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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)


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)


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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