Early viraemia clearance during antiviral therapy of chronic hepatitis C improves dendritic cell functions
Introduction
It is estimated that 170 million people worldwide are chronically infected with the hepatitis C virus (HCV), one of the principal causes of chronic hepatitis, cirrhosis and hepatocellular carcinoma [1], [2]. Some individuals are able to clear HCV spontaneously during acute HCV infection by mounting vigorous cellular immune responses directed to multiple HCV antigens [1], [3], [4], [5], [6]. However in the great majority of patients viraemia persists, associated with impaired HCV-specific T-cell reactivity [6], [7]. The mechanisms by which HCV establishes chronic infection are not fully understood.
Dendritic cells (DC), the most potent antigen presenting cells, have a critical role in the initiation of adaptive immune responses [8], [9], [10]. Consequently, DC functions are targeted by numerous viruses in order to disrupt the generation of efficient antiviral cellular immune responses [11], [12], [13], [14], [15], [16], [17]. In HCV infection, several studies, using monocyte-derived DC (MDDC), have suggested that dysfunctional DC are responsible for the impaired Th1 response [18], [19], [20], [21], [22], [23], [24]. However, other authors found no significant defects in the phenotype and function of MDDC generated from patients with chronic hepatitis C (CHC) [25], [26], [27], [28]. Similarly, controversial findings have been reported when using circulating myeloid or plasmacytoid dendritic cells, directly isolated from peripheral blood [27], [29], [30], [31], [32].
In the present study we investigated viraemia levels and MDDC functions and phenotype before treatment and early during antiviral therapy, trying to understand the role of DC in CHC. Our working hypothesis was that ‘early’ (by week 12 of treatment, TW12) clearance of viraemia and subsequent viral antigen loss leads to improvement of dendritic cell functions, promoting HCV-specific Th1 responses in the host. We further investigated whether improved adaptive immune response after ‘early’ viraemia clearance is due to restored DC function, or to improvement of CD4+ T-cell reactivity. In addition, we tested the relation between the presence of HCV genomic sequences and proteins (in particular HCV core) in patients' plasma and in DC lysates, and DC functions and phenotype.
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Patients
Thirty-five consecutive (n = 35), treatment-naïve patients with chronic hepatitis C, monitored at the Hepatitis Clinic, University College Hospital, London, were enrolled in the study (Table 1) after giving informed consent. All patients were positive for anti-HCV and HCV RNA (Amplicor HCV v2.0; Roche Molecular Systems, Pleasanton, CA). The HCV genotype was determined by a restriction–fragment–length–polymorphism method [33]. All patients were tested negative for HBsAg and antibodies against
Results
MDDC from CHC patients and healthy controls were tested both as ‘immature’ DC and as ‘mature’ DC following stimulation with LPS. ‘Immature’ DC from healthy controls showed a trend for higher allostimulatory capacity than MDDC from CHC patients (P = 0.063) (data not shown).The difference between the two groups was significant when testing ‘mature’ DC from the same subjects (P = 0.015) (Fig. 1).
Using ultra-sensitive PCR methodology (RT-PCR NAH), the positive strand of HCV RNA was detected in MDDC
Discussion
The mechanisms that HCV uses to down-regulate antiviral immunity, thus promoting HCV persistence, are still not well defined. To gain a better understanding, we investigated the impact of MDDC phenotypic and functional changes in relation to early on-treatment viraemia clearance on CD4+ T-cell reactivity, extending previous findings that rapid viraemia clearance is associated with enhanced HCV-specific, T-cell responses [36]. We demonstrated that in patients who cleared the virus by TW12, the
Acknowledgment
This study was funded in part by a research grant from Schering-Plough, Welwyn Garden City, United Kingdom.
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- 1
Currently in the Department of Gastroenterology and Hepatology, 424 Army General Teaching Hospital of Thessaloniki.
- 2
Current address is Immunology and Infectious Diseases, Novartis Pharma AG, CH-4002 Basel, Switzerland.