Jeffrey J. Post

Expression of the chemokine IP‐10 (CXCL10) by hepatocytes in chronic hepatitis C virus infection correlates with histological severity and lobular inflammation

The factors influencing lymphocyte trafficking to the liver lobule during chronic hepaititis C virus (HCV) infection are currently not well defined. Interferon‐γ‐inducible protein 10 (IP‐10), a chemokine that recruits activated T lymphocytes, has recently been shown by in situ hybridization to be expressed in the liver during chronic HCV infection. This study sought to define the cellular source of IP‐10 in the liver by immunohistochemistry, to examine the expression of its receptor, CXCR3, on T lymphocytes isolated from blood and liver tissue, and to correlate IP‐10 expression with the histological markers of inflammation and fibrosis. IP‐10 was expressed by hepatocytes but not by other cell types within the liver, and the most intense immunoreactivity was evident in the areas of lobular inflammation. The IP‐10 receptor was expressed on a significantly higher proportion of T lymphocytes in the liver compared with blood. CD8 T lymphocytes, which predominate in the liver lobule, were almost uniformly CXCR3‐positive. The expression of IP‐10 mRNA correlated with lobular necroinflammatory activity but not with inflammation or fibrosis in the portal tracts. These findings suggest that IP‐10 may be induced by HCV within hepatocytes and may be important in the pathogenesis of chronic HCV infection, as recruitment of inflammatory cells into the lobule is an important predictor of disease progression.

Clearance of Hepatitis C Viremia Associated with Cellular Immunity in the Absence of Seroconversion in the Hepatitis C Incidence and Transmission in Prisons Study Cohort

Understanding the earliest virological and immunological events in acute hepatitis C virus (HCV) infection may provide insight into the determinants of protective immunity. Four cases of HCV viremia with subsequent viral clearance, but without biochemical hepatitis or anti-HCV seroconversion, are reported from a prospective cohort study of prison inmates. Two of the subjects who developed sustained viremia were assessed for production of interferon (IFN)- gamma, by use of the enzyme-linked immunospot (ELISPOT) method and by assessment of HCV cytotoxic T lymphocyte (CTL) activity, CD4 lymphocyte proliferative responses, HCV load, and genotype. After 2-6 months of viremia, all 4 subjects cleared serum HCV RNA. Specific cellular responses were detected in both of the subjects who were assessed, and production of IFN- gamma was demonstrated in one subject. All subjects had weak, but consistent, serological reactivity against HCV nonstructural proteins on immunoblot testing, despite repeatedly nonreactive HCV ELISA tests. These cases highlight the potential for cellular immune responses against HCV to facilitate viral clearance, responses that may model those required for effective HCV vaccination.

Efavirenz and chronic neuropsychiatric symptoms: a cross-sectional case control study

The aim of the study was to investigate symptoms of long‐term central nervous system (CNS) toxicity in HIV‐positive patients treated with efavirenz (EFV).

The presence of an intrahepatic cytotoxic T lymphocyte response is associated with low viral load in patients with chronic hepatitis C virus infection

BACKGROUND/AIMS The role of cytotoxic T lymphocytes (CTL) in limiting viral replication and producing hepatocellular injury in patients with chronic hepatitis C virus (HCV) infection is controversial. METHODS Intrahepatic and peripheral blood HCV-specific CTL activity against the entire HCV polyprotein was assessed in 26 patients. CTL responses were assessed after effector lymphocytes were re-stimulated for 6 days in vitro using HCV-vaccinia virus-infected autologous cells expressing HCV antigens. Serum and hepatic viral loads were measured and immunohistochemistry for CD3 and CD8 was performed to localise and enumerate effector cells in liver. RESULTS A positive CTL response was detected in 39/52 (75%) of assays conducted with intrahepatic mononuclear cells and 21/52 (40%) of peripheral blood assays (P<0.001). The presence of an intrahepatic CTL response was associated with low hepatic viral load (P=0.004). Hepatic lobular infiltration by CD8(+)T cells correlated weakly with serum alanine aminotransferase levels (r=0.42, P=0.04) and no relationship was demonstrated between CTL activity and histological evidence of liver damage. CONCLUSIONS HCV-specific CTL activity is found more commonly in liver than in blood. An inverse relationship between CTL responses and viral load supports the hypothesis that HCV-specific CTL limit viral replication in patients with chronic HCV infection.

Host and viral factors in the immunopathogenesis of primary hepatitis C virus infection.

Individuals infected with hepatitis C virus (HCV) have two possible outcomes of infection, clearance or persistent infection. The focus of this review is the host mechanisms that facilitate clearance. The interaction between HCV viral components and the immune system ultimately determines the balance between the virus and host. Strong evidence points to the aspects of cellular immune response as the key determinants of outcome. The recent discovery of viral evasion strategies targeting innate immunity suggests that the interferon‐α/β induction pathways are also critical. A growing body of evidence has implicated polymorphisms in both innate and adaptive immune response genes as determinants of viral clearance in individuals infected with HCV.

Safety and Effectiveness of a Nurse-Led Outreach Program for Assessment and Treatment of Chronic Hepatitis C in the Custodial Setting

BACKGROUND The global burden of disease attributable to chronic hepatitis C virus (HCV) is very large, yet the uptake of curative antiviral therapies remains very low, reflecting the marginalized patient population and the arduous nature of current treatments. METHODS The safety and effectiveness of a nurse-led model of care of inmates with chronic HCV was evaluated in 3 Australian correctional centers. The model featured protocol-driven assessment, triage, and management of antiviral therapy by specifically trained nurses, with specialist physician support utilizing telemedicine. Outcomes were evaluated qualitatively with key informant interviews, and quantitatively with patient numbers completing key clinical milestones and adverse events. RESULTS A total of 391 patients with chronic HCV infection were enrolled, of whom 141 (36%) completed the clinical and laboratory evaluations for eligibility for antiviral therapy over 24 months. Treatment was initiated in 108 patients (28%), including 85 (79%) triaged for specialist review conducted by telemedicine only. The demographic and clinical characteristics of the patients who entered the model and completed workup and those who initiated treatment featured a high prevalence of individuals of indigenous background, injection drug users, and those with psychiatric disorder. Serious adverse events occurred in 13 of 108 treated patients (12%) with discontinuation in 8 (7%). The sustained virologic response rate among those with complete follow-up data (n=68) was 69%, and by intention-to treat analysis was 44%. CONCLUSIONS This nurse-led and specialist-supported assessment and treatment model for inmates with chronic HCV offers potential to substantively increase treatment uptake and reduce the burden of disease.

Immunological determinants of the outcomes from primary hepatitis C infection

Abstract.Individuals infected with hepatitis C virus (HCV) have two possible outcomes of infection, clearance or persistent infection, determined by a complex set of virus-host interactions. The focus of this review is the host mechanisms that facilitate clearance. Strong evidence points to characteristics of the cellular immune response as the key determinants of outcome, with evidence for the coordinated effects of the timing, magnitude, and breadth, as well as the intra-hepatic localisation of CD4+ and CD8+ T cell responses being critical. The recent discovery of viral evasion strategies targeting innate immunity suggests that interferon-stimulated gene products are also important. A growing body of evidence has implicated polymorphisms in both innate and adaptive immune response genes as determinants of viral clearance in individuals with acute HCV.

Prevalence of Production of Virus-Specific Interferon-γ among Seronegative Hepatitis C-Resistant Subjects Reporting Injection Drug Use

This report describes subjects who were highly likely to have been repeatedly exposed to hepatitis C virus (HCV) through injection drug use and who remained negative for anti-HCV antibody. Production of virus-specific interferon- gamma by peripheral blood mononuclear cells was seen in the majority of subjects (72%) and was associated with higher-risk behavior. For 92% of the subjects, results of recombinant immunoblot assays demonstrated faint bands against nonstructural proteins. The immune responses described are likely to have been primed and maintained by episodes of subclinical infection without classic seroconversion and may indicate a hepatitis C-resistant phenotype. Vaccine strategies to mimic this response may provide protection against persistent HCV infection.

HIV and co-infections

Despite significant reductions in morbidity and mortality secondary to availability of effective combination anti‐retroviral therapy (cART), human immunodeficiency virus (HIV) infection still accounts for 1.5 million deaths annually. The majority of deaths occur in sub‐Saharan Africa where rates of opportunistic co‐infections are disproportionately high. In this review, we discuss the immunopathogenesis of five common infections that cause significant morbidity in HIV‐infected patients globally. These include co‐infection with Mycobacterium tuberculosis, Cryptococcus neoformans, hepatitis B virus, hepatitis C virus, and Plasmodium falciparum. Specifically, we review the natural history of each co‐infection in the setting of HIV, the specific immune defects induced by HIV, the effects of cART on the immune response to the co‐infection, the pathogenesis of immune restoration disease (IRD) associated with each infection, and advances in the areas of prevention of each co‐infection via vaccination. Finally, we discuss the opportunities and gaps in knowledge for future research.

Risk factors for hepatitis C infection and perception of antibody status among male prison inmates in the Hepatitis C Incidence and Transmission in Prisons Study cohort, Australia.

The objective of this study was to compare the prevalence of risk factors for hepatitis C virus (HCV) infection among male prison inmates enrolling into a prospective cohort in Australia. We tested 121 inmates who were previously untested or were previously known to be anti-HCV antibody negative for anti-HCV antibodies by enzyme-linked immunosorbent assay. HCV-positive inmates were classified as cases (n=25) and HCV-negative inmates as controls (n=96). The study found that cases were less educated than controls and confirmed that prior imprisonment, drug injection, and a longer duration of injecting were risk factors for HCV infection. More than half of those who tested HCV positive perceived that they did not have HCV infection, and 44% were unsure of their HCV status. Those inmates who were incorrect about their HCV status tended to be less educated and were more likely to have been previously imprisoned than those who were correct about their HCV status. Inmates who were unsure of their HCV status were less likely to have been tested for HCV than those who had a clear perception of their HCV status, even if incorrect. Three (12%) inmates who tested positive denied injecting drug use, but reported other risk factors. Prisons are likely to remain an important site for the diagnosis of HCV infection and targeted interventions aimed at risk reduction among inmates with low education levels and a previous imprisonment history.