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Thèse numérisée par la Division de la gestion de documents et des archives de l'Université de Montréal

Woodchucks are the preferred animal model to study chronic viral hepatitis and the development of hepatocellular carcinoma (HCC), which occurs as a result of infection with woodchuck hepatitis virus. Significant elevations in the phosphomonoester peak in 31P-MRS spectrum correlated to the presence of HCC. Ex vivo 31P-NMR determined that HCC tissue had significantly elevated concentrations of PC compared to uninfected control tissues, confirming that PME is specific to the tumour’s growth. Finally, a recombinant vaccinia virus was constructed to stimulate the immune systems of infected woodchucks against cells expressing core antigens. Despite reductions in surface antigen expression and viral load, elevations in serum GGT and the PME in 31P-MRS indicated that there was tumour growth in treated woodchucks. In conclusion, the PME peak represents a potential biomarker of cancerous growth when used in conjunction with serological tests to detect HCC in the liver due to chronic hepatitis virus infection.

Hepatitis C Virus (HCV) infects 170 million people worldwide. The current treatment regimen, which is combination therapy with pegylated interferon (PegIFN) and Ribavirin (Rib), cures only 50% of the patients infected with the most prevalent HCV genotype. Therefore, there is a pressing need to understand the molecular mechanism of interferon resistance and to develop a prognostic tool to predict who will respond to treatment before initiation of therapy. It has been firmly established that the virus-host interaction plays an important role in determining treatment outcomes. My thesis investigated the host factors that are involved in interferon resistance with an aim to provide insights into the molecular mechanism of IFN resistance. cDNA microarray analysis identified 18 differentially expressed hepatic genes from pretreatment liver tissues of responders (Rs) and non-responders (NRs). Based on the differential expression levels of these 18 genes, a prognostic tool was developed to predict who will respond to therapy, with a positive predicting value (PPV) of 96%. Most of these 18 genes are interferon stimulated genes (ISGs) and they are more highly expressed in NR livers, indicating that preactivation of interferon signaling in the pre-treatment liver tissues contributes to NR. 3 out of the 18 genes are involved in an ubiquitin-like ISG15/USP18 signaling pathway that plays an important role in interferon response. Over-expression of USP18 and ISG15 in the pretreatment liver tissues of NR promotes HCV production and blunts interferon anti-HCV activity. There exists a distinct cell-type specific ISG activation in the pretreatment liver tissues of Rs and NRs. Up-regulation of the two ISGs that I tested (ISG15 and MxA) was found mainly in hepatocytes in NRs while ISG activation was preferentially observed in macrophages in Rs. Taking all these data together, pre-activation of interferon signaling and cell-type specific gene activation in the pretreatment liver tissues of patients infected with HCV are associated with treatment non-response. HCV exploits the host interferon system to favour its persistence by enhanced replication /secretion stimulated by a few ISGs (ISG15, USP18) in response to IFN. The developed prognostic tool can be used to stratify patients for treatment and the novel insights of the molecular mechanism of IFN resistance in HCV patients offer potential drug targets for future development.

La infecció pel VHC és la principal causa d'hepatopatia crònica arreu del món. Els nens constitueixen una petita proporció de la població infectada i en l'actualitat la principal via d'adquisició de la infecció pel VHC en la infància és la transmissió vertical. És probable que els pacients infectats durant la infancia, tal com passa en els adults, es mantinguin asimptomàtics durant un llarg període de temps, tot i que s'han descrit casos de cirrosi en un temps inferior als 10 anys. Donada l'absència de manifestacions clíniques en les primeres fases de la infecció, s'han estudiat diversos marcadors analítics per a definir la progressió de la malaltia. En l'actualitat, es disposa d'un tractament antiviral eficaç (interferó pegil·lat més ribavirina) per a la infecció crònica pel VHC. Aquest tractament ha estat autoritzat recentment per a la població pediàtrica. L'absència de comorbilitats i el curt temps d'evolució de la infecció converteixen al nen infectat pel VHC en el candidat ideal per a obtenir altes taxes de curació de la malaltia. En els darrers anys, la infecció pel VIH ha esdevingut una patologia de curs crònic mentre que l'hepatopatia és actualment una de les principals causes de morbilitat i mortalitat en els pacients co-infectats. En el pacient pediàtric co-infectat les consideracions prèvies sobre l'inici de tractament específic esdevenen especialment rellevants, ja que les probabilitats d'èxit del mateix probablement es relacionin amb la seva precocitat. Els objectius principals del nostre estudi són definir les característiques de la transmissió vertical del VHC en el nostre medi, descriure la història natural de la infecció crònica pel VHC en l'edat pediàtrica i establir el paper de la co-infecció pel VIH en l'evolució natural de la infecció crònica pel VHC en el nen.Per això hem dissenyat dos estudis prospectius observacionals que inclouen els fills de mares infectades pel VHC nascuts al nostre centre entre gener del 1999 i desembre del 2006 (estudi 1) i els nens infectats pel VHC controlats en el nostre centre (estudi 2). Tots elspacients han estat seguit de forma prospectiva. Les principals conclusions dels estudis són les següents: Estudi 1: La taxa prevalença de la infecció pel VHC en les gestants és del 0.49%. La taxa de transmissió vertical del VHC és del 2.8%. Existeix una relació entre la co-infecció materna pel VIH i la transmissió vertical del VHC en el grup de pacients estudiats. Estudi 2: La majoria dels pacients romanen asimptomàtics i sense troballes clíniques al llarg del seguiment. La meitat dels pacients estan infectats pels genotips 1a o 1b; en els fills de mare UDVP, hi predominen les infeccions pels genotips 3 i 4. La biòpsia hepàtica mostra signes d'hepatitis crònica en la majoria dels casos. D'entre els pacients no tractats, un 12% evolucionen al clearence espontani de la infecció (tots ells són pacients infectats per transmissió vertical) mentre que el 82% dels pacients evolucionen a un patró d'hepatitis crònica. La taxa de prevalença de cirrosi és de l'1.8%. Només 4 de 27 pacients tractats amb interferó en monoteràpia durant 12 mesos assoleixen el clearence de la virèmia. El 86% dels pacients pateixen efectes secundaris del tractament, tot i que solen ser lleus. Els pacients co-infectats mostren unes xifres màximes d'ALT més altes que la resta i evolucionen en la majoria de casos seguint un patró d'hepatitis crònica. / HCV infection is the main cause of hepatopathy worldwide. Children represent a small proportion of the infected people and vertical transmision is the main way of acquisition in childhood. Patients infected during childhood will probably remain asymptomatic for a long time, as happens in adults, but some cases of cirrhosis have been described. Regarding the lack of clinical manifestations during the first years of the infection, several serum markers have been studied to define the progression of the illness. Nowadays an efective treatment is available (pegilated interferon plus ribavirin) for the chronic HCV infection and it has been recently authorised for childhood. The absence of comorbilities and the short course of the infection will probably lead to a higher rate of response in this group of patients. Early treatment will probably be effective also in HIV co-infected patients. Main objectives of our study are to define HCV vertical transmission in our media, to describe natural history of the chronic HCV infection in childhood and to stablish the role of HIV co-infection in the evolution of HCV infection. Two prospective studies have been conducted. They include children from HCV infected mothers born in our center between january 1999 and december 2006 (Study 1) and HCV infected children visited in our center (Study 2). Main conclusions of our study are: Study 1: Prevalence rate of HCV infection among pregnant women is 0.49%. HCV vertical transmision is 2.8%. There is a relation between vertical transmision and maternal HIV co-infection. Study 2: Most of the HCV infected patients remain asymtomatic during the follow up. Half of the patients belong to 1a or 1b HCV genotipes; in children born from drug users genotipes 3 and 4 are frequent. 12% of the patients that have'nt received treatment experiment spontaneous clearence of the infection (all are vertically infected) while 82% end in a chronic hepatitis. Prevalence rate of cirrhosis is 1.8%. Only 4 of 27 patients treated with interferon reach the clearence of the viremia and 86% suffer secundary effects, usually mild. Co-infected patients have higher ALT determinations and usually end in a chronic hepatitis.

Bibliography: leaves 162-174. / xiv, 177 leaves : ill. ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Thesis (Ph.D.)--University of Adelaide, Dept. of Clinical and Experimental Pharmacology, 1989

This thesis documents my research on the epidemiology of Human Immunodeficiency Virus (HIV), hepatitis C virus (HCV) and other transmissible infections among 'at risk' young people, injecting drug users and sex workers in inner Sydney, and how this contributed to the early understanding of these infections in these potentially vulnerable populations in Australia. It also demonstrates how this work informed the development of innovative health service models in Sydney??s Kings Cross, including the Kirketon Road Centre (KRC) and the Sydney Medically Supervised Injecting Centre (MSIC), to address the public health risks affecting these populations over time. Sub-themes include the establishment of sentinel surveillance systems at KRC to monitor HIV and HCV prevalence and incidence as well as trends in drug use in these populations, considered to be key drivers of these epidemics in Australia. Another sub-theme is the clinical trials of pharmacotherapies for both opioid and psychostimulant dependence and the development of the dual treatment approach to HIV (and later HCV) and drug dependence that built upon this. KRC has been an exemplar of this approach, which has been shown to enhance treatment adherence among people who inject drugs ?? necessary to achieve treatment outcomes comparable to other affected populations. In more recent years my research has also included a focus on the epidemiology, physiology and treatment of opioid overdose and other injecting-related harms among IDUs. Underlying my work over the past 20 years has been my commitment to the social justice belief that health is a basic human right and that these socially marginalised populations should have equitable access to high quality evidence-based health care.

[Truncated abstract] The hepatitis C virus (HCV) is a significant human pathogen for which there are limited post-infection therapies and no effective vaccine. Research into HCV is notoriously difficult due to the absence of suitable in vitro and in vivo model systems with which to study the virus. Furthermore, our understanding of HCV host interaction is limited and the mechanisms by which it subverts the host immune system remains largely unknown. Due to the difficult nature associated with studying HCV, the work presented in this thesis was designed to addresses a broad range of issues relating to both clinical and molecular aspects of HCV. Chronic HCV infection is often associated with the development of cirrhosis, end stage liver disease and hepatocellular carcinoma. To date, histological examination of liver biopsies provides the only approved method with which to assess the level of liver damage. While clinically informative, liver biopsies are highly invasive and may be contraindicative for patients such as haemophiliacs. Cytokine specific ELISPOT assays were used to determine whether cytokine secretion from PBMCs isolated from chronically infected HCV patients could be used as a non-invasive method to assess liver damage. Chronically infected patients with sever liver fibrosis demonstrated a significantly reduced ability to produce IFN-γ in response to HCV Core, but not other unrelated antigens, indicating that decreased IFN-γ secretion by PBMCs in response to HCV antigen could be used as a non-invasive marker for the development of liver fibrosis ... A series of HCV expression vectors covering the full length of the HCV ORF were constructed and their expression extensively tested before being used to assess the ability of HCV proteins to interact with Jak/STAT mediated Type I IFN signalling. Additionally, an alternative set of HCV IRES-EGFP reporter vectors were developed and used to access HCV IRES functionality between different eukaryotic cell lines. HCV Core protein expressed alone or in concert with E1-P7 and non-structural protein NS5B were shown to significantly reduce Jak/STAT mediated IFN expression. While the influence of HCV Core on Type I IFN signalling is consistent with previous reports in the literature, these results identify a new role for NS5B as a possible candidate protein involved in inhibition of Type I IFN signalling.

Diss. (sammanfattning) Stockholm : Karol. inst., 2002. / Härtill 4 uppsatser.