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Howard C Thomas

Publications and source records attributed to Howard C Thomas.

29 records · Page 2Linked to original sources
PubMed2004

Identification of unique hepatitis C virus quasispecies in the central nervous system and comparative analysis of internal translational efficiency of brain, liver, and serum variants.

Reports of cerebral dysfunction in chronic hepatitis C virus (HCV) infection have led to the suggestion that HCV may infect the central nervous system (CNS). We used reverse transcription-PCR, cloning, and sequencing to define quasispecies for the HCV internal ribosomal entry site (IRES) and hypervariable region 1 (HVR1) in autopsy-derived brain, liver, lymph node, and serum samples. There was evidence of tissue compartmentalization of sequences in the brain in two patients, with between 24 and 55% of brain-derived IRES sequences absent from the serum, and significant phylogenetic and phenetic clustering of the brain and lymph node HVR1 sequences. The IRES initiates cap-independent translation of the viral polyprotein. Two unique brain-derived IRES mutations (C(204)-->A and G(243)-->A), which have previously been associated with lymphoid replication and altered translational efficiency in cell culture, were found in one patient. We used a dicistronic reporter vector to test whether brain-derived variants showed altered IRES-mediated translational efficiency, which might favor CNS infection. The translational efficiencies of the brain-derived IRES sequences were generally reduced compared to those of the master serum and liver sequences in rabbit reticulocyte cell lysates and two human cell lines, HuH7 (liver) and CHME3 (microglial). The C(204)-->A and G(243)-->A mutations showed preserved translational efficiency in HuH7 cells but reduced efficiency in CHME3 cells. Our data provide evidence that the CNS is a site of HCV replication, consistent with the recent demonstration of negative-strand HCV RNA in brain, and suggest that IRES polymorphisms may be important as a viral strategy of reduced translation to favor latency in the CNS.

Base Sequence↗
PubMed2003

Interleukin-10 promoter polymorphisms and the outcome of hepatitis C virus infection.

The natural outcome and response to treatment in hepatitis C virus (HCV) infection varies between individuals. Whereas some variation may be attributable to viral and environmental variables, it is probable that host genetic background also plays a significant role. Interleukin (IL)-10 has a key function in the regulation of cellular immune responses and in the suppression of pro-inflammatory cytokine secretion. Functional polymorphisms in the IL-10 gene have been described. We investigated the role of these polymorphisms in the outcome of HCV infection, treatment response and development of fibrosis in a case-control association study. Self-limiting infection was associated with the IL-10 (-592) AA genotype (OR=2.05; P=0.028). Persistent infection was associated with the IL-10 (-1082) GG genotype (OR=0.48; P=0.018). Sustained response to interferon therapy was associated with the IL-10 (-1082) GG genotype (OR=2.28; P=0.005) and the haplotype GCC (OR=2.27; P=0.020). The IL-10 (-1082) AA genotype and the ATA/ATA and ACC/ACC homozygous haplotypes were more frequent among patients with rapid fibrosis. Furthermore, the microsatellites IL-10.R and IL-10.G were associated with interferon response with IL-10R.2 conveying susceptibility (OR=1.80; P=0.034), and IL-10R.3 and IL-10.G13 being protective (OR=0.47; P=0.003 and OR=0.59; P=0.042, respectively). We conclude that polymorphisms in the IL-10 promoter appear to have some influence on the outcome of HCV infection, treatment and development of fibrosis.

Disease Progression↗
PubMed2003

Changes in hypervariable region 1 of the envelope 2 glycoprotein of hepatitis C virus in children and adults with humoral immune defects.

The N-terminal end of the hepatitis C virus (HCV) envelope glycoprotein E2 contains a stretch of 27 amino acids that exhibit increased variability. This hypervariable region 1 (HVR-1), as it is normally referred to, is thought to contain epitopes that come under humoral immune attack. In the present study, 10 patients (5 children and 5 adults) with humoral immune defects and chronic HCV infection were investigated, to see how HVR-1 sequences behave over time in these patients who are unable to produce antibodies. Amplicons of this region showed little or no variation at all over time, indicating that quasispecies variation in this region is driven by the host's humoral immune response.

Adolescent↗
PubMed2003

Association of genetic variants of the chemokine receptor CCR5 and its ligands, RANTES and MCP-2, with outcome of HCV infection.

The effect of host genetic variation on the outcome of hepatitis C virus (HCV) infection and its treatment is poorly understood. The chemokine receptors CCR5, CCR2, and CCR3 and their ligands, RANTES, MCP-1, MCP-2, and MIP-1alpha, are involved in the immune responses and the selective recruitment of lymphocytes to the liver in HCV infection. We studied 20 polymorphisms within these genes and investigated their association with persistent carriage of HCV, severity of liver disease, hepatic inflammation, and response to treatment in a large European cohort. Significant associations were found between CCR5-delta32 and reduced portal inflammation (P =.011, odds ratio [OR]: 2.3, 95% confidence interval [CI]: 1.09-4.84) and milder fibrosis (P =.015, OR: 1.97, 95% CI: 1.13-3.42). A promoter polymorphism at position -403 in the RANTES gene was associated with less severe portal inflammation (P =.004). An amino acid change in MCP2, Q46K, was associated with severity of fibrosis (P =.018, OR: 2.29, 95% CI: 1.14-4.58). In conclusion, our study suggests a possible role of the polymorphisms CCR5-delta32, RANTES -403, and MCP-2 Q46K in the outcome of HCV infection.

Base Sequence↗
PubMed2002

Evolution of epitope-specific memory CD4(+) T cells after clearance of hepatitis C virus.

The generation of memory lymphocytes is one of the hallmarks of the specific immune response. The CD4(+) T cell response is of critical importance in maintaining long-term protective immunity after clearing many infections. However, accurate characterization of these memory CD4(+) T cells has relied mainly on mouse studies and is poorly understood in humans. We have detected and counted epitope-specific populations of CD4(+) memory cells in patients who have cleared hepatitis C virus. The kinetics of the recall response and the expression of the chemokine receptor CCR7 suggested the presence of distinct populations. A population of memory cells measured in an ex vivo IFN-gamma ELISPOT assay steadily declined after viral clearance. However, memory CD4(+) T cells only characterized after short-term culture with Ag and IL-2, and, recognizing the same epitopes, developed into a long-term stable population. Depletion of CCR7(+) cells from PBMCs markedly reduced the responses in the culture-positive population while having little effect on the ex vivo responses. The demonstration of these key memory subsets in man opens the way to defining their role in protective immune responses.

Adult↗
PubMed2002

Changing international trends in mortality rates for liver, biliary and pancreatic tumours.

BACKGROUND/AIMS: The age-standardized mortality rate for hepatocellular carcinoma is increasing in several countries. However, in England and Wales we previously reported an increase in mortality rates from intrahepatic cholangiocarcinoma. Trends in cholangiocarcinoma in most other industrialized countries are unknown. To further study trends in hepatobiliary and pancreatic tumours, we analysed mortality data from the United States, Japan, Australia and Europe. METHODS: Age-standardized mortality rates for men and women for subcategories of liver tumours, tumours of the gall bladder and extrahepatic biliary tree and pancreas from 1979 to 1998 were obtained from the World Health Organization mortality database. RESULTS: We confirmed previously reported increases in hepatocellular carcinoma, but also found increases in other countries, particularly Australia (3-year average rise from 1.20 to 2.27, men). Mortality for intrahepatic cholangiocarcinoma increased in men in all countries studied, with the largest increases in Australia (from 0.10 to 0.70) and England and Wales (from 0.20 to 0.83). CONCLUSIONS: We present a hitherto unreported rise in age-standardized mortality rates from intrahepatic cholangiocarcinoma across four continents. The cause remains uncertain. An impact on the observed trends of improved diagnostic techniques and death certificate misclassification cannot be completely ruled out. Future research should include epidemiological studies to examine possible case-clustering and investigation of potential aetiological and host factors.

Australia↗
PubMed2002

Hepatitis C and cognitive impairment in a cohort of patients with mild liver disease.

Patients with chronic hepatitis C virus (HCV) infection frequently report fatigue, lassitude, depression, and a perceived inability to function effectively. Several studies have shown that patients exhibit low quality-of-life scores that are independent of disease severity. We therefore considered whether HCV infection has a direct effect on the central nervous system, resulting in cognitive and cerebral metabolite abnormalities. Twenty-seven viremic patients with biopsy-proven mild hepatitis due to HCV and 16 patients with cleared HCV were tested with a computer-based cognitive assessment battery and also completed depression, fatigue, and quality-of-life questionnaires. The HCV-infected patients were impaired on more cognitive tasks than the HCV-cleared group (mean [SD]: HCV-infected, 2.15 [1.56]; HCV-cleared, 1.06 [1.24]; P =.02). A factor analysis showed impairments in power of concentration and speed of working memory, independent of a history of intravenous drug usage (IVDU), depression, fatigue, or symptom severity. A subgroup of 17 HCV-infected patients also underwent cerebral proton magnetic resonance spectroscopy (1H MRS). The choline/creatine ratio was elevated in the basal ganglia and white matter in this group. Patients who were impaired on 2 or more tasks in the battery had a higher mean choline/creatine ratio compared with the unimpaired patients. In conclusion, these preliminary results demonstrate cognitive impairment that is unaccounted for by depression, fatigue, or a history of IVDU in patients with histologically mild HCV infection. The findings on MRS suggest that a biological cause underlies this abnormality.

Adult↗
PubMedDate not supplied

New insights into hepatitis C.

Hepatitis C infection is characterised by three key features, which are the consequence of a complex interaction between genetic determinants of immune and other host factors and viral characteristics: 1. A high rate of viral persistence after acute infection resulting from a combination of weak T cell responsiveness and specific viral mechanisms of immune escape. 2. Marked interindividual variability in end-organ damage (fibrosis and cirrhosis), probably due to host genetic polymorphisms in genes governing the immune response and fibrosis pathways in addition to viral pathogenicity factors. 3. Significant resistance to antiviral therapies. Viral mechanisms of antiviral resistance parallel those of viral persistence, and include the intriguing possibility that hepatitis C may infect immunologically privileged sites such as the central nervous system.

Antiviral Agents↗