急性丙型肝炎患者免疫状况的研究

用间接免疫荧光法、酶联免疫吸附试验（ＥＬＩＳＡ）及ＬＤＨ释法，对１６例急性输血后丙型肝炎（抗－ＨＣＶ、ＨＣＶ－ＲＮＡ均阳性）患者，分别进行外周血单个核细胞（ＰＢＭＣ）的Ｔ细胞亚群计数、Ｔ４／Ｔ８比值、Ｔａｃ受体的检测及血清可溶性白细胞介素２受体（ｓＩＬ－２Ｒ）ＮＫ细胞活性的测定。并与正常人组比较，经ｔ检验发现，急性丙型肝炎患者的Ｔ４亚群所占百分比、Ｔ４／Ｔ８比值及ＰＢＭＣＴａｃ受体表达均明显低于正常人组（Ｐ＜０．０５），而ＮＫ细胞活性、血清ｓＩＬ－２Ｒ明显高于正常人组（Ｐ＜０．０５）。患者的这些免疫状态改变，可能对其发病机理的研究有一定意义。     

STUDY ON PERIPHERAL BLOOD MONONUCLEAR CELL(PBMC) PROLIFERATIVE RESPONSES TO DIFFERENT HCV ANTIGENS IN PATIENTS WITH HEPATITIS C

为探讨丙型肝炎（ＨＣ）病人细胞免疫功能和丙型肝炎病毒（ＨＣＶ）的致病机制及机体对其免疫保护作用,收集２４例ＨＣ病人（急性３例,慢性２１例）,用３Ｈ－ＴｄＲ掺入法研究病人外周血单个核细胞（ＰＢＭＣ）对不同ＨＣＶ抗原增殖反应,并用流式细胞仪（ＦＡＣＳ）检测了ＰＢＭＣ中ＣＤ４＋、ＣＤ８＋淋巴细胞亚群在ＨＣＶ抗原刺激后的变化。结果：ＨＣ病人ＰＢＭＣ对ＨＣＶ合成肽ＣＰ９,ＮＳ４和基因重组抗原Ｃ,Ｅ１,Ｅ２,ＮＳ３刺激后出现不同程度增殖反应,刺激指数（ＳＩ）分别为１．６９±０．５１,１．６１±０．５４,１．６８±０．５８,１．４９±０．４４,１．４４±０．４４和１．３３±０．３３。３例急性ＨＣ中２例病人的ＰＢＭＣ对ＨＣＶ抗原呈有效增殖反应（ＳＩ≥２．１）,且血清ＨＣＶＲＮＡ阴转伴ＡＬＴ正常。细胞表型分析显示：增殖的细胞表型是ＣＤ４＋淋巴细胞,而ＣＤ８＋淋巴细胞增殖反应较弱。结论：ＨＣ病人ＰＢＭＣ确实存在对ＨＣＶ抗原的增殖反应;ＣＤ４＋淋巴细胞比ＣＤ８＋淋巴细胞增殖反应要强,急性ＨＣ病人ＰＢＭＣ对ＨＣＶ抗原有效的增殖反应预示可能有良好的临床愈合     

非小细胞肺癌患者放疗前后机体免疫功能变化的研究

目的：报道３０例非小细胞肺癌（ＮＳＣＬＣ）患者放疗前后免疫功能的变化。方法：采用双抗体夹心法和比浊法检测血清中ｓＩＬ－２Ｒ、免疫球蛋白（ＩｇＧ,ＩｇＡ,ＩｇＭ）含量,用单克隆抗体和流式细胞仪技术检测外周血中Ｔ细胞亚群,Ｂ细胞,ＮＫ细胞百分数;与健康人做对照。结果：放疗前ｓＩＬ－２Ｒ显著增高（Ｐ〈０．０１）,ＩｇＧ及ＩｇＭ６亦增高（Ｐ〈０．０５）,Ｂ细胞百分数低于（Ｐ〈０．０１）,ＣＤ３＾＋细胞降低     

系统性硬化病血管内皮活性因子测定的临床意义

目的：从蛋白分子水平探讨血管内皮活性因子同系统性硬化病的关系。方法：选择４２例ＳＳｃ病人采用放射免疫测定法检测血浆内皮素（ＥＴ）、血栓素Ｂ２（ＴＸＢ２）、６－酮－前列腺素Ｆ１α（６－Ｋ－ＰＧＦ１α）,采用Ｇｒｉｓｓ方法检测血浆一氧化氮（ＮＯ）水平,关免疫法检测细胞间粘附分子－１（ＩＣＡＭ－１）、选择素（Ｐ－Ｓ）。结果;所有ＳＳＣ患者均存在高ＥＴ、ＴＸＢ２、ＩＣＡＭ－１、Ｐ－Ｓ血症,存在低ＮＯ、６－     

外周血单个核细胞中乙型肝炎病毒感染的研究进展

乙型肝炎病毒（ＨＢＶ）感染乙肝（ＨＢ）患者外周血单个核细胞（ＰＢＭＣｓ），ＨＢＶ－ＤＮＡ以游离和整合型两种形式存在于ＰＢＭＣｓ内。在ＰＢＭＣｓ内复制与表达。研究ＰＢＭＣｓ内ＨＢＶ感染对于探讨ＨＢ的临床进程、治愈和指导治疗等均具有重要的意义。最近提出了一种与上述相反的观点，ＰＢＭＣｓ内有关的ＨＢＶ－ＤＮＡ和ＲＮＡ是吸附的结果，而非病毒的复制。     

丙型肝炎患者外周血单个核细胞HCV感染的电镜研究

目的 以常规电镜和免疫电镜技术,发现和证实慢性丙型肝炎患者外周血单个核细胞９ＰＢＭＣｓ）内丙型肝炎病毒（ＨＣＶ）颗粒。试图在病毒形态学和形态发生学上证实ＰＢＭＣｓ的ＨＣＶ感染和复制。方法 以逆转录多聚酶链反应（ＲＴ－ＰＣＲ）和免疫组织化学方法,分别检测２８例患者ＰＢＭＣｓ内ＨＣＶ ＲＮＡ和ＨＣＶＡｇ,对其中阳性标本重点进行电镜研究。结果 ＨＣＶ ＲＮＡ和ＨＣＶ Ａｇ阳性检出率分别为７７．２７％（１     

HBcAg/HBeAg对慢性乙型肝炎患者PBMC中Th1/Th2类细胞应答的影响

目的 探讨ＨＢｃＡｇ／ＨＢｅＡｇ对慢性乙型肝炎患者ＰＢＭＣ中Ｔｈ１／Ｔｈ２类细胞应答的影响。方法 用套式ＰＣＲ法检测６４便慢性ＨＢＶ感染者ＰＢＭＣ中ＨＶＢ ＤＮＡ;分别用ＰＨＡ、ＨＢｃＡｇ和ＨＢｅＡｇ体外培养;ＥＬＩＳＡ法检测ＰＢＭＣ产生Ｔｈ１类细胞因子（ＩＬ－２、ＩＦＮ－γ）和Ｔｈ２类细胞因子（ＩＬ－４、ＩＬ－１０）的含量。结果 表明ＨＢＶ ＤＮＡ阳性组和阴性组相比,无论是在ＰＨＡ还是在ＨＢｃＡ     

髓磷脂碱性蛋白促进单个核细胞对内皮细胞的粘附效应

目的：探讨ＭＢＰ对外周血单个核细胞（ＰＢＭＮＣ）与人脐静脉内皮细胞（ＨＵＶＥＣ）粘附性的影响,以揭示中枢神经系统（ＣＮＳ）炎症时ＰＢＭＮＣ进入ＣＮＳ的可能原因。方法：用细胞粘附试验,研究ＰＢＭＮＣ与ＨＵＶＥＣ的粘附性,用细胞免疫化学法、ＦＡＣＳ分别观察ＶＣＡＭ－１和ＩＣＡＭ－１的表达。结果：ＭＢＰ活化的ＰＢＭＮＣ与ＭＢＰ刺激的ＰＢＭＮＣ培养上清作用的ＨＵＶＥＣ的粘附性较对照有显著提高。ＩＣＡＭ＿１     

丙型肝炎病毒非结构区抗原制备及其相应抗体的检测

目的 研究丙型肝炎病毒非结构区３（Ｈｅｐａｔｉｔｉｓ Ｃ ｖｉｒｕｓ ｎｏｎｓｔｒｕｃｔｕｒｄ ｒｅｇｉｏｎ３,ＨＣＶ－ＮＳ３）与丙型肝炎发病的关系,寻求一种可用于判断临床干扰素（Ｉｎｔｅｒｆｅｒｏｎ,ＩＦＮ）治疗疗效的检测方法。方法 采用基因重组,以大肠埃岙菌表达,提取ＨＣＶ－ＮＳ３不同末端蛋白作为抗原,并回顾性的对ＩＦＮ治疗的６３例ＨＣＶ－ＲＮＡ阳性的丙型肝炎患者血清用免疫印迹（Ｗｅｓｔｅｒｎ     

人巨细胞病毒感染对肾移植受者血清sIL－2R水平的影响

用ＰＣＲ检测ＨＣＭＶ－ＤＮＡ，ＥＬＩＳＡ法检测ＨＣＭＶ－ＩｇＭ及ＩｇＧ，以诊断肾移植受者ＨＣＭＶ感染。用双抗体夹心法ＥＬＩＳＡ检测６５例肾移植受者血清ｓＩＬ－２Ｒ水平，结果表明：ＨＣＭＶ感染后宿主血清ｓＩＬ－２Ｒ水平明显增高（Ｐ＜０．０１），且ＨＣＭＶ疾病组ｓＩＬ－２Ｒ增高程度大于无症状感染组（Ｐ＜０．０１）；６例原发性ＨＣＭＶ感染者ｓＩＬ－２Ｒ水平与ＩｇＭ水平呈正相关（ｒ＝０．９９０８），提示随感染程度增加，血清ｓＩＬ－２Ｒ水平随之增高，还发现血清ｓＩＬ－２Ｒ水平与Ｃ９４／ＣＤ８比值是负相关（ｒ＝－０．９７８９），说明ＨＣＭｖ感染后ｓＩＬ－２Ｒ水平增高与Ｔ细胞亚群改变有关，反之也说明ｓＩＬ－２Ｒ增高程度可表明体内免疫抑制状态。对于ＨＣＭＶ感染后血清ｓＩＬ－２Ｒ水平增高的机理有待进一步探讨。     

血清中丙型肝炎NS3抗原ELISA检测方法的建立和初步应用

目的 评价血清中丙型肝炎病毒(HCV)游离NS3抗原的酶联免疫吸附(ELISA)检测方法的特异性和灵敏度,初步探讨该方法在临床应用中的意义.方法 对77例正常人血清标本,173例抗-HCV阳性标本和3708例抗-HCV阴性的其他类型肝炎血清标本检测HCV游离NS3抗原;对部分HCV NS3抗原阳性标本进行验证,包括HCV RNA测定、中和试验和免疫斑点试验;对11例患者的25份系列血清标本进行了HCV游离NS3抗原、HCV RNA和HCV抗体的联合检测,并结合临床资料综合分析.结果 3708例抗-HCV阴性的其他类型肝炎血清标本中有48例为HCV NS3抗原阳性,其中3030例单纯乙型肝炎和445例其他类型肝炎血清标本中分别有44例和4例为HCV NS3抗原阳性;173例HCV抗体阳性标本中有42例为HCV NS3抗原阳性;77例正常人血清标本的HCV NS3抗原检测结果均为阴性;15例HCV NS3抗原阳性标本中有9例为HCV RNA阳性;23例HCV NS3抗原阳性标本的中和率和免疫斑点试验的阳性率分别为87.0%和69.6%;25份系列血清标本的检测结果显示其HCV NS3抗原的吸光度值与时间呈负相关,并有2例HCV NS3抗原阳性标本随着血清中HCV NS3抗原的吸光度值下降,其HCV抗体转阳.结论 血清中HCV游离NS3抗原的ELISA检测方法有较好的特异性和敏感度,在发展中国家应用此方法进行HCV感染的早期诊断有一定的临床意义和推广价值.     

STUDY ON PERIPHERAL BLOOD MONONUCLEAR CELL(PBMC) PROLIFERATIVE RESPONSES TO DIFFERENT HCV ANTIGENS IN PATIENTS WITH HEPATITIS C

为探讨丙型肝炎(HC)病人细胞免疫功能和丙型肝炎病毒(HCV)的致病机制及机体对其免疫保护作用,收集24例HC病人(急性3例,慢性21例),用3H-TdR掺入法研究病人外周血单个核细胞(PBMC)对不同HCV抗原增殖反应,并用流式细胞仪(FACS)检测了PBMC中CD4+、CD8+淋巴细胞亚群在HCV抗原刺激后的变化.结果:HC病人PBMC对HCV合成肽CP9,NS和基因重组抗原C,E1,E2,NS3刺激后出现不同程度增殖反应,刺激指数(SI)分别为1.69±0.51,1.61±0.54,1.68±0.58,1.49士0.44,1.44±0.44和1.33±0.33.3例急性HC中2例病人的PBMC对HCV抗原呈有效增殖反应(SI≥2.1),且血清HCVRNA阴转伴ALT正常.细胞表型分析显示:增殖的细胞表型是CD4+淋巴细胞,而CD8+淋巴细胞增殖反应较弱.结论:HC病人PBMC确实存在对HCV抗原的增殖反应;CD4+淋巴细胞比CD8+淋巴细胞增殖反应要强,急性HC病人PBMC对HCV抗原有效的增殖反应预示可能有良好的临床愈合.     

Fiber-modified recombinant adenoviral constructs encoding hepatitis C virus proteins induce potent HCV-specific T cell response

Hepatitis C virus (HCV)-specific cytotoxic T lymphocytes (CTLs) play an important role in HCV clearance. The frequency of HCV-specific T(CD8) in peripheral blood of HCV-infected donors is very low and HCV cannot be cultivated for reinfection of antigen presenting cells, making it difficult to detect T(CD8) of broad HCV specificities from peripheral blood mononuclear cells (PBMCs). We have developed a recombinant adenoviral system that efficiently reactivates and expands HCV-specific CTLs from PBMCs of HCV-infected donors. Replication-incompetent adenoviruses expressing individual HCV proteins (core and NS3) were produced and PBMCs from HCV-infected donors were transduced with these recombinant adeno-HCV constructs to stimulate HCV-specific CTL populations. T cells expanded from adeno-HCV stimulated cultures were potent producers of HCV-specific IFN-gamma and TNF-alpha and efficiently lysed target cells pulsed with HCV peptides. These constructs could stimulate T(CD8) directed towards multiple HCV peptides while preserving the determinant hierarchy. This approach therefore overcomes some of the shortcomings of the selective expansion of CTLs with peptide-based vaccine strategies. These findings provide an effective approach for the expansion of HCV-specific CTLs from PBMCs of HCV-infected patients and have potential for immunotherapeutic/vaccine development.     

小儿慢性丙型肝炎外周血T细胞亚群和TH1/TH2型细胞因子的研究

目的通过研究小儿慢性丙型肝炎外周血T细胞亚群及TH1/TH2型细胞因子的表达,进一步探讨小儿慢性丙型肝炎的免疫发病机制。方法(1)流式细胞仪(FACS)检测16例慢性丙型肝炎患儿及10例正常对照外周血T细胞亚群。(2)将慢性丙型肝炎患儿和正常对照外周血单个核细胞(PBMC)体外培养72h后,用ELISA法检测培养上清中TH1型细胞因子(IFN-γ、IL-2、IL-12和TNF-γ)和TH2型细胞因子(IL-4、IL-10)的浓度。结果(1)CD4 细胞无明显变化。CD8 细胞与正常对照比较明显升高(P<0.05)。CD3 细胞升高,CD4 /CD8 比值下降,但与正常对照比较无统计学意义(P>0.05)。(2)PBMC培养上清中IFN-γ、IL-10和TNF-α的水平明显升高(P<0.01),而没有检测到IL-2、IL-4、IL-12的基础分泌。结论慢性丙型肝炎患儿体内T淋巴细胞存在数量和功能的异常,CD8 细胞数升高,CD4 细胞功能异常,表现在以TH2型细胞因子的分泌为主。这可能与丙肝病毒(HCV)感染的慢性化有关。     

CD4+/CD8+ ratio of liver-derived lymphocytes is related to viraemia and not to hepatitis C virus genotypes in chronic hepatitis C.

The pathogenic mechanisms that lead to chronic hepatitis C are unknown. As hepatitis C virus (HCV) has been shown to induce T cell response, we assessed whether a particular T lymphocyte subset could be preferentially detected in the liver of patients with chronic hepatitis C in relation to viraemia or HCV genotypes. The immunophenotypes of liver-derived lymphocytes were analysed in 26 patients by flow cytometry and immunohistochemistry. Viraemia was quantified by branched DNA assay. Using this assay, HCV RNA was not detectable in six patients. HCV RNA was detected in 20 patients, and titres ranged from 8 to 137 x 10(6) Eq/ml. Genotyping was performed using a line probe assay. Type 1a, 1b, 2a, 3a and 4a were found to infect 2, 10, 2, 7 and 3 patients, respectively. The CD4+/CD8+ ratio of liver-derived lymphocytes was significantly higher (P < 0.01) in patients with detectable viraemia than in patients without detectable viraemia. In contrast, neither the percentage of gamma/delta T lymphocytes nor that of CD2+CD57+ cells was different in the groups. When comparing the CD4+/CD8+ ratio, the percentage of gamma/delta T lymphocytes or CD2+CD57+ cells according to genotype, the differences were not significant. These results suggest that the CD4+/CD8+ ratio of liver-derived lymphocytes is related to viraemia but not to HCV genotypes in patients with chronic hepatitis C, and that T lymphocytes may be involved in the pathogenesis of liver lesions in chronic hepatitis C.     

The use of class-I HLA tetramers for the detection of hepatitis C virus NS3-specific CD8(+) T cells in patients with chronic infection

BACKGROUND/AIMS: New methods to detect virus-specific T-cell responses have recently been developed. Several human leukocyte antigen (HLA)-peptide tetramers for the detection of hepatitis C virus (HCV)-specific CD8(+) T cells are under evaluation. METHODS: Evaluation of one HLA class I-tetramer (HCVNS3-2) for the detection of HCV NS3-specific CD8(+) T cells in a series of 38 HLA-A2(+) chronically infected patients. RESULTS: Almost half (42%) of the patients had detectable NS3-specific CD8(+) T cells. The frequencies of such cells ranged from 0.01% to 0.22% of total CD8(+) T cells. No significant differences in clinical features or mean viral load were detected between patients with or without tetramer + CD8(+) T cells. CONCLUSIONS: The tetramer HCVNS3-2 may be very useful for the study of the HCV-specific CD8(+) immune response. Combination of this reagent with other tetramers based on other HCV peptides may help in the understanding of the immune response to the virus. However, a panel of tetramers based on several parts of the HCV polyprotein may be a mandatory requirement to explore the whole breadth of the CD8(+) T-cell response against HCV and to detect that response in the majority of patients with chronic infection.     

Lack of evidence for the Th2 predominance in patients with chronic hepatitis C

A T helper (Th)1 to Th2 shift has been proposed to be a critical pathogenic determinant in chronic hepatitis C. Here, we evaluated mitogen-induced and hepatitis C virus (HCV) core antigen-induced cytokine production in 28 patients with biopsy-proven chronic hepatitis C. Flow cytometry demonstrated that after mitogenic stimulation the percentage of Th2 cells (IL-4 + or IL-13 +) and Th0 cells (IFN-gamma/IL-4 + or IL-2/IL-13 +) did not differ between patients and controls. In contrast, the percentage of Th1 cells (IFN-gamma + or IL-2 +) was significantly increased in CD4 +, CD8 +, 'naive'-CD45RA + and 'memory'-CD45RO + T-cell subsets from patients versus controls. Similar results were obtained by ELISA testing supernatants from mitogen-stimulated, unfractionated peripheral blood mononuclear cell (PBMC) cultures. Interferon-alpha treatment was associated with a reduction in the mitogen-induced Th1 cytokine response in those patients who cleared their plasma HCV-RNA. Analysis of cytokine expression by CD4 + T cells after HCV core antigen stimulation in a subgroup of 13 chronic hepatitis C patients demonstrated no cytokine response in 74% of these patients and an IFN-gamma-restricted response in 26%. Finally, no Th2 shift was found in lipopolysaccharide-stimulated monocytes. These data indicate that a Th1 to Th2 shift does not occur in chronic hepatitis C.     

CD28–Negative CD8–Positive Cytotoxic T Lymphocytes Mediate Hepatocellular Damage in Hepatitis C Virus Infection

The pathogenic mechanism for hepatocellular damage in hepatitis C virus (HCV) infection has not been clearly understood. Analysis of costimulatory molecules on lymphocytes may give us insight into the pathogenic mechanism of hepatocellular damage in HCV infection. Peripheral blood mononuclear cells (PBMCs) and liver infiltrating mononuclear cells (LIMCs) isolated from the HCV-infected patients were analyzed with antibodies directed against a variety of costimulatory molecules by flow cytometry. Blocking experiment against HLA-A24-restricted HCV-specific CTLs and immunohistochemical analysis were also performed. PBMCs expressing CD8, CD28, CD80, or CD154 were significantly reduced in HCV-infected patients compared with the healthy controls. CD28(+)CD8(+) PBMCs in the patients inversely correlated with ALT levels. Conversely, levels of CD28(-)CD8(+) LIMCs correlated with ALT levels. HCV-specific CTL activity was blocked by the treatment with anti-CD8 antibody, but not with anti-CD4 or anti-CD28 antibody. Immunohistochemical analysis revealed the accumulation of CD28(+) cells around the portal area in the liver of a patient with chronic active hepatitis C. These results suggest that CD28(+)CD8(+) T cells leave the circulation, move to the livers, and are activated in the portal area in proportion to the extent of liver diseases. CD28(-)CD8(+) T cells may finally function as effector T cells causing the hepatocellular damage in HCV infection.     

Hepatitis C virus (HCV) infection of peripheral blood mononuclear cells in patients with type II cryoglobulinemia

Objectives

Type II cryoglobulinemia is a common extrahepatic manifestation of chronic hepatitis C virus (HCV) infection. The mechanisms behind its development are unclear, but could be related to direct infection of the immune cells.

Methods

Peripheral blood mononuclear cells from 18 patients with type II cryoglobulinemia were separated into CD3+ (T cells), CD19+ (B cells) and CD14+ (monocytes) and analyzed for the presence of negative strand HCV RNA, which is a viral replicative intermediate, and for the presence of HCV non-structural protein 3 (NS3). Control group consisted of 182 consecutive chronic hepatitis C patients prior to initiation of antiviral therapy.

Results

Negative strand HCV RNA was detected in PBMC from six (33.3%), patients and in 15 (8.2%) controls (p < 0.01). Negative strand was most frequently detected in B cells (3 patients), followed by T cells (2 patients), and monocytes (2 patients). One patient was positive both in CD3+ and CD14+ cells. NS3 protein was detected in six (33.3%) patients; five were positive in T cells, three in B cells, and another three were positive in monocytes. Two patients were positive in all analyzed cell subpopulation and one patient was positive in CD14+ and CD19+ cells, but not in CD3+ cells. Altogether, 11 patients (61.1%) were positive either for the negative strand HCV RNA or NS3 protein in at least one of the analyzed cell compartments.

Conclusion

Our findings of common presence of viral replication in cells of the immune system suggest that direct HCV infection could play a role in the etiology of cryoglobulinemia.     

Lack of optimal T-cell reactivity against the hepatitis C virus is associated with the development of fibrosis/cirrhosis during chronic hepatitis

Chronic hepatitis C virus (HCV) infection develops in 85% of exposed individuals and 20% develop cirrhosis. However, the pathogenesis of this process is not well-understood. The objective of this study was to determine whether HCV-reactive T cells play a role in the process of development of cirrhosis during chronic HCV infection. We analyzed 21 human leukocyte antigen (HLA)-A2 patients with chronic HCV infection (9 with histology of inflammation and 12 with histology of fibrosis/cirrhosis). The frequency of CD8(+) T cells reactive to 12 HCV-derived epitopes was determined by an interferon-gamma enzyme-linked immunospot (ELISPOT) assay. The frequency of CD4(+) Th1 and Th2 cells reactive to the HCV core antigen was determined by interferon-gamma and interleukin-5 ELISPOT assays, respectively. Patients with histology of inflammation showed a significantly higher CD8(+) T-cell response to five HCV-derived epitopes (YLLPRRGPRL [core], CINGVCWTV [NS3], LLCPAGHAV [NS3], ILAGYGAGV [NS4B], and GLQDCTMLV [NS5B]) as compared with patients with histology of fibrosis/cirrhosis. Also, patients with histology of inflammation showed a significantly higher CD4(+) Th1 response to the HCV core antigen as compared to patients with histology of fibrosis/cirrhosis. These results indicate that a lack of an optimal T-cell response to HCV is associated with the development of cirrhosis during chronic HCV infection.