal of hepatology 61:98-107 Cerca con Google

110. Xie K.L., Zhang Y.G., Liu J., Zeng Y., Wu H.(2014) MicroRNAs associated with HBV infection and HBV-related HCC. Theranostics 4:1176-1192 Cerca con Google

111. Xu J., Wu C., Che X., Wang L., Yu., Zhang T., Huang L., Li H., Tan., Wang C., Lin D. (2011) Circulating microRNAs, miR-21, miR-122 and miR-223, in patients with hepatocellular carcinoma or chronic hepatitis. Molecular carcinogenesis 50:136-142 Cerca con Google

112. Yamamoto M., Sakamoto N., Nakamura T., Itsui Y., Nakagawa M., Nishimura-Sakurai Y., Kakinuma S., Azuma S., Tsuchiya K., Kato T., Wakita T., Watanabe M. (2011) Studies on virus kinetics using infectious fluorescence-tagged hepatitis C virus cell culture. Hepatology research 41:258-269 Cerca con Google

113. Yau A.H.L.Y. and Yoshida E.M. (2014) Hepatitis C drugs: the end of the pegylated interferon era and the emergence of all-oral, interferon-free antiviral regimens: A concise review. Cancer Journal Gastroenterol Hepatology 28:445-451 Cerca con Google

114. Vukotic R., Di Donato R., Conti F., Scuteri A., Serra C., Andreone P. (2017) Secondary prophylaxis of hepatocellular carcinoma: the comparison of direct-acting antivirals with pegylated interferon and untreated cohort. Journal of Viral Hepatitis 24:13-16 Cerca con Google

115. Zeisel M.B., Fofana I., Fafi-Kremer S., Baumert T.F. (2011) Hepatitis C virus entry into hepatocytes: molecular mechanisms and targets for antiviral therapies. Journal of hepatology 54:566-576 Cerca con Google

116. Zeng Q., Yang B., Sun H., Feng G., Jin L., Zou Z., Zhang Z., Zhang L., Wang F. (2014) Myeloid-derived suppressor cells are associated with viral persistence and downregulation of TCR ? chain expression on CD8+ T cells in chronic hepatitis C patients. Molecules and Cells 37:66-73 Cerca con Google

117. Zhai N., Li H., Song H., Yang Y., Cui A., Li T., Niu J., Crispe I.N., Su L., Tu Z. (2017) Hepatitis C Virus Induces MDSCs-Like Monocytes through TLR2/PI3K/AKT/STAT3 Signaling. Plos one 12:e0170516 Cerca con Google

118. Zhang S., Ouyang X., Jiang X., Dayong G., Lin Y., Kong S.K., Xie W. (2015) Dysregulated serum microRNA expression profile and potential biomarkers in hepatitis C virus-infected patients. International journal of medical sciences 12:590-598 Cerca con Google

119. Zuniga E.I., Macal M., Lewis G.M., Harker J.A.(2015) Innate and Adaptive Immune Regulation During Chronic Viral Infections. Annual review of virology 2:573-597 Cerca con Google

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