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Copies of author's previously published articles contained in back cover pocket. / Bibliography: leaves 129-152. / xiv, 152, [60] leaves, [28] leaves of plates : ill. (some col.) (some folded) ; 30 cm. / Title page, contents and abstract only. The complete thesis in print form is available from the University Library. / Examines hepadravirus and HDV replication and gene expression with particular emphasis on the block(s) preventing HBV infection invitro, the extent of the helper function provided by HDV by HBV and the mechanism of HDV RNA replication. / Thesis (Ph.D.)--University of Adelaide, Depts. of Microbiology and Immunology, 1992

Improved methods for the in situ hybridisation detection of messenger RNA ( mRNA ) in sections of liver tissue, were derived by use of an experimental system. This involved the use of tritiated-poly ( dT ) probes to detect poly ( A ) sequences attached to the 3 ' end of mRNA in sections of mouse liver that had been processed in various ways. The improved - methods were applied to the detection of hepatitis B virus ( HBV ) - and hepatitis delta virus ( HDV ) - RNA. In situ hybridisation and immunostaining techniques were then applied to studies of the pathogenesis of HBV and duck hepatitis B virus ( DHBV ) infection. In situ hybridisation studies of liver biopsy tissue from HBV - infected immunosuppressed renal transplant patients demonstrated an anatomical association between piecemeal necrosis and HBV replication at the cellular level in some patients. However, widespread replicative infection of hepatocytes also occurred in some patients in the presence of normal hepatocyte morphology and mild inflammatory changes indicating that at the cellular level virus replication was not necessarily a direct cytopathic process. These findings supported the view that hepatocyte Injury may : ( i ) result from immune - mediated damage directed against cells undergoing replicative, but not restricted infection ; ( ii ) eliminate cells undergoing replicative infection and favour clonal regeneration of cells undergoing restricted infection. Localisation of interferon - alpha ( IFN - alpha ) expression in liver tissue chronically infected with HBV and HDV, identified mononuclear cells and fibroblasts ( but not hepatocytes ) as the main producers of IFN - alpha. IFN - alpha - positive cells were associated with areas of liver tissue containing cells supporting virus replication and exhibiting the greatest degree of liver damage, suggesting that locally produced IFN - alpha may be a natural regulator of virus replication in chronic liver disease. Experimental DHBV infection of Pekin - Aylesbury ducks showed that virus inoculated either intravenously or intraperitoneally, gained access to randomly distributed hepatocytes without first replicating in other cell types in the liver. Virus was seen to disseminate to contiguous cells following anatomical boundaries by the third day post - inoculation. Markers of DHBV infection in liver and serum showed reproducible kinetics, and duck hepatocytes in this system appeared to be highly permissive as large amounts of DHBV DNA and DHBsAg were produced intracellularly without the development of ongoing cytopathology. Hepatocytes were the major cell type responsible for early significant DHBV replication, in contrast to pancreas, kidney, spleen and circulating mononuclear cells where significant levels of infection were detected only after the first week of infection and the onset of viraemia. / Thesis (Ph.D.)--Department of Microbiology and Immunology, 1989.

Improved methods for the in situ hybridisation detection of messenger RNA ( mRNA ) in sections of liver tissue, were derived by use of an experimental system. This involved the use of tritiated-poly ( dT ) probes to detect poly ( A ) sequences attached to the 3 ' end of mRNA in sections of mouse liver that had been processed in various ways. The improved - methods were applied to the detection of hepatitis B virus ( HBV ) - and hepatitis delta virus ( HDV ) - RNA. In situ hybridisation and immunostaining techniques were then applied to studies of the pathogenesis of HBV and duck hepatitis B virus ( DHBV ) infection. In situ hybridisation studies of liver biopsy tissue from HBV - infected immunosuppressed renal transplant patients demonstrated an anatomical association between piecemeal necrosis and HBV replication at the cellular level in some patients. However, widespread replicative infection of hepatocytes also occurred in some patients in the presence of normal hepatocyte morphology and mild inflammatory changes indicating that at the cellular level virus replication was not necessarily a direct cytopathic process. These findings supported the view that hepatocyte Injury may : ( i ) result from immune - mediated damage directed against cells undergoing replicative, but not restricted infection ; ( ii ) eliminate cells undergoing replicative infection and favour clonal regeneration of cells undergoing restricted infection. Localisation of interferon - alpha ( IFN - alpha ) expression in liver tissue chronically infected with HBV and HDV, identified mononuclear cells and fibroblasts ( but not hepatocytes ) as the main producers of IFN - alpha. IFN - alpha - positive cells were associated with areas of liver tissue containing cells supporting virus replication and exhibiting the greatest degree of liver damage, suggesting that locally produced IFN - alpha may be a natural regulator of virus replication in chronic liver disease. Experimental DHBV infection of Pekin - Aylesbury ducks showed that virus inoculated either intravenously or intraperitoneally, gained access to randomly distributed hepatocytes without first replicating in other cell types in the liver. Virus was seen to disseminate to contiguous cells following anatomical boundaries by the third day post - inoculation. Markers of DHBV infection in liver and serum showed reproducible kinetics, and duck hepatocytes in this system appeared to be highly permissive as large amounts of DHBV DNA and DHBsAg were produced intracellularly without the development of ongoing cytopathology. Hepatocytes were the major cell type responsible for early significant DHBV replication, in contrast to pancreas, kidney, spleen and circulating mononuclear cells where significant levels of infection were detected only after the first week of infection and the onset of viraemia. / Thesis (Ph.D.)--Department of Microbiology and Immunology, 1989.

Murine hepatitis virus type 3 (MHV-3), a member of the coronavirus family, induces a response that varies with the age and genetic background of the host mouse strain. A/J mice are fully resistant to the virus, while Balbc/J are fully susceptible and C3HebFe/J are semi-susceptible, making it possible to predictably reproduce the major human responses to hepatitis viruses. Although there has been considerable discussion of viral pathology in the literature, there has been much less emphasis on pathogenesis. In the experiments described here, histological, biophysical, and immunological techniques have been used to define the processes and cells involved. Transmission electron microscopic observations have confirmed that Kupffer and endothelial cells of hepatic sinusoids show clear changes by 12 hrs post-infection (p.i.), which are more advanced than hepatocellular changes. No replicating virus was seen in altered hepatocytes up to 3 days p.i. Scanning electron microscopy demonstrated that areas of necrosis are focal in nature and at 2-3 days p.i. consist of small spherical areas without flow. In vivo microcirculatory studies confirm the localized nature of the lesion and have shown that red cell velocity can be recorded in individual sinusoids . Velocities were found to vary from zero within a lesion to a normal velocity of 69±31 um/sec over a distance of not more than 3 sinusoids. In-vivo microcirculatory studies also revealed the ability of macrophages to move upstream (against flow) in the hepatic sinusoids. Using fluorescein labelled antibodies to cell surface markers (Thy-1, Lyt-2, and L3T4) it was shown that no T-cells of any subset were present in the areas of hepatocellular necrosis. Furthermore, treatment with cyclosporine A, which would be expected to decrease necrosis due to cell mediated cytotoxicity, did not significantly alter the course of the disease. The only cells which increased in number in the liver post infection were cells of the monocyte/macrophage lineage (Mac 1+), which had increased twofold at 12 hrs (p<.025) p.i. and to greater than twenty fold (p<.005) by 3 days p.i. Resistance in the A/J strain did not reflect an inability of the immunocompetent cells to present and respond to viral antigen. It was demonstrated that MHV-3 infected macrophages from resistant A/J mice are better able to stimulate proliferation of allogeneic and syngeneic lymphocytes than those from the sensitive Balb/cJ strain. In contrast, MHV-3 infection caused a significant enhancement of chemiluminescence from Balb/cJ macrophages, which did not occur in A/J animals. In vivo studies demonstrated a significant increase in free radical reaction products, including conjugated dienes (of long chain free fatty acids and aldehydes), thiobarbituric acid reactive substances, and lipid soluble fluorescent products between 12-72 hours p.i. with MHV-3 in the livers of susceptible Balb/cJ strain mice. All of these are products of oxidative cleavage of cellular and membrane polyunsaturated fatty acids, and result from the action of oxygen free radicals. Free radical inhibitors, or quenchers of free radical reaction products, were able to significantly reduce the liver necrosis in the susceptible mouse strain following infection. Radioimmune assays for antibody to MHV-3 have confirmed the presence of preformed antibodies to (or cross-reactive with) MHV-3 in the sera of both susceptible and resistant mice, pre and post-infection. Immunofluorescent labelled antibodies have also been used to demonstrate the presence of IgG deposits in the sinusoids of the liver both pre and post infection. This suggests the possibility that these mice have been infected with a non-virulent MHV strain prior to these experiments. From these studies, we conclude that the hepatic injury caused by MHV-3 infction in Balb/cJ mice is mediated predominantly by fixed and migratory cells of the mononuclear phagocytic series. Susceptibility and resistance are related to strain dependant differences in the response of macrophages (and Kupffer cells) to infection, and include the release of procoagulant activity (previously shown) and reactive oxygen radicals (and possibly other macrophage activation products such as PAF) that act together to induce hepatocellular necrosis. Preformed non-neutralizing antibody and an intact complement cascade may enhance viral uptake and activation of macrophages in the Balbc/J mice. Resistance to necrosis may be enhanced by a genetic deficiency of C5 in the A/J mice, preventing the formation of the membrane attack complex and hence complement dependant cell lysis, or macrophage activation. / Medicine, Faculty of / Pathology and Laboratory Medicine, Department of / Graduate

Please read the abstract in the 00front part (pp12-17) of this document / Dissertation (MSc (Medical Virology))--University of Pretoria, 2004. / Medical Virology / unrestricted

Tez (Uzmanlık) - Süleyman Demirel Üniversitesi, Tıp Fakültesi, Enfeksiyon Hastalıkları ve Klinik Mikrobiyoloji Anabilim Dalı, 2008. / Kaynakça var.

Recently a new Flavivirus, GB Virus C also referred to as Hepatitis G virus (GBV-C/HGV) was identified in humans with indeterminate hepatitis . Whilst in non-African countries this discovery led to an enormous enthusiasm to elucidate an association with liver disease, very little was known about the prevalence and pathogenicity of GBV-C/HGV infection in KwaZulu Natal, South Africa, where Hepatitis B Virus (HBV) infection is endemic and infection with the Human immunodeficiency virus (HIV) is a catastropic health problem. Sera from patients with liver disease (chronic liver disease [n = 98]; alcoholic liver disease [n = 50]); high risk groups (haemodialysis patients [n = 70]; HIV positive mothers and their babies [n = 75]) and control groups (alcoholics without liver disease [n = 35] and blood donors from the four racial groups [n = 232]) were screened for GBV-C/HGV RNA and Anti-E2 antibodies by reverse transcription polymerase chain reaction (RT-PCR) and an enzyme linked immunosorbent assay (ELISA), respectively. Overall 43.9% (43/98) of patients with chronic liver disease; 60 % (30/50) of patients with alcoholic liver disease; 47.1% (33/70) of haemodialysis patients; 60% (21/35) of alcoholics without liver disease and 31.9% (74/232) of blood donors (Africans] 44/76; 5.9%); Asians (5/52; 9.6%); Whites (15/49; 30.6%) and "Coloureds" [mixed origin] (9/54; 16.6%)]) were exposed to GBV-C/HGV infection as determined by the detection of Anti-E2 &/or RNA in serum. There was a significant difference in the prevalence of GBV-C/HGV infection (RNA &/or anti E2) between African blood donors and the other racial groups (p < 0.001), between blood donors and haemodialysis patients (p = 0.02) and or patients with chronic liver disease (p =0.04). There was no significant difference in the prevalence of GBV-C/HGV between African blood donors (45/76, 59.2%) and alcoholics with and without liver disease (30/50, 60% and 21/35, 60%, respectively). Anti-E2 antibodies and GBV-C/HGV RNA were almost mutually exclusive. GBV-C/HGV infected dialysis patients tended to have had more transfusions (p = 0.03) and had a longer duration of dialysis than non infected patients, indicating that the majority of patients on maintenance haemodialysis acquire their GBV-C/HGV infection through the transfusions they receive. There was no evidence for in utero and/or intrapartum transmission of GBV-C/HGY. However, there is some mother-to-infant transmission of GBV-C/HGV, though it is very probable that in KZN GBV-C/HGV is transmitted by as yet undefined non-parenteral routes. Sequence and phylogenetic analysis of the 5' non-coding region (5' NCR) and E2 gene segments of the GBV-C/HGV genome identified an additional "genotype" (Group 5) of GBV-C/HGV that is distinct from all other known GBV-C/HGV sequences (Groups 1-4). Although there is a high prevalence of Group 5 GBV-C/HGV isolates in KZN, there was no significant difference in liver biochemistry between GBV-C/HGV infected and noninfected patients with liver disease or between blood donors in each of the four racial groups. There was no significant differences in CD4 (461.12 ± 163.28 vs 478.42 ± 181.22) and CD8 (680.83 ± 320.36 vs 862.52 ± 354.48) absolute cell counts between HIV positive patients co-infected with GBV-C/HGV and those not infected with GBV-C/HGV, respectively. However, significantly higher relative CD3 [80.0 ± 4.17% vs 70.99 ± 19.79%] (p = 0.015), gamma delta T cells (yLT) [3.22± 1.30% vs 2.15 ± 29.12%] (p = 0.052) and lower CD 30 [35.45 ± 17.86% vs 50.59 ± 9.20%] (p = 0.041) status were observed in GBV-C/HGV positive compared to GBV-C/HGV negative HIV infected patients, respectively. Although there is a high prevalence of novel Group isolates of GBV-C/HGV in KZN, the lack of elevated liver enzymes and clinical hepatitis in blood donors and haemodialysis patients suggests that GBV-C/HGV is not associated with liver disease. HBV and not GBV-C/HGV modifies the course of alcoholic liver disease. The relatively higher number of CD3 cells and increased yLT expression, together with a decrease in CD 30 cells tends to suggest an association with protection and or delayed progression of HIV disease in GBV-C/HGV infected patients. Whilst GBV-C/HGV is not associated with liver disease, it may be an important commensal in HIV infected patients. / Thesis (Ph.D.)-University of Natal, 2003.

Thesis (Ph. D.)--University of Virginia, 2008. / Title from title page. Includes bibliographical references. Also available online as viewed 10/12/2009 through Digital Dissertations.

Thesis (M.Sc.)--Memorial University of Newfoundland, Faculty of Medicine, 2000. / Typescript. Bibliography: leaves 219-243.