HIV and hepatotropic viruses: interactions and treatments.
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AIDS-Related Opportunistic Infections↗
Biomedical subjects
H C Thomas
Publications and source records attributed to H C Thomas.
Mutation of gene of mannose-binding protein associated with chronic hepatitis B viral infection.
BACKGROUND: Persistent with hepatitis B virus (HBV) affects 350 million people worldwide, and 20-40% of infected patients die of cirrhosis and liver cancer. Little is known about the host factors that determine the variable natural history. Studies have focused on the role of acquired rather than innate immunity. We have investigated the prevalence of mutations in the gene for mannose-binding protein (MBP), which have been associated with susceptibility to bacterial and fungal infections. METHODS: Mutations in the MBP gene were sought by sequence-specific oligonucleotide hybridisation, site-directed sequencing in Caucasian and Asian patients with HBV infection, and in HBsAg-negative controls. FINDINGS: A mutation in codon 52 of the MBP gene was present in two (11%) of 19 Caucasian patients with acute hepatitis B and nine (27%) of 33 Caucasian patients with chronic hepatitis B, compared with four (4%) of 98 Caucasian controls (p = 0.0004). By contrast the prevalence of the mutation was similar in Asian patients with chronic hepatitis B and in Asian controls (one [5%] of 20 vs two [2%] of 117). Mutations in codon 54 and codon 57 were found in similar proportions of patients and controls. INTERPRETATION: These findings show in Caucasian, but not Asian, patients an association of the codon 52 mutation of the MBP gene with persistent HBV infection. They suggest an important role for this gene, or a gene in linkage disequilibrium with MBP, in determining outcome after HBV infection in adult but not neonatal life.
Acute Disease↗
Viral dynamics in hepatitis B virus infection.
Treatment of chronic hepatitis B virus (HBV) infections with the reverse transcriptase inhibitor lamivudine leads to a rapid decline in plasma viremia and provides estimates for crucial kinetic constants of HBV replication. We find that in persistently infected patients, HBV particles are cleared from the plasma with a half-life of approximately 1.0 day, which implies a 50% daily turnover of the free virus population. Total viral release into the periphery is approximately 10(11) virus particles per day. Although we have no direct measurement of the infected cell mass, we can estimate the turnover rate of these cells in two ways: (i) by comparing the rate of viral production before and after therapy or (ii) from the decline of hepatitis B antigen during treatment. These two independent methods give equivalent results: we find a wide distribution of half-lives for virus-producing cells, ranging from 10 to 100 days in different patients, which may reflect differences in rates of lysis of infected cells by immune responses. Our analysis provides a quantitative understanding of HBV replication dynamics in vivo and has implications for the optimal timing of drug treatment and immunotherapy in chronic HBV infection. This study also represents a comparison for recent findings on the dynamics of human immunodeficiency virus (HIV) infection. The total daily production of plasma virus is, on average, higher in chronic HBV carriers than in HIV-infected patients, but the half-life of virus-producing cells is much shorter in HIV. Most strikingly, there is no indication of drug resistance in HBV-infected patients treated for up to 24 weeks.
Alanine Transaminase↗
Hepatitis B virus envelope variation after transplantation with and without hepatitis B immune globulin prophylaxis.
Hepatitis B virus (HBV) replicates via an intermediate RNA step. High frequency of polymerase errors with additional selection pressure leads to mutations in the HBV genome. We investigated the number, type, and antigenic effects of mutations in the coding region of the HBV surface antigen in eight patients who underwent orthotopic liver transplantation (OLT) for HBV-related end-stage liver disease and were experiencing infection of the graft and who received hepatitis B surface antigen antibody (anti-HBs) prophylaxis (hepatitis B immune globulin [HBIG]) after OLT. Controls were chronic HBV patients who underwent kidney transplantation and received the same immunosuppressive regime but no HBIG. The S-gene was amplified from serum before and after transplantation, sequenced, and changes in the genome were analyzed. In the five patients who experienced reinfection while receiving anti-HBs, clear mutations occurred in the S-gene. In the patient who did not receive HBIG and those who experienced reinfection only after termination of HBIG, no mutations were found in the S-gene. In the kidney recipients, mutations in the S-gene occurred in only one of eight patients. Because the a determinant contains neutralizing epitopes, this region was chosen for antibody binding to quantify antigenic effects of the mutations. The two patients who selected mutations in the a determinant and became reinfected while receiving HBIG had reduced antibody binding after OLT. Our results suggest that HBIG after OLT imposes a selection pressure on the S-gene, and that mutations are one mechanism for reinfection while receiving HBIG.
Amino Acid Sequence↗
Cell cycle alterations associated with covalent binding of monocrotaline pyrrole to pulmonary artery endothelial cell DNA.
In the monocrotaline (MCT) rat model of pulmonary hypertension, the pulmonary vascular endothelium is thought to be the early target of the bifunctionally reactive metabolite monocrotaline pyrrole (MCTP). In previous studies, bovine pulmonary arterial endothelial cells (BPAEC) exposed to MCTP exhibited inhibition of proliferation. Since other compounds that crosslink DNA lead to cell cycle alterations, we utilized BPAEC to correlate the effects of MCTP on the cell cycle with the extent of covalent binding of [14C]MCTP to BPAEC DNA. Dose response (0.0 to 50.0 micrograms MCTP/ ml) and 96-hr time course (5 micrograms MCTP/ml low dose or 34.5 micrograms MCTP/ml high dose) studies were carried out followed by flow cytometric cell cycle analysis. High concentrations of MCTP caused cell cycle arrest in S phase, beginning by 24 hr, while an S phase delay was observed at low concentrations, but progressed to a G2 + M phase arrest by 48 hr. Covalent DNA binding (34.5 micrograms/ml of [14C]MCTP incubated with BPAEC) occurred within 1 hr and progressively increased through 96 hr. In conclusion, covalent binding of MCTP to DNA is associated with cell cycle arrest; however, the position of cell cycle arrest is dependent on dose, with an S phase arrest at high concentrations and a G2 + M phase arrest at low concentrations of MCTP. The mechanism by which MCTP induces proliferative inhibition could be cell cycle arrest.
Animals↗
Pathogenesis of chronic hepatitis C and associated clinical manifestations.
In 20% of patients exposed to hepatitis C virus, infection is transient but, after a few months, the patient remains susceptible to infection with the same strain. Protective immunity is short-lived. This suggests that recovery is related to the cellular immune response, which presumably lyses infected cells, and that the need during recovery for a virus-neutralizing anti-envelope response, is transient. In 80% of patients the infection is persistent, and it seems that antigenic variation of the envelope proteins allows the virus to escape neutralization by anti-envelope responses. The fact that this antigenic variation occurs at a much lower rate in agammaglobulinaemic subjects suggests that the major immune pressure producing this variation is humoral. How the virus-infected cells avoid lysis by cytotoxic T cells, which can be demonstrated in small numbers in the infected liver, remains unclear. The recent observation, that HCV infects CD8 lymphocytes, raises the possibility that virus infection of CD8 cells may impair their function and contribute to persistent infection. The mechanisms of production of cryoglobulin and of autoantibody formation are both unclear.
Hepacivirus↗
Granulomas and hepatitis C.
Hepatitis C (HCV) is associated with a number of characteristic histological features. A recent paper has identified an increased frequency of granulomas in resection specimens from cases of HCV. We have carried out a retrospective study of 155 cases of HCV to assess the frequency of granulomas in biopsy specimens. We had two control groups: 151 cases of hepatitis B (HBV) and 129 cases of alcohol induced liver disease. Granulomas were found in 14 cases of HCV (10%), three cases of HBV (2%) and three cases of alcohol induced liver disease (2%). Granulomas were significantly commoner in cases of HCV than in the other two groups. Of the 14 cases of HCV, the granulomas could be ascribed to another cause in seven cases. When the analysis was carried out, excluding those granulomas which could be ascribed to another cause, they were still significantly commoner in cases of HCV. We conclude that granulomas are more frequent in HCV but that in half of cases in which they are found another cause can be identified. This means that if granulomas are seen in association with hepatitis C another aetiology should be sought before ascribing them to HCV.
Granuloma↗
Different relative activities of human cell-derived interferon-alpha subtypes: IFN-alpha 8 has very high antiviral potency.
Interferon-alpha (IFN-alpha) subtypes were separated by HPLC from the IFN mixtures produced by virus-stimulated human lymphoblastoid cells and leukocytes. Together with preparations of lymphoblastoid IFN and recombinant IFN-beta, these were tested in three human tumor cell lines derived from liver, lung, and neuroblasts. Their relative antiviral activities differed markedly: subtype IFN-alpha 8 was the most potent and IFN-alpha 1 the least. The results were broadly similar in all three cells, with some minor differences. when the same preparations were tested for inhibition of thymidine incorporation, the relative activities were quite different: subtypes IFN-alpha 10, IFN-alpha 17, IFN-alpha 21, and IFN-alpha 5 were now the most active, and IFN-alpha 2 was the least active. IFN-alpha 1 and IFN-alpha 8 had comparable intermediate activity. Thus, the differences in activity were not caused by degradation of some subtypes during their separation. IFN-alpha 8 not only had the greatest antiviral activity but also, like IFN-beta, induced an antiviral state in U1 mutant cell lines, which lack the tyrosine kinase, Tyk2, required for signal transduction by other IFN-alpha subtypes.
Antiviral Agents↗
The expression of hepatitis B virus polymerase in hepatocytes during chronic HBV infection.
A recombinant protein corresponding to part of the amino-terminal domain of hepatitis B virus (HBV) polymerase was expressed in Escherichia coli. Antisera raised against this protein stained hepatocytes, from human liver biopsies, predominantly in the nucleus but some cytoplasmic staining was also observed. No staining was observed in hepatocytes from uninfected patients. Liver biopsies, taken from patients who were infected with human immunodeficiency virus (HIV) as well as HBV showed more intense staining with these antisera than that seen in patients who were infected with HBV alone. The staining pattern suggests that either the whole HBV polymerase protein, or a portion encoding the amino-terminal domain, is translocated to the nucleus. This event may be an important early step in replication of the HBV genome.
AIDS-Related Opportunistic Infections↗
Whole genome analysis of hepatitis B virus from four cases of fulminant hepatitis: genetic variability and its potential role in disease pathogenicity.
The precore stop-codon variant of hepatitis B virus (HBV) has been associated with fulminant hepatitis but is also found in patients with persistent infection and chronic hepatitis. We have examined the possibility that the severe outcome of infection in patients with fulminant disease may be a result of additional genomic variation. We sequenced the entire HBV genome from three patients of Greek and one patient of Chinese origin with fulminant hepatitis, and from two patients with hepatitis B e antigen (HBeAg) positive chronic infection from the same regions, using direct sequencing of amplified viral DNA. Three of the fulminant cases were infected with the precore stop-codon variant HBeAg negative) and the fourth with the wild-type (HBeAg) positive virus. We compared sequences from our four fulminant isolates, and an additional fulminant isolate reported by others, with HBeAg positive carriers from the same regions and 12 published HBV genomes. There was a higher number of nucleotide and amino-acid substitutions throughout the HBV genome in the precore variant fulminant sequences than in the wild type. A cluster of mutations previously identified in the X region (126-132) in sequences reported in Japanese patients and encompassing the Enhancer II-Core Promoter region (1751-1768), were not found in our patients. We conclude that although there are no changes common to all sequences of HBV isolates from fulminant cases, some of these changes are in recognized cis-acting regulatory elements, whilst others are in the immediate vicinity of such elements. The effect of these mutations on viral genome transcription must now be determined.
Amino Acid Sequence↗
A double blind, placebo-controlled study to assess the effect of famciclovir on virus replication in patients with chronic hepatitis B virus infection.
This is the first double-blind controlled study of famciclovir, an oral antiviral agent, as potential therapy for chronic hepatitis B virus (HBV) carries. A fall of more than 90% in HBV DNA levels was noted in six of 11 evaluable patients treated with a 10 day course of oral famciclovir. Further studies with more prolonged therapy are ongoing.
2-Aminopurine↗
Hepatitis G virus RNA in the serum of patients with elevated gamma glutamyl transpeptidase and alkaline phosphatase: a specific liver disease? [corrected].
We tested the sera of 67 consecutive patients for hepatitis G virus (HGV) RNA by reverse transcriptase-polymerase chain reaction (RT-PCR). These patients (42 males and 25 females, median age 35 years, range 13-64 years) had liver disease of unknown aetiology and were without markers of hepatitis (A-E) viruses or signs of genetically determined, autoimmune, alcoholic or drug-induced liver disease. The controls in this study were 110 patients (50 females and 60 males, median age 45 years, range 9-65 years) with chronic hepatitis B virus (HBV) infection (19 patients) or hepatitis C virus (HCV) infection (91 patients). Ten of 67 (14.9%) patients with cryptogenic disease were positive for HGV RNA by at least three separate tests; HGV RNA was also detected in one of 19 (5.3%) hepatitis B surface antigen (HBsAg) carriers and in nine of 91 (16.6%) patients with antibody to HCV. These data suggest that HGV occurs as frequently in HCV-infected patients as in those with cryptogenic disease. Elevated serum gamma glutamyl transpeptidase (gamma-GT) (higher than twice the normal value) and alkaline phosphatase levels were found in eight of 10 (80%) HGV RNA positive patients and in six of 57 (10.5%) HGV RNA negative patients (P < 0.0001). Five (50%) HGV RNA positive patients had non-specific inflammatory bile duct lesions. A statistically significant difference was observed between HGV RNA positive and negative patients with chronic HBV or HCV infections (P < 0.029). Therefore, the spectrum of liver disease associated with HGV is wide, but a characteristic lesion of the bile duct leading to elevation of cholestatic enzymes might be specific for this virus.
Adolescent↗
Hepatitis C and bile duct loss.
AIM: To assess whether bile duct loss is associated with the bile duct damage induced by chronic hepatitis C. METHODS: Sections were examined from 171 liver biopsy specimens from patients with chronic hepatitis C, 98 biopsy specimens from patients with chronic hepatitis B, 25 postmortem specimens from patients with no evidence of liver disease, and 23 patients who underwent protocol liver biopsy at the time of cholecystectomy. RESULTS: The bile duct:portal tract ratio for the hepatitis C group was 0.89, for the hepatitis B group was 0.93 and for the two control groups was 0.96 and 0.90, respectively. The ratio was lower in the hepatitis C group than in the other three. In no case of chronic hepatitis C was the ratio less than 0.60. In the hepatitis C group greater bile duct loss was seen in cirrhotic patients. CONCLUSIONS: Hepatitis C is associated with bile duct loss and this was related to the stage of the disease. However, in the cases studied this did not reach what is generally considered to be significant (that is, greater than 50% of portal tracts lacking bile ducts). This does not preclude a contributory effect of hepatitis C to bile duct loss in the presence of other risk factors, especially in liver transplant recipients.
Bile Duct Diseases↗
Pathophysiology and treatment of hepatitis C.
Hepatitis C virus (HCV) infection is associated with a variable disease course and response to therapy. Some infected patients may develop little or no disease for 30 to 40 years, whereas others will develop cirrhosis within 5 to 10 years. Both host and viral factors influence the rate of disease progression. The management of patients is determined by the severity of their disease assessed by liver biopsy. Those with mild hepatitis without fibrosis do not require treatment but should undergo liver biopsy every 3 years. Patients with mild hepatitis with fibrosis, or with moderate or severe hepatitis with or without fibrosis, should be offered treatment. Interferon-alpha (IFN alpha) is currently the only licensed treatment for HCV infection. Although initial response rates to IFN alpha are high, over half the patients relapse and a sustained response is achieved in only 10 to 35% of patients. Higher doses of IFN alpha and a longer treatment duration are associated with better response rates. Treatment options for those who fail to respond to IFN alpha include a second course of IFN alpha at a higher dose or IFN alpha in combination with ribavirin, phlebotomy or ursodeoxycholic acid. At present, however, there are insufficient data to routinely recommend any of these options.
Hepatitis C↗
Association between an MHC class II allele and clearance of hepatitis B virus in the Gambia.
BACKGROUND: The course of hepatitis B virus (HBV) infection does not appear to be determined by variations in viral virulence and may be influenced by the host immune response. We studied the distribution of human leukocyte antigens in children and adult men in the Gambia who spontaneously recovered from HBV infection as compared with the distribution of these antigens in subjects with persistent infection. METHODS: In a two-stage, case-control study, we analyzed the frequency of MHC class I antigens and class II haplotypes in people with either transient or persistent HBV infection. MHC class I typing was performed by microlymphocytotoxicity assays. MHC class II typing was performed with analysis of restriction-fragment-length polymorphisms (RFLPs), supplemented by other techniques. RESULTS: In the first stage (the study of children up to the age of 10 years), the RFLP pattern 25-1, which includes the class II allele HLA-DRB1*1302, was found in 58 of 218 subjects with transient HBV infection (26.6 percent) and 30 of 185 subjects with persistent infection (16.2 percent) (relative risk of carrying the 25-1 pattern in the persistently infected group as compared with the transiently infected group, 0.53; 95 percent confidence interval, 0.32 to 0.90; P = 0.012). In the second stage (the study of adults), HLA-DRB1*1302 was found in 50 of 195 subjects with transient HBV infection (25.6 percent) and in 3 of 40 subjects with persistent infection (7.5 percent) (relative risk, 0.24; 95 percent confidence interval, 0.04 to 0.80; P = 0.012). The RFLP pattern 13-2, which includes the class II allele DRB1*1301, was less frequent in children with persistent infection than in those with transient infection, an association that was neither confirmed nor excluded by the data on adults. Possible associations with HLA class I antigens found in children were not supported by the data on adults. CONCLUSIONS: The MHC class II allele DRB1*1302 was associated with protection against persistent HBV infection among both children and adults in the Gambia.
Adult↗
Fibrosing cholestatic hepatitis in a renal transplant recipient associated with the hepatitis B virus precore mutant.
A patient with evidence of chronic infection with hepatitis B virus (seropositive for hepatitis B surface antigen, and with antibody to hepatitis B e antigen) underwent renal transplantation, which subsequently failed. The patient developed abnormal liver function tests and 8 months after the removal of the transplanted kidney, hepatitis B virus DNA was detected in the serum in the absence of hepatitis B e antigen. Liver biopsy revealed the presence of fibrosing cholestatic hepatitis. Sequence analysis of the serum hepatitis B virus DNA showed the presence of the pre-core mutant. This case shows that fibrosing cholestatic hepatitis can occur outside the setting of liver transplantation, and coincided with the development of the pre-core mutant of hepatitis B virus.
Base Sequence↗
A unique insertion in the S gene of surface antigen--negative hepatitis B virus Chinese carriers.
The presence of unique hepatitis B virus (HBV) variants has been investigated in two Chinese patients with chronic liver disease, whose sera were positive for HBV-DNA by dot blot hybridization or polymerase chain reaction (PCR) but hepatitis B surface antigen (HBsAg)-negative by conventional polyclonal antibody based immunoassays. PCR amplification of HBV-DNA followed by direct sequencing showed an insertion of six nucleotides, which introduced two additional amino acids between codons 122 and 123 in one patient (Isolate 1), whereas a nine nucleotide insertion in the other patient (Isolate 2) gave rise to three amino-acids between codons 123 and 124 immediately upstream from the 'a' determinant in the S gene. These insertions have not been described previously in any published sequences of the known subtypes and were absent from sequences of 30 HBsAg-positive Chinese patients from the same region. In the cases under study, the insertion is associated with four consecutive adenine molecules from nucleotides 516 to 519. It seems likely that this area is a hot spot for insertions in HBV. We found none of the previously described amino-acid deletions or substitutions in the pre-S1, pre-S2 and S genes, which are involved in unusual antigenic profiles. This finding suggests that genetic mutations in the S gene outside the 'a' determinant may be responsible for failure to detect HBsAg in some Chinese patients with chronic hepatitis caused by HBV infection.
Adult↗