Evidence for a relation between the viral load and genotype and hepatitis C virus-specific T cell responses☆
Introduction
It is well documented that viral load and genotype are strong predictors for the outcome of antiviral therapy in patients with chronic hepatitis C virus (HCV) infection. This is true also for the most recent regimens including pegylated interferons in combination with ribavirin [1]. However, the factors that control the viremia in untreated and treated patients with chronic HCV infections are poorly understood, and generally the immune response during chronic infection is rather weak [2]. In contrast, the resolution of an acute HCV infection has been shown to correlate with the presence of a vigorous and multi-specific host T cell response to HCV [3], [4]. Recent data suggest that the clearance of acute HCV infection in chimpanzees may be less dependent on the T cell response [5]. Another report suggests that the memory CD8+ T cell response is crucial for a rapid clearance of an acute HCV infection [6]. These different observations suggest that the exact role of the T cell response is still not fully understood. Antiviral therapy initiated during acute HCV infections prevents the development of chronic infection in almost 100% [7].
No direct association between the viral load and the host immune response has been documented during chronic HCV infection [8], whereas the development of a vigorous T cell response has been correlated with clearance of the virus [9]. During therapy of chronic HCV infection several factors seem to have an influence on the viral replication rate. Kinetic studies show that alpha-interferon (αIFN) has a pronounced and direct effect on the replication of HCV [10], and have revealed that the half-life of serum HCV RNA is in the order of 2–3 h [11]. The decline in HCV RNA levels during antiviral therapy with αIFN alone, or in combination with ribavirin, is characterized by two distinct phases [10], [12], [13]. The first phase represents an initial rapid decline in viral replication, mainly reflecting a block of the HCV replication, and a rapid clearance of the virus from serum [10], [12], [13]. This is followed by a slower decline-phase that starts on the second or third day of treatment. The latter phase is thought to reflect the elimination of infected hepatocytes [10], possibly mediated by the host immune response [14]. Direct experimental evidence to substantiate this hypothesis, has as yet not been provided. It is well known that the HCV genotype is a strong predictor for the response to antiviral therapy and the rate at which the viral load declines [12].
Clearance of HCV infected cells, or the shutting down of HCV replication, may be mediated by either CD4+ or CD8+ T cells or by natural killer (NK) or NKT cells. In a chimpanzee model of hepatitis B virus infection it has been shown that all these cell types can block viral replication [15], [16], [17]. There is also evidence that T cell responses to HCV during antiviral therapy may be more complex than anticipated [18].
The present study aimed to determine if an association exists between host immune response in peripheral blood and the viral genotype or to the decline in viral load during antiviral therapy.
Section snippets
Patients
A total of 71 non-treated patients with documented chronic HCV infections were included in this survey. Another 37 patients treated with recombinant interferon alpha-2b or natural leukocyte interferon alpha, alone or in combination with ribavirin, were sampled at different time points during treatment to measure viral load and NS3-specific lymphoproliferation. In 32 of these 37 patients at least four successful proliferation assays per patient were performed during the initial 12 weeks of
Relation between the proliferative responses to NS3 and the viral genotype in patients not receiving antiviral therapy
The baseline proliferation to recombinant NS3 protein of HCV genotype 1 was determined in 71 consecutive patients with chronic HCV infection sampled while not receiving any type of treatment. Of these 71 patients, 35 were infected with HCV genotype 1, 23 with genotype 2, and 13 with genotype 3. A proliferative response was detected in 18 (25%) out of the 71 patients. An NS3-specific proliferative response occurred significantly more frequently in patients infected with HCV genotype 3 than in
Discussion
Detailed studies have shown that there is a correlation between the clearance of acute HCV infections and a strong proliferative HCV-specific T cell response in PBMC [3], [4]. After clearance of the infection, these proliferating cells may remain in the periphery for long periods, which is consistent with the memory T cells [24]. New data also show that early treatment of acute HCV infections leads to clearance of the infection in the vast majority of patients [7], [25]. Much less is known
Acknowledgements
The study was supported by grant number K2000-06X-12617-03A from the Swedish Science Council, and by grant number QLK2-1999-00588 from the European Community.
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The authors declare that they have not a relationship nor did they receive any funding from the manufacturers of the drugs involved to carry out the study.