Clinical implications of chemokines in acute and chronic hepatitis C virus infection

Hepatitis C virus (HCV), a non-cytopathic positive-stranded RNA virus, is one of the most common causes of chronic liver diseases such as chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. Upon HCV infection, the majority of patients fail to clear the virus and progress to chronic hepatitis C. Chemokines are small chemotactic cytokines that direct the recruitment of immune cells and coordinate immune responses upon viral infection. Chemokine production during acute HCV infection contributes to the recruitment of immune cells with antiviral effector functions and subsequent viral clearance. In chronic HCV infection, however, continuous production of chemokines due to persistent viral replication might result in incessant recruitment of inflammatory cells to the liver, giving rise to persistence of chronic inflammation and liver injury. In this review, we will summarize the roles of chemokines in acute and chronic settings of HCV infection and the clinical relevance of chemokines in the treatment of hepatitis C.     

Low expression of erythrocyte complement receptor type 1 in chronic hepatitis C patients

Primate erythrocyte complement receptor type 1 (CR1) plays an essential role in complement-associated immune complex clearance by transporting complexes to macrophages in the liver and/or spleen. Antibody-bound hepatitis C virus, which consists of immune complexes, is observed in patients with chronic hepatitis C. The aim of this study was to clarify the pathophysiological roles of erythrocyte CR1 in hepatitis C virus-infected individuals. We quantified the expression of erythrocyte CR1 with a fluorescence-activated cell sorter system in 57 chronic hepatitis C and 37 chronic hepatitis B cases and 20 normal volunteers. Complement-bound immune complexes were quantified by means of an enzyme-linked immunosorbent assay using anti-C1q and anti-C3d antibodies. Hepatitis C virus-infected patients showed lower erythrocyte CR1 and higher C3d immune complex levels than volunteers (P < 0.01 and P < 0.05, respectively). An inverse correlation was observed between the erythrocyte CR1 and C3d immune complex levels in hepatitis C virus infection (r = - 0.300, P = 0.032). The erythrocyte CR1 levels in hepatitis C virus infection were lower in patients with severe liver inflammation, cirrhosis, or hepato-cellular carcinoma than in those with mild inflammation, whereas the levels did not differ regardless of the disease stage in hepatitis B virus infection. These findings demonstrate that the expression of erythrocyte CR1 is related to immune complex quantity and the severity of liver disease in hepatitis C virus infection. © 1996 Wiley-Liss, Inc.     

Circulating immune complexes in chronic hepatitis C

For assessing the role of circulating immune complexes (CIC) in chronic hepatitis C, the relative frequency of CIC was determined in 54 patients with chronic hepatitis C, 15 asymptomatic hepatitis C virus (HCV) carriers, and 54 healthy controls. IgM and IgG containing CIC were studied using both Clq and conglutinin (K) in an immunoglobulin-specific solid-phase enzyme immunoassay. CIC were a common feature of chronic hepatitis C with 96.3% of patients with at least one abnormal test result. The prevalence of elevated IgG-K, IgM-K, IgG-C1q, and IgM-C1q CIC was 70.3%, 50.0%, 64.8%, and 35.1%, respectively. The prevalence of IgG class CIC was higher than IgM class CIC (P = 0.038 for K-CIC and P = 0.01 for C1q-CIC, respectively). There is correlation between IgG-K CIC and IgG-C1q CIC (r = 0.445, P= 0.0021, IgG-K CIC and ISM-Clq CIC (r = 0.348, P = 0.020). IgM-K CIC and aspartic arninotransferase (r = 0.321, P= 0.015). IgM-K CIC and alanine aminotransferase (r =0.301, P = 0.027). Compared to patients with chronic persistent hepatitis and chronic lobular hepatitis, patients with chronic active hepatitis have a higher prevalence of elevated IgG-K CIC (77.2% vs. 40.0%, P = 0.029) and IgM-K CIC (56.8% vs. 20.0%, P = 0.038). The concentration of IgG-K, IgM-K, and IgM-C1q CIC in the former was significantly higher than that in the latter, respectively. In conclusion, IgG class CIC is the major type of CIC in chronic hepatitis C. Conglutinin-binding CIC correlates with more severe tissue damage. CIC may play a role in the pathogenesis of chronic hepatitis C. © 1995 Wiley-Liss, Inc.     

Autoimmune forms of chronic hepatitis associated with hepatitis C virus (HCV) infection with and without HCV-RNA: histological differences from pure autoimmune hepatitis and chronic hepatitis C

Liver biopsy specimens of pure autoimmune hepatitis (pAIH), autoimmune forms of chronic hepatitis with positivity for anti-hepatitis C virus (anti-HCV) and negativity for HCV-RNA (cAIH-RNA(-)), autoimmune forms of chronic hepatitis with positivity for anti-HCV and HCV-RNA (cAIH-RNA(+)), and chronic hepatitis C (CHC) were compared histologically and statistically to clarify the histological character of the autoimmune form of chronic hepatitis with HCV infection. The following representative histological features were used to investigate: inflammation, fibrosis, plasma cell infiltration, lymphoid aggregates/follicles, non-suppurative destructive cholangitis, and the shape of the enlarged portal tracts. While a considerable overlap in histological features between the pAIH and cAIH-RNA(-) groups and between the CHC and cAIH-RNA(+) groups was recognized, the overlap between the pAIH and CHC groups was small. Significant differences were found between cAIH-RNA(-) and cAIH-RAN(+) groups, especially in necroinflammatory findings. In conclusion, most cases of cAIH-RNA(-) with histological features similar to those of pAIH were shown to be AIH. The remaining cases might be CHC with subsidence of viral duplication. Conversely, many cases of cAIH-RNA(+) with histological findings similar to those of CHC were shown to be CHC clinically mimicking pAIH. The remaining cases might represent coexistence of pAIH and HCV infection.     

Concurrent hepatitis C virus and hepatitis delta virus superinfection in patients with chronic hepatitis B virus infection.

Since hepatitis C virus (HCV) and hepatitis delta virus (HDV) are transmitted by the same routes as hepatitis B virus (HBV), simultaneous or concurrent HCV and HDV infection in patients with chronic HBV infection may occur. To test this hypothesis and to examine the clinicohistological and immunopathological presentations of such multiple hepatitis virus infections, acute and/or convalescent serum specimens from 86 patients with acute HDV superinfection were tested by enzyme immunoassay for antibodies to HCV. Of the 86 patients, 18 (20.9%) were associated with HCV infection. Although patients with early mortality cannot be evaluated by the HCV markers used in this study, the results showed that the clinical and histologic features were similar except that patients with HCV infection were older than those without HCV infection (P less than 0.01). Immunopathological studies carried out within 2 months after the onset of acute HDV superinfection demonstrated that hepatitis B core antigen (HBcAg) was not detected in any patient and HDV antigen was detected in 18.2% of the patients with HCV infection whereas HBcAg and HDAg were found in 7% and 65.1%, respectively, of those without HCV coinfection (P less than 0.02). It is concluded that concurrent HCV and HDV superinfections can and do occur in patients with chronic HBV infection. In these triple viral infections, HCV may even transiently suppress HDV and HBV.     

The association between indirect bilirubin levels and liver fibrosis due to chronic hepatitis C virus infection

We proposed to evaluate the association between serum indirect bilirubin levels and liver fibrosis in patients with chronic hepatitis C (CHC) genotype 1b. Biopsy proven CHC genotype 1b patients’ demographics, clinical and histopathological characteristics were evaluated. Logistic regression analysis was done to evaluate the clinical, laboratory and demographic features of the histologically proven liver fibrosis in CHC patients. A total of 112 biopsy proven CHC genotype 1b patients were enrolled into the study. Liver fibrosis scores were measured by using Ishak fibrosis scores and were divided into two groups; fibrosis scores ≤2 were categorized as mild fibrosis, 82 patients (73.2%), whereas fibrosis scores >2 were categorized as advanced fibrosis group, 30 patiens (26.8%). Patients with advanced fibrosis had lower indirect bilirubin levels than the mild fibrosis group (0.28 ± 0.02 mg/dl vs. 0.44 ± 0.032 mg/dl, p < 0.001, respectively). Indirect bilirubin level was negatively correlated with advanced fibrosis scores (r = −0.416 and p < 0.001). In multivariate logistic regression analysis, low indirect bilirubin level was an independent predicting factor of advanced liver fibrosis (OR: 0.001, 95% CI: 0.0–0.005, p < 0.001). There is an inverse relationship between indirect bilirubin levels and advanced liver fibrosis caused by CHC genotype 1b.     

Immunoglobulin and hepatitis B surface antigen-specific circulating immune complexes in chronic hepatitis with hepatitis delta virus infection

IgM, IgG, and HBsAg containing circulating immune complexes (CIC) were determined, by conglutinin (K) and C1q assays, for assessing the role of CIC in hepatitis delta virus (HDV) infection in 54 HBsAg-negative controls and 85 HBsAg-positive patients with chronic hepatitis. The prevalence of HDV markers (HDV antigen and anti-HD) was 24.70% (21/85). CIC were a common feature of HDV infection with 95.24% of patients having at least one abnormal test resutlt. The prevalence of elevated IgM-K, IgG-K, IgM-C1q, and IgG-C1q CIC were 85.71, 85.71, 57.14, and 85.71%, respectively. The prevalence of IgM class CIC were statistically higher in patients with HDV infection than in those without (P = .001 for the K assay and P = .023 for the C1q assay). There was no difference in the prevalence of IgG class CIC. Patients with HDV infection also have significantly higher median levels of IgM K-CIC (P = .002), IgG K-CIC (P = .049), and IgG C1q-CIC (P = .008). In patients with HDV infection, there was positive correlation between IgM C1q-CIC and transminase levels (r = .519, P = .016 for AST; r = .500, P = .021 for ALT). There was no difference in the prevalence of HBsAg containing CIC between patients with HDV infection (76.19%) and those without (74.60%). In conclusion, IgM class CIC are the major CIC and correlate with disease activity in HDV infection. CIC may play a role in the pathogenesis of HDV infection.     

Long-term follow-up of hepatitis B virus and hepatitis C virus replicative levels in chronic hepatitis patients coinfected with both viruses

Dual infection with hepatitis B and C viruses is often encountered in endemic areas of both viruses. However, understanding of the clinical and virological implications is limited. The aim of this study was to investigate the role of each virus in liver injury and the interaction between the two viruses in dual infection with hepatitis B and C viruses. Three patients who had chronic infection with both hepatitis B and C viruses were examined, and a longitudinal study of both serum hepatitis B virus DNA and hepatitis C virus RNA levels over 4 years was undertaken. The results were correlated with serum alanine aminotransferase levels. Serum alanine aminotransferase values showed a relationship with hepatitis B virus replicative levels, but not with hepatitis C virus replicative levels in all 3 patients. Serial changes of replicative levels of both viruses were studied, and it was found that hepatitis C virus replicative levels were enhanced after the decline of hepatitis B virus replication in 1 of the 3 patients. In the remaining 2 patients, a transient rise of hepatitis C virus replicative levels in association with a decrease of hepatitis B virus replication was also observed during part of the follow-up period. These findings indicate that hepatitis B virus may play a dominant etiological role in liver injury, and that a suppressive action between hepatitis B and C viruses may occur in dual infection with both viruses. © 1995 Wiley-Liss, Inc.     

Dysregulation of toll‐like receptor (TLR) 2 expression on monocytes and upregulation of the frequency of T cells expressing TLR2 in patients with chronic hepatitis C virus infection

Toll‐like receptors (TLRs) initiate inflammatory responses that may play a role in disease progression in patients infected with hepatitis C virus (HCV). TLR2 and TLR4 surface expression were assessed on CD14⁺ monocytes, CD4⁺ and CD8⁺ T cells in treatment naïve patients with chronic HCV infection with fibrosis, without fibrosis, co‐infected with human immunodeficiency virus (HIV), and in healthy controls. Increased expression of TLR2 was found on monocytes in HCV‐infected patients with fibrosis (p < 0.01), co‐infected with HIV (p = 0.03), and possibly in patients without fibrosis (p = 0.07) when compared to controls. TLR2 positive CD4⁺ and CD8⁺ T cells were upregulated in patients with fibrosis only (p < 0.01). However, expression of TLR2 was not associated with T cell activation. TLR4 expression was similar in patients and healthy controls. In conclusion, TLR2 expression on monocytes and the frequency of T cells expressing TLR2 may contribute to disease progression in chronic HCV infection.     

Human platelet antigen genotype is associated with progression of fibrosis in chronic hepatitis C

Although progression of fibrosis in the chronic hepatitis C depends on environmental, viral, and host factors, genetic polymorphisms have been associated recently with this progression, including the expression of integrins, adhesion proteins. Some integrins expressed on the platelet membrane show polymorphic antigenic determinants called human platelet antigens (HPA), where the major ones are HPA‐1, ‐3, ‐5. The association between HCV infection and HPA‐5b has been demonstrated. Similarly, the HPA profile could determine if HPA is related to progression of fibrosis. The goal of this study was to evaluate the association between the frequencies of HPA‐1, ‐3, and ‐5 and degree of fibrosis in HCV‐infected patients. Genomic DNA from 143 HCV‐infected patients was used as the source for HPA genotyping by PCR‐SSP or PCR‐RFLP. Progression of fibrosis was evaluated using the METAVIR scoring system, and the patients were grouped according to degree of fibrosis into G1 (n = 81, with F1, portal fibrosis without septa or F2, few septa) and G2 (n = 62, with F3, numerous septa, or F4, cirrhosis). Statistical analysis was performed using the proportional odds model. The genotypic frequency of HPA‐1a/1b was significantly higher in the patients in G2. To evaluate the influence of the time of infection to the development of fibrosis and its effect on the genetic factor HPA‐1, 96 patients from 143 studied were evaluated considering the time of HCV infection, and these results suggest that the HPA‐1a/1b genotype promotes the development of fibrosis in HCV infection with time. J. Med. Virol. 84:56–60, 2011. © 2011 Wiley Periodicals, Inc.     

Tattooing as a risk of hepatitis C virus infection.

The association of hepatitis C virus (HCV) infection and tattooing was studied in 87 tattooed and 126 tattoo free healthy young men who did not engage in intravenous drug use or multiple sexual activity. Antibody against HCV (anti-HCV) was tested in serum specimens by enzyme immunoassay with C100-3, NS3, and core antigens; 11 of the 87 (12.6%) tattooed and 3 of the 126 (2.4%) tattoo free subjects were positive for anti-HCV (odds ratio = 5.9, 95% CI = 1.6-22.0). A relationship was demonstrated by an increased risk for HCV infection with an increasing number of tattooed site (P(trend) = 0.002). All but one of the 87 tattooed subjects had been infected by hepatitis B virus (HBV) and 25 were carriers of hepatitis B surface antigen (HBsAg). None of the 25 HBsAg carriers was positive for anti-HCV whereas 11 of the 62 HBsAg non-carriers had anti-HCV, suggesting a negative association between the HBsAg carriage and the long lasting anti-HCV (P = 0.02, Fisher's exact). The status of the tattooer was also an important determinant for HCV infection; the risk was higher if tattooing was done by a non-professional friend than by a professional tattooist. Tattooing, probably with improperly sterilized needles, can clearly pose an increased risk for HCV infection in Taiwan. This study indicates the need for legal standards for hygienic tattooing as part of preventive measures for the control of parenterally transmitted infections.     

Identification of GBV-C hepatitis G RNA in chronic hepatitis C patients

Sera from patients with chronic hepatitis C were examined for the presence of GBV-C/HGV RNA by RT-PCR. The amplified products, derived from the 5′ non-coding, NS3, and NS5a regions, were detected in 19 (19%) of the 100 HCV RNA-positive samples. Analysis of GBV-C/HGV prevalence rates revealed that dual infections are related to shared parenteral risk factors. Intravenous drug abuse and multiple transfusions were the factors clearly associated with a simultaneous HCV and GBV-C/HGV infection. Apart from this, patients with dual infections had a statistically significant lower mean age compared to those patients infected solely by HCV. Determination of HCV genotypes involved in GBV-C/HGV coinfection by RFLP analysis showed no correlation between the presence of GBV-C/HGV and a distinct HCV genotype. The study demonstrates that, based on the assessment of risk criteria, GBV-C/HGV is transmitted efficiently parenterally and is frequently linked to hepatitis C coinfection, regardless of HCV genotype. © 1996 Wiley-Liss, Inc.     

Changes in antibody titers to hepatitis C virus following interferon therapy for chronic infection

The use of quantitative assays for hepatitis C virus specific antibodies (anti-HCV) as a prognostic marker was evaluated in 31 patients with chronic hepatitis C treated with interferon (IFN). Changes in titers of serum HCV-RNA and anti-HCV antibodies; anti-C11 (anti-core), anti-C100 (anti-NS3), and anti-C7 (anti-NS3) were investigated. Recombinant IFN-α 2a was administered and the patients were followed for more than 1 year. The patients were classified into three groups according to their responses to IFN: 11 sustained responders with continuous normalizations of serum alanine aminotransferase (ALT) levels; 14 transient responders with transient decreases in ALT; and six nonresponders who had no changes in ALT levels. Ten of 11 sustained responders had a continuous decrease in anti-C11 titers after completion of treatment, decreasing to less than half of pretreatment titers. No patients in the other two groups had a continuous decrease in anti-C11 titers. Although sustained responders had decreases in anti-C100 and anti-C7 titers after IFN therapy, these titers also decreased in some patients in the other two groups. HCV-RNA was not detected in the sera of 10 of 11 sustained responders following IFN therapy. In contrast, while 9 of 10 transient and nonresponders had a decrease or disappearance of HCV-RNA at the completion of therapy, they had increased levels thereafter. These results indicate that anti-HCV-core (anti-C11) titers most closely reflect the status of HCV replication. A quantitative assay for anti-HCV-core antibody can be used as a predictive marker of remission in IFN-treated patients with chronic hepatitis C. © 1994 Wiley-Liss, Inc.     

The affinity of anti-HBc antibodies in acute and chronic hepatitis B infection.

Antibodies to hepatitis B core antigen (anti-HBc) are found in the sera of all individuals infected with hepatitis B virus. A role for these antibodies has been suggested in determining the outcome of infection. In this study, the affinity of anti-HBc antibodies in asymptomatic virus carriers was compared with that of antibodies present in the sera of patients with chronic liver disease. Persistently infected individuals with no evidence of clinical disease were found to have anti-HBc antibodies of greater affinity, compared with the chronic liver disease group. Sera from patients with chronic hepatitis contained high levels of low-affinity antibody whereas antibody levels in asymptomatic carriers were significantly lower. These findings are discussed in relation to the predicted role of anti-HBc antibodies in mediating hepatitis B virus-related hepatocellular injury.     

Longitudinal study of hepatitis C viremia in chronic hepatitis C

Serial serum samples from 20 untreated patients with chronic hepatitis C virus (HCV) infection were tested for HCV RNA by a nested polymerase chain reaction assay using primers from the highly conserved 5′ noncoding region to determine the relationship between hepatitis C viremia and the activity of liver disease during the natural course of chronic HCV infection. Semiquantitation of serum HCV RNA level was achieved by testing serial 10-fold dilutions of RNA extracts to determine the end-point titer. All the patients were HCV RNA positive at presentation. There was a poor correlation between the initial HCV RNA titer and serum transaminase levels. All patients except one were persistently HCV RNA positive during a follow-up period of 1.5-15 years, although 17 (85%) had periods of normal or near-normal transaminase levels. There was no correlation between changes in the serum transaminase levels and HCV RNA titer. Patients with chronic HCV infection have persistent viremia despite fluctuations in ALT levels.     

IgM antibody to a hepatitis C virus core peptide (CP14) for monitoring activity of liver disease in patients with acute or chronic hepatitis C

Antibodies to the hepatitis C virus (HCV) core of various immunoglobulin classes were determined by enzyme immunoassays with three synthetic peptides, CP14 (amino acids 5-40 of the core protein), CP10 (5-23), and CP9 (39-74). In 135 patients with chronic type C liver disease, anti-CPU, anti-CP10, and anti-CP9 of IgG class were detected in 99%, 94%, 82%, respectively; those of IgM class in 86%, 69%, and 39%; and those of IgA class in 56%, 40%, and 4%. Thus anti-CP14 was more prevalent than anti-CPlO or anti-CP9 in every immunoglobulin class. The prevalence of IgM anti-CP14 was much higher (P < 0.001) in patients (116/135 or 86%) than in asymptomatic carriers of HCV (13/39 or 33%). In seven patients with acute hepatitis C, IgM anti-CP14 continued to decrease in two in whom hepatitis resolved, but increased in five in whom hepatitis once resolved and then exacerbated. IgM anti-CP14 was followed in 30 patients with chronic hepatitis C during 24 weeks while they received recombinant interferon α-2a. IgM anti-CP14 decreased remarkably within 8 weeks in all of them. Thereafter, it continued to decrease in nine patients who responded to interferon and lost HCV RNA from circulation, but started to increase in five non-responders who continued to have high titers of HCV RNA. In the remaining 16 patients in whom HCV RNA decreased once and then increased, IgM anti-CP14 continued to decrease till 20 weeks and then increased. These results indicate that IgM anti-CP14 reflects the activity of liver disease, and is useful in following the outcome of patients with acute hepatitis C and in monitoring the response to interferon in patients with chronic hepatitis C. © 1994 Wiley-Liss, Inc.     

Evolution of viral quasispecies in four dominant HlA-A2 restricted T cell epitopes is not a major reason for viral persistence in interferon-treated patients with chronic hepatitis C

In most patients, chronic hepatitis C virus (HCV) infection persists despite antiviral treatment with interferon-alpha (IFN-alpha) and ribavirin. The aim of the study was to determine whether HCV could evade cellular immune responses through mutations within T cell epitopes. Viral sequences flanking four major CTL epitopes within the HCV core and envelope regions were analyzed by PCR amplification, cloning and sequencing in seven HLA-A2 positive HCV patients before, during and after antiviral therapy. In addition, cytotoxic T lymphocyte precursor (CTLp) frequencies specific to these epitopes were quantitated by ELISPOT. A total of 13 coding mutations were observed among 650 cloned and sequenced PCR products under or post IFN treatment but no clear selection of viral variants. In detail, the diversity of quasispecies in the two core epitopes remained fairly stable over time despite variable CTLp induction in some individuals. The overall mutation rate in the two envelope epitopes was higher but there was no correlation with specific CTLp frequencies. In conclusion, although evolution of the viral quasispecies during and after antiviral therapy was demonstrated, immune evasion by epitope specific mutations seemed to be not common in interferon nonresponders because the viral complexity did not increase.     

慢性丙型肝炎发生肝脂肪变与血清瘦素的关系

目的 探讨慢性丙型肝炎(chronic hepatitis C,CHC)患者发生肝脂肪变与血清瘦素水平的关系.方法 将未治疗的成年CHC患者80例分为有肝脂肪变组(8例)与无肝脂肪变组(72例),以单纯非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)26例作为对照组,比较各组血清瘦素等生化指标有无差异.结果 CHC有肝脂肪变组ALT、AST水平高于NAFLD组(t=2.10,P＜0.05;t=3.56,P＜0.05),血清总胆固醇、低密度脂蛋白胆固醇、载脂蛋白A和B水平低于NAFLD组(t=-2.78,P＜0.05;t=-3.23,P＜0.05;t=-3.81,P＜0.05;t=-2.76,P＜0.05),两组瘦素水平差异无统计学意义(t=-0.30,P＞0.05).两组CHC的ALT、AST、FPG、TG、TC、LDL-C、APO-A、APO-B、胰岛素抵抗指数、HCVRNA水平、血清瘦素水平和体质量指数差异均无统计学意义(t值分别为-1.25,0.29,0.16,-0.53,0.90,1.58,1.93、0.40、0.24,-0.84,-0.05、-0.91,P均大于0.05).血清瘦素水平女性显著高于男性(t=2.22,P＜0.05).结论 CHC发生肝脂肪变时炎症程度重于NAFLD,胆固醇代谢异常程度轻于NAFLD.血清瘦素水平女性高于男性.CHC发生肝脂肪变与血清瘦素水平无关.     

Antibody responses to hepatitis C envelope proteins in patients with acute or chronic hepatitis C

Antibody responses to the hepatitis C virus (HCV) envelope proteins E1 and E2 were analyzed using two original assays in sera from 86 patients in different stages of disease. A Western blot assay and an immunofluorescence assay (IFA) were developed using envelope proteins produced, respectively, in Escherichia coli and in CV1 cells infected with a recombinant SV40. As a third method, the INNO-LIA HCV Ab III assay including E2 synthetic peptides was used. Of 38 chronically infected patients positive for anti-E2 antibodies by IFA, 26 were positive in the Western blot assay (68%) and 25 in the INNO-LIA test (66%). Thus, the detection of anti-envelope antibodies is highly dependent on the antigen formulation, and a native glycosylated form of the proteins is probably needed for their efficient detection. This study shows that the antibody response to HCV envelope proteins depends on the phase of infection. A few acutely infected patients displayed a response to E1 or E2 (36% by Western blot, 7% by IFA), and these antibodies seem to develop in patients evolving toward chronicity. The high prevalence in chronically infected subjects (62% to E2 by Western blot, 90% by IFA), particularly in subjects with essential mixed cryoglobulinemia (68% and 100%), confirms that the resolution of infection involves more than these antibodies. The antienvelope response in patients treated with interferon was investigated, but no significant relationship was found between antibody level prior to treatment and the evolution of hepatitis. The detection of anti-envelope antibodies, therefore, is not predictive of the response to antiviral therapy. © 1996 Wiley-Liss, Inc.