Kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4+ T cell responses in HCV and Schistosoma mansoni coinfection: relation to progression of liver fibrosis

The kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4(+) T cell responses and their role in progression of fibrosis have not previously been characterized. Subjects with HCV/Schistosoma mansoni coinfection have a more rapid progression of HCV liver fibrosis than do those with HCV infection alone. The present prospective longitudinal study compared the liver histology, HCV-specific intrahepatic and peripheral CD4(+) T cell proliferative responses, and cytokines (enzyme-linked immunospot) in 48 subjects with unresolved acute HCV infection with or without S. mansoni coinfection, at 6-10 months after acute infection and at the end of follow-up (96+/-8.7 months), and the findings were correlated to the rate of progression of fibrosis per year. Coinfected subjects had significant worsening of fibrosis, compared with subjects with HCV infection alone. At baseline, subjects with HCV infection alone had stronger multispecific intrahepatic HCV-specific CD4(+) T helper 1 responses than did coinfected subjects, who had either no responses or weak, narrowly focused responses, and, over time, these T cell responses were maintained only in the liver. The rate of progression of fibrosis and virus load inversely correlated with intrahepatic HCV-specific CD4(+) T cell response. The present prospective analysis indicates that enhancement of progression of liver fibrosis is associated with failure to develop early, multispecific, HCV-specific CD4(+) Th1 responses, suggesting that novel therapeutic approaches inducing strong cellular immune responses might limit subsequent liver damage in individuals with chronic hepatitis C.     

Acute hepatitis C without and with schistosomiasis: correlation with hepatitis C-specific CD4(+) T-cell and cytokine response

BACKGROUND & AIMS: Immune responses during the first few months of acute hepatitis C virus (HCV) infection seem crucial for viral control, but the relationship of these responses to natural history is poorly characterized. METHODS: This prospective study investigated the HCV-specific CD4(+) and cytokine responses in patients with acute HCV hepatitis with or without Schistosoma mansoni coinfection, a parasitic infection with T helper (Th) 2 immune bias. HCV-specific CD4(+) proliferative responses and cytokine production in peripheral blood mononuclear cells were correlated with liver biopsy results at 6 months and at the end of follow-up. RESULTS: Whereas 5 of 15 patients with HCV alone recovered from acute HCV, all (17 of 17) patients with S. mansoni coinfection progressed to histologically proven chronic hepatitis. Coinfected patients had either absent or transient weak HCV-specific CD4(+) responses with Th0/Th2 cytokine production. The magnitude of the HCV-specific CD4(+) response at week 12 was inversely correlated with the fibrosis progression rate in chronically infected patients. CONCLUSIONS: Patients with acute hepatitis C and schistosomiasis coinfection cannot clear viremia and show rapid progression once chronic infection is established. This rapid progression is associated with a strong Th2 response in peripheral immune responses, suggesting that early development of vigorous Th1 responses not only facilitates clearance but delays disease progression.     

Different cytokine patterns in patients coinfected with hepatitis C virus and Schistosoma mansoni

Schistosoma mansoni (S. mansoni) and hepatitis C virus (HCV) coinfection is common in Egypt and other developing countries. Patients coinfected with HCV and schistosomiasis exhibit a unique clinical, virological and histological pattern manifested by viral persistence with high HCV RNA titers as well as higher necroinflammatory and fibrosis scores in their liver biopsy samples. Dual infections of schistosomiasis and viral infections display significant influences on host immune reactions including cytokine shift pattern alteration, cytotoxic T lymphocyte response and other impaired immunologic functions with diminished capacity to clear the virus. We investigated the cytokine pattern against HCV and S. mansoni antigens in patients coinfected with HCV and S. mansoni and compared them with responses in patients infected with HCV or S. mansoni alone. This study included 4 groups; (Gr I) included 20 patients infected with chronic HCV, their sera were reactive for anti-HCV antibodies, samples were verified for RNA detection to identify those who have viremia. (Gr II) included 15 patients infected with schistosomiasis alone, they were subjected to detection of S. mansoni ova in stool, rectal snip or serological test. (Gr III) included 20 patients with chronic HCV and schistosomiasis coinfection, which were diagnosed by the above-mentioned criteria. (Gr IV) included 15 healthy individuals, who were matched for age and sex and have no evidence of liver diseases served as control subjects. The results showed that a highly significant increase in serum IFN-gamma and IL-18 levels in patients infected with HCV alone compared with the other patient groups and control. On the other hand, a highly significant increase was found in serum IL-4 and IL-10 levels in coinfected patients and patients with schistosomiasis alone compared with the control but a significant increase was found in the two groups compared with HCV patients. A significant increase in serum IL-4 and IL-10 were also found in HCV patients compared with the control. In conclusions, our data showed that coinfected patients have dominant Th2 cytokine profile induced by S. mansoni and this Th2 antagonized and down-regulated the antiviral activities of Th1 cytokine profile in HCV infection that probably acquired after S. mansoni infection resulting in failing to mount significant HCV specific Th1 response and thereby fail to clear the virus in coinfected, compared with patients infected with HCV or schistosomiasis alone.     

Preservation of intrahepatic hepatitis C virus (HCV)-specific CD4+ T cell responses despite global loss of CD4+ T cells in HCV/HIV coinfection

BACKGROUND: Human immunodeficiency virus (HIV) coinfection and low peripheral blood CD4(+) T cell counts are associated with increased hepatitis C liver disease. METHODS: Hepatitis C virus (HCV)-specific CD4(+) T cell responses were assessed using interferon (IFN)- gamma enzyme-linked immunospot assays on peripheral blood mononuclear cells and expanded liver lymphocytes from HCV-monoinfected and HCV/HIV-coinfected subjects. Cell frequencies were determined using flow cytometry. RESULTS: HIV coinfection was associated with decreased CD4(+) T cell percentages in both peripheral blood (21% vs. 48%; P<.0001) and liver (15% vs. 36%; P<.0001) and with reduced responsiveness of peripheral CD4(+) T cells to HCV antigens compared with HCV monoinfection (22% vs. 45%; P=.021). However, intrahepatic HCV-specific responses were maintained in HCV/HIV coinfection, compared with HCV monoinfection (38% vs. 32%; P=.7). Notably, the presence of HCV-specific responses was not related to the frequency of liver CD4(+) T cells (P=.4). Circulating and liver CD4(+) T cell percentages were correlated (r=0.58; P<.0001). Circulating percentages were also inversely associated with liver fibrosis stage among HCV/HIV-coinfected subjects (P=.029). Neither hepatic CD4(+) T cell percentages nor HCV-specific IFN- gamma responses in the liver or periphery predicted stage. CONCLUSIONS: Despite decreases in peripheral blood HCV-specific CD4(+) T cell responses and intrahepatic CD4(+) T cell percentages, intrahepatic HCV-specific CD4(+) IFN- gamma responses were preserved in HCV/HIV coinfection.     

CD8+ cell responses to hepatitis C virus (HCV) in the liver of persons with HCV-HIV coinfection versus HCV monoinfection

OBJECTIVE: Cellular immune responses are difficult to detect in the peripheral blood of persons with chronic hepatitis C virus (HCV) infection. We sought to determine whether T cell responses were present in the liver of patients with human immunodeficiency virus (HIV) and HCV coinfection. METHODS: T cells were expanded from liver-biopsy samples from 10 patients coinfected with HIV and HCV (median CD4(+) cell count, 456 cells/mm(3)) and 8 patients infected with HCV alone. CD8(+) cell responses were detected by use of a modified enzyme-linked immunospot (ELISpot) assay with recombinant vaccinia virus, and CD4(+) cell responses were detected by use of ELISpot with recombinant HCV proteins core, nonstructural (NS) 3, and NS5. RESULTS: Intrahepatic CD8(+) cell responses to HCV were detected in 7 of 10 patients coinfected with HCV and HIV (median frequency, 638 spot-forming cells [sfc]/1 x 10(6) cells) and were similar to those observed in patients singly infected with HCV (7/8; median, 647 sfc/1 x 10(6) cells). Intrahepatic HCV-specific CD4(+) cell responses were also comparable in both groups and correlated with the intrahepatic CD8(+) cell responses (r=0.59; P=.03). CONCLUSION: HCV-specific CD8(+) cell responses are present in the liver of persons with chronic HCV infection even when they are coinfected with HIV; these correlate with intrahepatic HCV-specific CD4(+) cell responses.     

The magnitude and breadth of hepatitis C virus-specific CD8+ T cells depend on absolute CD4+ T-cell count in individuals coinfected with HIV-1

CD8(+) T-cell responses are an essential antiviral host defense in persistent viral infections, and their sustained effectiveness is thought to be critically dependent on CD4(+) T-helper cells. To determine the relationship between HIV-1-induced CD4(+) T-cell depletion and hepatitis C virus (HCV)-specific CD8(+) T-cell responses during viral persistence, we studied 103 persons positive for HCV, 74 coinfected with HIV-1. CD8(+) T-cell responses to the entire HCV polyprotein were determined by using an interferon-gamma enzyme-linked immunospot (ELISpot) assay. Although HIV-1 infection by itself was not associated with a diminished HCV-specific response, HIV-1-associated CD4(+) depletion was associated with significantly lower HCV-specific CD8(+) T cells (R = 0.48, P < .0001). In contrast, declining CD4(+) counts over the same range were not associated with diminished Epstein-Barr virus (EBV)- (R = 0.19, P = .31) or HIV-1-specific (R = -0.13, P = .60) CD8(+) T-cell responses in persons infected with all viruses. These data indicate that frequencies of circulating HCV-specific CD8(+) T-cell responses are sensitive to absolute CD4(+) T-cell counts and provide a possible explanation for the accelerated HCV disease course in persons coinfected with HIV-1 and HCV.     

Impact of HIV on host-virus interactions during early hepatitis C virus infection

BACKGROUND: Human immunodeficiency virus (HIV) may influence the outcome and natural history of hepatitis C virus (HCV) infection through an impact on acute HCV-specific T cell responses. METHODS: Fifty-five HIV-positive males with acute HCV infection were identified; monoinfected individuals (n = 8) were used for peripheral blood mononuclear cell comparison. In 14 coinfected and 8 HCV-monoinfected patients, HCV-specific T cell responses against a range of HCV antigens were assessed using interferon (IFN)-gamma enzyme-linked immunospot (ELISpot) and proliferation assays. E1/E2 region genetic diversity and the selection pressure on the virus were measured in 8 coinfected patients by use of cloned sequences over time. RESULTS: HCV persisted in 52 (95%) coinfected individuals. HCV/HIV coinfection significantly reduced IFN-gamma ELISpot responses versus those in HCV-monoinfected individuals, especially against nonstructural proteins (1/10 vs. 5/8; P = .008). In coinfected patients, increased HCV genetic diversity was observed between the first and subsequent time points, with no evidence for positive selection in the E1/E2 region sequenced. CONCLUSION: HIV coinfection is associated with increased rates of HCV persistence and a lack of critical CD4 T cell responses, with no evidence of immune selection pressure during early HCV infection. Loss of key cellular immune responses against HCV during acute disease may contribute to the failure of early host control of HCV in HCV/HIV-coinfected patients.     

HCV and HIV: a tale of two viruses

Liver disease has emerged as a major cause of morbidity and mortality in patients infected with the human immunodeficiency virus. Hepatic injury is highly associated with hepatitis C virus (HCV) infection, though hepatitis B virus and drug-induced hepatotoxicity are also important cofactors. HCV coinfection is linked to increased hepatic fibrosis progression, leading to development of cirrhosis and liver failure earlier than in HCV monoinfected patients. Initiation of highly active antiretroviral treatment regimens may paradoxically increase HCV loads. Some data suggest that HCV coinfection may hasten progression of AIDS, but this remains controversial. Three major randomized clinical trials demonstrate improved efficacy of peginterferon with ribavirin for treatment of HCV in coinfected subjects compared to those with HCV alone. However, response rates are lower than those observed in patients with HCV monoinfection. Sustained virologic response rates of 27% to 40% are reported.     

Differential CD4(+) and CD8(+) T-cell responsiveness in hepatitis C virus infection

This study was performed to compare the vigor and phenotype of virus-specific CD4(+) and CD8(+) T-cell responses in patients with different virologic and clinical outcomes after hepatitis C virus (HCV) infection. The results show that a vigorous and multispecific CD4(+) proliferative T-cell response is maintained indefinitely after recovery from HCV infection whereas it is weak and focused in persistently infected patients. In contrast, the HCV-specific CD8(+) T-cell response was quantitatively low in both groups despite the use of sensitive direct ex vivo intracellular interferon gamma (IFN-gamma) staining. Furthermore, although HCV-specific cytolytic CD8(+) memory T cells were undetectable ex vivo, they were readily expanded from the peripheral blood of chronically HCV-infected patients but not from recovered subjects after in vitro stimulation, suggesting that ongoing viremia is required to maintain the HCV-specific memory CD8(+) T-cell response. HCV-specific CD8(+) T cells displayed a type 1 cytokine profile characterized by production of IFN-gamma despite persistent HCV viremia. The paradoxical observation that HCV-specific CD4(+) T cells survive and CD8(+) T cells are lost after viral clearance while the opposite occurs when HCV persists suggests the existence of differential requirements for the maintenance of CD4(+) and CD8(+) T-cell memory during HCV infection. Furthermore, the relative rarity of circulating CD8(+) effector T cells in chronically infected patients may explain the chronic insidious nature of the liver inflammation and also why they fail to eliminate the virus.     

Stronger hepatitis C virus‐specific CD8+ T‐cell responses in HIV coinfection

Summary. Hepatitis C virus (HCV) is a widespread chronic infection that shares routes of transmission with human immunodeficiency virus (HIV). Thus, coinfection with these viruses is a relatively common and growing problem. In general, liver disease develops over years with HIV coinfection, when compared to decades in HCV monoinfection. The role of the immune system in the accelerated pathogenesis of liver disease in HIV/HCV coinfection is not clear. In this study, we compared the frequency, magnitude, breadth and specificity of peripheral blood CD4⁺ and CD8⁺ T‐cell responses between HCV‐monoinfected and HCV/HIV‐coinfected individuals and between HIV/HCV‐coinfected subgroups distinguished by anti‐HCV antibody and HCV RNA status. While HIV coinfection tended to reduce the frequency and breadth of anti‐HCV CD8⁺ T‐cell responses in general, responses that were present were substantially stronger than in monoinfection. In all groups, HCV‐specific CD4⁺ T‐cell responses were rare and weak, independent of either nadir or concurrent CD4⁺ T‐cell counts of HIV‐infected individuals. Subgroup analysis demonstrated restricted breadth of CD8⁺ HCV‐specific T‐cell responses and lower B‐cell counts in HIV/HCV‐coinfected individuals without anti‐HCV antibodies. The greatest difference between HIV/HCV‐coinfected and HCV‐monoinfected groups was substantially stronger HCV‐specific CD8⁺ T‐cell responses in the HIV‐coinfected group, which may relate to accelerated liver disease in this setting.     

Analysis of T cell responses against hepatitis C virus genotype 4 in Egypt

BACKGROUND/AIMS: Hepatitis C virus (HCV) remains the most common cause of chronic liver disease in Egypt. Despite the high prevalence of HCV and Schistosoma mansoni (S. mansoni) in Egypt, the effect of co-infection on the immune response against HCV genotype 4a has not been extensively examined. METHODS: We evaluated the HCV 4a-specific responses against the core and non-structural 5B proteins in chronic HCV with or without S. mansoni co-infection in 38 volunteers from Egypt. RESULTS: HCV 4a-specific responses were detected in 8/15 and 13/23 individuals with HCV alone or with concomitant schistosomiasis, respectively. Despite the alteration in the Th1 cytokine profile caused by schistosomiasis, the overall immune response rate against HCV was not affected (P=0.11). Seven individuals demonstrated HCV-specific responses against conserved regions of the Core that were previously identified for genotypes 1, 2 and 3 despite differences in HLA class I distribution. CONCLUSIONS: Egyptian patients infected with HCV genotype 4 can mount HCV-specific T cell responses, both CD4+ and CD8+ T cell-mediated, despite the prevalence of concomitant schistosomiasis. These findings suggest that S. mansoni co-infection may not represent a major obstacle to developing an HCV vaccine in this population.     

Quantification of hepatic FOXP3+ T‐lymphocytes in HIV/hepatitis C coinfection

Coinfection with HIV adversely impacts every stage of hepatitis C (HCV) infection. Liver damage in HCV infection results from host antiviral responses rather than direct viral pathogenesis. Despite depressed cellular immunity, coinfected patients show accelerated hepatic fibrosis compared with HCV monoinfected patients. This paradox is poorly understood. T‐regulatory (Treg) cells (CD4+ and FOXP3+) are hypothesized to limit hepatic damage in HCV. Our hypothesis was that reduced frequency of hepatic Treg in HIV/HCV coinfection compared with HCV monoinfection may explain poorer outcomes. We quantified FOXP3+, CD4+, CD8+ and CD20+ cells in liver biopsies of 35 male subjects matched by age and ISHAK fibrosis score, 12 HIV monoinfected, 11 HCV monoinfected and 12 HIV/HCV coinfected. Cell counts were performed using indirect immunohistochemical staining and light microscopy. HIV/HCV coinfected subjects had fewer hepatic FOXP3+ (P = 0.031) and CD4+ cells (P = 0.001) than HCV monoinfected subjects. Coinfected subjects had more hepatic CD8+ cells compared with HCV monoinfected (P = 0.023), and a lower ratio of FOXP3+ to CD8+ cells (0.08 vs 0.27, P < 0.001). Multivariate analysis showed number of CD4+ cells controlled for differences in number of FOXP3+ cells. Fewer hepatic FOXP3+ and CD4+ cells in HIV/HCV coinfection compared with HCV monoinfection suggests lower Treg activity, driven by an overall loss of CD4+ cells. Higher number of CD8+ cells in HIV/HCV coinfection suggests higher cytotoxic activity. This may explain poorer outcomes in HIV/HCV coinfected patients and suggests a potential mechanism by which highly active antiretroviral therapy may benefit these patients.     

Distribution and effects of polymorphic RANTES gene alleles in HIV/HCV coinfection -- a prospective cross-sectional study

AIM: Chemokines and their receptors are crucial for immune responses in HCV and HIV infection. RANTES gene polymorphisms lead to altered gene expression and influence the natural course of HIV infection. Therefore, these mutations may also affect the course of HIV/HCV coinfection. METHODS: We determined allele frequencies of RANTES-403 (G→A), RANTES-28 (C→G) and RANTES-IN1.1 (T→C) polymorphisms using real-time PCR and hybridization probes in patients with HIV (n = 85), HCV (n = 112), HIV/HCV coinfection (n = 121), and 109 healthy controls. Furthermore, HIV and HCV loads as well as CD4+ and CD8+ cell counts were compared between different RANTES genotypes. RESULTS: Frequencies of RANTES-403 A, RANTES-28 G and RANTES-IN1.1 C alleles were higher in HIV infected patients than in healthy controls (-403: 28.2% vs 15.1%, P = 0.002; -28: 5.4% vs 2.8%, not significant; IN1.1: 19.0% vs 11.0%, P = 0.038). In HIV/HCV coinfected patients, these RANTES alleles were less frequent than in patients with HIV infection alone (15.4% P = 0.002; 1.7%; P = 0.048; 12.0%; not significant). Frequencies of these alleles were not significantly different between HIV/HCV positive patients, HCV positive patients and healthy controls. CONCLUSION: All three RANTES polymorphisms showed increased frequencies of the variant allele exclusively in patients with HIV monoinfection. The finding that the frequencies of these alleles remained unaltered in HIV/HCV coinfected patients suggests that HCV coinfection interferes with selection processes associated with these alleles in HIV infection.     

Schistosoma infection inhibits cellular immune responses to core HCV peptides

Patients coinfected with hepatitis C virus (HCV) and the trematode, Schistosoma mansoni, have an increased incidence of viral persistence and accelerated fibrosis. To investigate immunological mechanisms responsible for this more aggressive natural history of HCV, the core HCV-specific T-cell responses were analysed in 44 donated blood units rejected because they had antibodies to HCV (anti-HCV). Half also had anti-S. mansoni antibodies, evidence of past or active infection. HCV-specific ELISPOT responses were examined using pools of 180 overlapping 9-mer peptides with offsets of one covering the core of HCV genotype 4a. Comparison of T-cell responses in blood units positive for both anti-HCV and anti-Schistosoma antibodies with blood units positive only for anti-HCV antibodies showed a significant decrease in core-specific T-cell IFN-gamma (505+/- 46 vs. 803 +/- 66 ISC/10(6) cells, P < 0.001), IL-4 (2 +/- 108 vs. 641 +/- 131 ISC/10(6) cells, P < 0.001), and IL-10 (159 +/- 105 vs. 466 +/- 407 ISC/10(6) cells, P < 0.002) responses. In contrast, there was no significant difference in cell-mediated immune response (CMI) to PHA mitogen between these two groups. Therefore, we concluded T cells from persons with anti-Schistosoma have reduced IFN-gamma, IL-4, and IL-10 secreting HCV-specific T-cell responses. This may explain why Schistosoma coinfection increases persistence and severity of HCV infection.     

Antigen-specific cytokine response to hepatitis C virus core epitopes in HIV/hepatitis C virus-coinfected patients.

OBJECTIVE: Epidemiological data indicate that hepatitis C virus (HCV) infection runs a more rapid and severe course of disease in HIV-coinfected patients, probably because of an altered immune response. DESIGN: We investigated whether HCV-specific cytokine responses are affected by HIV coinfection. METHODS: Using triple colour flow cytometry on peripheral blood lymphocytes after stimulation with the four major immunodominant HCV core T cell epitopes, CT1-CT4, we determined intracytoplasmic production of IFN-gamma, IL-2, IL-4, IL-10 and CD30 expression, a putative surrogate marker of type 2 cells. Fifteen patients with asymptomatic HIV/HCV coinfection (group A), 15 patients with chronic HCV infection (group B) and 10 HIV-infected patients without hepatitis C (group C) were included in the study. RESULTS: In group A, HCV antigens induced significantly higher IL-2 and IFN-gamma production than groups B and C (P < 0.05). Groups A and B showed a similar induction of CD30, which was significantly higher than in group C (P < 0.001). Remarkably, in group A HCV antigens induced IL-4 production in addition to IL-10 and IFN-gamma in the CD30 subset, whereas in groups B and C no IL-4 induction was observed in this T cell subset (P < 0.002). CONCLUSION: Our data suggest that asymptomatic HIV coinfection importantly alters the HCV-specific cytokine response towards a greater production of proinflammatory type 1 cytokines. Moreover, the antiviral activity of type 1 cytokines may be modified by an increased production of type 2 cytokines in the CD30 subset. The altered cytokine pattern may contribute to the adverse natural course of hepatitis C in HIV coinfection.     

HIV infection and the liver: the importance of HCV-HIV coinfection and drug-induced liver injury

Hepatitis C virus-Human immunodeficiency virus (HCV-HIV) coinfections are identified in up to 30% of patients infected with HIV and in 8% of patients infected with HCV. Now that progression of HIV and deaths due to AIDS can be prevented by highly active antiretroviral therapy (HAART), it is clear that HCV coinfection is associated with accelerated progression to cirrhosis and increased liver-related morbidity and mortality. Antiviral therapy with pegylated interferon and ribavirin for HCV in HCV-HIV coinfected patients is less successful than in patients with HCV monoinfection, and HAART can cause drug-induced liver injury. Multiple barriers limit the number of HCV-HIV coinfected patients who receive antiviral therapy for HCV, and the role of orthotopic liver transplantation (OLT) in HIV monoinfected and HCV-HIV coinfected patients remains controversial. Clinical trials of HCV-specific protease or polymerase inhibitors combined with pegylated interferon and ribavirin are needed urgently in coinfected patients, both before and after OLT.     

Suppression of HCV-specific T cells without differential hierarchy demonstrated ex vivo in persistent HCV infection

Hepatitis C virus (HCV) has a high propensity for persistence. To better define the immunologic determinants of HCV clearance and persistence, we examined the circulating HCV-specific T-cell frequency, repertoire, and cytokine phenotype ex vivo in 24 HCV seropositive subjects (12 chronic, 12 recovered), using 361 overlapping peptides in 36 antigenic pools that span the entire HCV core, NS3-NS5. Consistent with T-cell-mediated control of HCV, the overall HCV-specific type-1 T-cell response was significantly greater in average frequency (0.24% vs. 0.04% circulating lymphocytes, P =.001) and scope (14/36 vs. 4/36 pools, P =.002) among the recovered than the chronic subjects, and the T-cell response correlated inversely with HCV titer among the chronic subjects (R = -0.51, P =.049). Although highly antigenic regions were identified throughout the HCV genome, there was no apparent difference in the overall HCV-specific T-cell repertoire or type-1/type-2 cytokine profile relative to outcome. Notably, HCV persistence was associated with a reversible CD4-mediated suppression of HCV-specific CD8 T cells and with higher frequency of CD4(+)CD25(+) regulatory T cells (7.3% chronic vs. 2.5% recovered, P =.002) that could directly suppress HCV-specific type-1 CD8 T cells ex vivo. In conclusion, we found that HCV persistence is associated with a global quantitative and functional suppression of HCV-specific T cells but not differential antigenic hierarchy or cytokine phenotype relative to HCV clearance. The high frequency of CD4(+)CD25(+) regulatory T cells and their suppression of HCV-specific CD8 T cells ex vivo suggests a novel role for regulatory T cells in HCV persistence.     

Analysis of the efficacy of treatment with peginterferon α‐2a and ribavirin in patients coinfected with hepatitis B virus and hepatitis C virus

Objective: To study the virological features of patients coinfected with hepatitis B virus (HBV) and hepatitis C virus (HCV) and the efficacy of combination therapy with peginterferon α‐2a and ribavirin in these patients. Methods: The epidemiological and virological data of 50 patients coinfected with HBV and HCV were analysed. The virological response rates of patients treated with peginterferon α‐2a and ribavirin between the HBV and HCV coinfection group and the HCV monoinfection group were compared. Results: HCV‐dominant virus strains accounted for 92.0% of the 50 coinfected individuals, and HCV‐ and HBV‐dominant virus strains accounted for the remaining 8.0%. The HBV DNA level of the patients coinfected with HBV and HCV was 4.6±0.9 log₁₀ copies/ml, which was significantly lower than that in the HBV monoinfection group (5.9±1.2 log₁₀ copies/ml) (t=5.964, P<0.01). The HBeAg‐positive rate (12.0%, 6/50) of the coinfection group was significantly lower than (45.3%, 19/42) that of the HBV monoinfection group (χ²=12.743, P<0.01). The partial early virological response (pEVR) rate and the end‐of‐treatment virological response (ETVR) rate (50.0%, 15/30; 90.0%, 27/30) of patients with genotype 1 in the coinfection group were significantly higher than those (16.0%, 4/25; 56.0%, 14/25) in the HCV monoinfection group (χ²=6.971, P=0.008; χ²=8.307, P=0.004). The relapse rate (55.6%, 15/27) of patients with genotype 1 in the coinfection group was significantly higher than that (21.4%, 3/14) in the HCV monoinfection group (χ²=4.360, P=0.037). The sustained virological response (SVR) rate (40.0%, 12/30) of patients with genotype 1 in the coinfection group was compared with that of the HCV monoinfection group (44.0%, 11/25) (χ²=0.090, P=0.765). There was no significant difference in the on‐treatment virological response, ETVR, SVR and relapse rates between two groups for patients with genotype 2. The incidence of side effects (30%, 15/50) of patients in the coinfection group was significantly higher than that (13%, 6/46) in the HCV monoinfection group (χ²=4.031, P=0.045). The reactivation rate of HBV DNA (33.3%, 9/27) with HCV SVR was significantly higher than that of patients without SVR (8.7%, 2/23) (χ²=4.393, P=0.036). Conclusions: The replication of HBV was suppressed, and HCV was the dominant virus strain. Compared with HCV‐monoinfected patients, pEVR, ETVR and relapse rates of patients with genotype 1 in the coinfection group were high, while they shared similar SVR rates. HBV and HCV coinfection had no impact on the rate of virological response for genotype 2.     

Comparison of HCV-specific intrahepatic CD4+ T cells in HIV/HCV versus HCV

Persons with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection are at increased risk for progression to cirrhosis compared with persons with HCV alone, but the reasons for this are unclear. In chronic HCV, the mechanism of liver injury is presumed to be due to HCV-specific T cell destruction of hepatocytes, so it is paradoxical that immunosuppressed hosts have higher rates of fibrosis progression. We examined intrahepatic cellular immune responses to HCV antigens to determine whether there were qualitative or quantitative differences in subjects with and without HIV. Expanded, CD4-enriched, liver-infiltrating lymphocytes from 18 subjects with chronic HCV and 12 subjects with HIV/HCV were cultured in the presence of HCV core protein, nonstructural proteins NS3 and NS5, and recall antigens tetanus toxoid and Candida. Secretion of interferon gamma (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), and interleukin (IL) 10 was determined using enzyme-linked immunosorbent spot assay. There were no significant differences in liver biopsy grade or stage for HIV/HCV versus HCV groups. There were no significant differences between groups in the secretion of IFN-gamma or TNF-alpha in response to HCV or recall antigens. However, there was a significant increase in IL-10 secretion in response to NS3 and NS5 in subjects with HCV compared with HIV and HCV coinfection. In conclusion, subjects with coinfection have an alteration of intrahepatic HCV-specific IL-10 cytokine response that may have implications for HCV-related disease progression.     

Recurrence of hepatitis C virus after loss of virus-specific CD4(+) T-cell response in acute hepatitis C.

BACKGROUND & AIMS: The prospective comparison of patients with acute hepatitis C virus (HCV) who spontaneously clear the virus with those who cannot achieve viral elimination and progress to chronic hepatitis offers the unique opportunity to analyze natural mechanisms of viral elimination. METHODS: We studied the HCV-specific CD4(+) T-cell response in 38 patients with acute HCV and correlated the clinical course with the antiviral immune response. The individual HCV-specific T-cell response was assessed in a proliferation assay ((3)H-thymidine uptake) and an enzyme-linked immunospot assay. RESULTS: Patients were classified according to their clinical course and pattern of CD4(+) T-cell responses in 3 categories: first, patients mounting a strong and sustained antiviral CD4(+)/Th1(+) T-cell response who cleared the virus (HCV RNA-negative; n = 20); second, patients who were unable to mount an HCV-specific CD4(+) T-cell response and developed chronic disease (n = 12); and third, patients who initially displayed a strong CD4(+) T-cell response and eliminated the virus (HCV PCR-negative) but subsequently lost this specific T-cell response (n = 6). The loss of the HCV-specific CD4(+) T-cell response was promptly followed by HCV recurrence. CONCLUSIONS: The results indicate that a virus-specific CD4(+)/Th1(+) T-cell response that eliminates the virus during the acute phase of disease has to be maintained permanently to achieve long-term control of the virus. The induction and/or maintenance of virus-specific CD4(+) T cells could represent a promising therapeutic approach in HCV infection.