Analysis and Modulation of Virus-Host Interaction in Ani

Diabetes, Digestive, Kidney Diseases

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Abstract

Hepatitis C virus (HCV) readily establishes persistent infection in the majority of infected persons, and cannot yet be prevented by vaccines. The small percentage of patients (20-40%) who spontaneously clear the virus and recover from hepatitis C, mount vigorous HCV-specific CD4-positive and CD8-positive T cell responses. Memory T cell responses are maintained for decades after recovery and mediate protective immunity in HCV-recovered chimpanzees upon rechallenge with homologous and heterologous HCV. Unfortunately, most patients (60-80%) do either not mount an HCV-specific CD4-positive and CD8-positive T cell response of sufficient vigor and breadth or their response is rapidly lost during HCV infection. [unreadable] [unreadable] The identification of those factors and mechanisms that contribute o the high incidence of HCV persistence is a field of intense investigation. Most recently, an increased frequency of CD4-positive, CD25-positive T cells has been described in the blood of patients with persistent HCV infection as compared to those who spontaneously cleared HCV. Based on this finding and the observation that in vitro depletion of CD25-positive T cells resulted in increased HCV-specific T cell responsiveness, it has been proposed that CD4-positive, CD25-positive cells contribute to HCV persistence by suppressing HCV-specific T cell responses and that they are absent or less functional after recovery from hepatitis C. The latter conclusion is based on limited information, however, because time and route of infection, length of recovery and genotype sequence of the previously infecting virus are often unknown and not comparable among patients so that the immune status after recovery cannot be precisely assessed. [unreadable] [unreadable] Here, we compare frequency and function of Foxp3-positive, CD4-positive, CD25-positive T cells with regulatory activity (T-Regs) between HCV-recovered and persistently infected chimpanzees, the sole nonhuman species susceptible to HCV infection. The chimpanzees included in this study are well-characterized as regards to the clinical, virological and immunological course of infection, including the demonstration of protective, T-cell based immunity in those chimpanzees that recovered spontaneously. [unreadable] [unreadable] First, we formally demonstrated the presence of CD4-positive, CD25-positive T-Regs that express Foxp3, display hypoproliferation (anergy) and suppress anti-CD3-stimulated proliferation of CD4-positive, CD25-negative T cells in nonhuman primates. It contrast to previous reports in humans, which focus on the role of CD4-positive, CD25-positive T cells in established chronic HCV infection, we show that CD4-positive, CD25-positive T-Regs can also be detected after HCV clearance. Both, the frequency of Foxp3-positive, CD4-positive, CD25-positive T-Reg cells and the extent of suppression, were as high in spontaneously HCV-recovered chimpanzees as in persistently HCV-infected chimpanzees. Foxp3-positive, CD4-positive, CD25-positive T-Reg cells suppressed IFN-gamma-production, expansion and activation-induced cell death of HCV-specific T cells after recovery from HCV infection and in persistent HCV infection. Thus, T-Regs control HCV-specific T cells not only in persistent infection but also after recovery, where they may regulate memory T cell responses by controlling their activation and preventing apoptosis. [unreadable] [unreadable] Second, we demonstrate that Foxp3-positive, CD4-positive, CD25-positive T-Reg cells of both HCV-recovered and HCV-infected chimpanzees differed from Foxp3-positive CD4-positive CD25-positive T-Reg cells of HCV-naive chimpanzees in two important aspects. Specifically, T-Reg cells of chimpanzees that had encountered HCV displayed increased IL-2 responsiveness and lower T cell receptor excision circle content implying a history of in vivo proliferation. This result suggests that HCV infection itself alters the population of Foxp3-positive, CD4-positive, CD25-positive T-Reg cells. The study thereby extends previous data obtained in HCV-infected humans and sets the stage for experimental intervention and modulation of T-Reg activity in this nonhuman primate model.