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Biomedical subjects

M G Anderson

Publications and source records attributed to M G Anderson.

At least 19 recordsLinked to original sources
PubMed1992

Two strains of SIVmac show differential transactivation mediated by sequences in the promoter.

Two infectious molecular clones of simian immunodeficiency virus, SIVmac251 and SIVmac239, have very different in vivo properties, SIVmac239 being much more pathogenic than SIVmac251. To assess whether the in vivo differences between the two viruses would be reflected in transcriptional rates in vitro, transcriptional activity in the presence of the transactivation protein tat was analyzed by transient transfection assays in HUT-78 and U937 cells. Whereas the two promoters had similar basal activities (Anderson and Clements, 1991, J. Virol. 65, 51-60) the promoter of SIVmac239 was transactivated to a greater extent. Removal of sequences 5' to -225 and 3' to +18 maintained the basal activity, yet made the promoter unresponsive to tat. Addition of bases +19 to +149 reconstituted transactivation and decreased basal activity. Analysis of deletion mutants with reconstituted transactivation response region determined that differences between the two strains were maintained even when only the proximal sequences, -225 to +18 of the U3 and R region were placed upstream of the TAR sequences. This region contains four nucleotide differences and the potential Sp-1-binding sites, where there are an additional 11 bases in SIVmac239 that create a third potential Sp-1 site, compared to only 2 in SIVmac251. Transactivation in this assay system was found to correlate better to RNA differences shortly after transfection (12 hr) than later (46 hr).

Base Sequence↗
PubMed1992

Differences in neutralization of simian lentivirus (SIVMAC) in lymphocyte and macrophage cultures.

Comparison of neutralization of SIVmac251 in primary macrophage cultures with neutralization in lymphocytes (CEM174 cells) showed that neutralizing antibodies induced by SIV251 in infected rhesus macaques protected both macrophages and T lymphocytes against infection when the virus was preincubated with the antibodies. In macrophages, the neutralizing antibodies also protected against infection when added 1 hour after the virus. Addition of antisera to macrophages between 24 and 48 hours after virus inoculation resulted in infection with continuous release of small amounts of p24 into the supernatant fluids but these antibody-treated cultures failed to exhibit cytopathic virus replication. In contrast, the same neutralizing antisera did not protect lymphocytes against infection and subsequent cytopathic replication of the virus when added only 1 hour after virus inoculation. This distinction in the effect that neutralizing antibodies had on the development of cytopathic infection in lymphocytes and macrophages when added after virus inoculation, suggests that they could alter the dynamics of virus replication and therefore the pathogenesis of disease.

Animals↗
PubMed1992

Neutralizing antibodies modulate replication of simian immunodeficiency virus SIVmac in primary macaque macrophages.

Cultured macaque macrophages are permissive for the replication of SIVmac251, and inoculation with virus is followed by the production of viral p27. Neutralizing macaque polyclonal and murine monoclonal antibodies preincubated with the virus prevented infection but did not prevent cytopathic virus replication when added more than 3 days after inoculation with virus. However, application of the neutralizing antibodies to macrophages 24 h after inoculation with virus resulted in sustained, low-level production of viral antigen. Cell lysates and individual macrophages from treated cultures contained less viral protein by Western blot (immunoblot) and immunocytochemistry than untreated controls. In situ hybridization and polymerase chain reaction procedures for detecting and estimating relative amounts of viral RNA and DNA showed that both viral nucleic acids failed to increase beyond the levels obtained before the addition of neutralizing antibodies. The data suggest that macrophages may need to be infected with a minimum threshold of virus particles in order to reach their full potential for virus replication and that their exposure to neutralizing antibodies prior to reaching this threshold resulted in limited virus replication.

Animals↗
PubMed1991

Safety of alcohol after viral hepatitis.

To test the validity of the generally held belief that moderate consumption of alcohol during convalescence from acute viral hepatitis adversely affects outcome, 87 adults recovering from acute viral hepatitis (hepatitis A in 36, hepatitis B in 34, hepatitis non-A, non-B in 17) were studied. Criteria for entry to the study attempted to ensure that no patient was a chronic hepatitis B carrier. Patients were randomised either to a moderate alcohol intake, or to continued complete abstention. Drinkers consumed 26 g alcohol daily (mean) and none remained abstinent. At 3 months all patients were well, with normal liver function tests. There were no significant differences between the two groups at anytime. The findings suggest that moderate alcohol intake during convalescence from acute viral hepatitis does not seem to be harmful.

Acute Disease↗
PubMed1991

Comparison of the transcriptional activity of the long terminal repeats of simian immunodeficiency viruses SIVmac251 and SIVmac239 in T-cell lines and macrophage cell lines.

The U3 regions of the long terminal repeats (LTRs) of simian immunodeficiency viruses SIVmac251 and SIVmac239 were analyzed for basal transcriptional activity and for interaction with cellular factors in the T-cell line HUT-78 and the monocyte/macrophage cell line U937. A number of 5' deletions and mutations were made in the U3 regions of the two LTRs, and these constructs were placed upstream of a plasmid containing the bacterial chloramphenicol acetyltransferase reporter gene. The nucleotide sequences between -225 and +18 were sufficient to maintain full transcriptional activity of both LTRs in HUT-78 and U937 cells. Nucleotide sequence analysis revealed several differences between SIVmac251 and SIVmac239 within this region. Analysis of deletion mutants revealed that an additional removal of bases, from -124 to -225, had little effect on the transcriptional activity of the clone 239 LTR, whereas this deletion resulted in a significant reduction of activity in the clone 251 LTR. DNase protection assays using nuclear extracts from HUT-78 and U937 cells showed that bases within this region bound cellular factors. In addition, the NF-kappa B site was protected in DNase assays with HUT-78 cells and 12-O-tetradecanoylphorbol-13-acetate-treated U937 cells. An additional DNase footprint was detected in SIVmac239, at -52 to -38, just upstream of the TATA box. This site overlaps the 3' half of the 3'-most Sp-1 site and is downstream of 11 bases that are found in SIVmac239 but not SIVmac251. Thus, differences in the sequences in the U3 region of the LTRs of SIVmac251 and SIVmac239 have been identified which appear to alter the transcriptional activity of these promoters as well as changing the interaction of cellular proteins with sequences in the LTRs.

Base Sequence↗
PubMed1988

Differential effect of alpha-interferons on CD4- and CD8-positive lymphocytes in chronic hepatitis B virus carriers.

alpha-Interferons are an effective therapy in a proportion of chronic hepatitis B virus (HBV) carriers. The mode of action is almost certainly dependent upon immune modulation in addition to direct antiviral effects but the precise mechanism is unknown. To investigate whether the aberrant T-cell activation present in HBV carriers was responsive to interferons, we have studied the in vitro effect of alpha-interferons on Tac antigen expression and DNA synthesis as early and late markers of T-cell activation, respectively. At a concentration of 1000 U/ml the effect of alpha-interferons on Tac expression was contrasting in the two major T-cell subsets; there was enhancement of Tac expression on CD4-positive T-cells but inhibition of the CD8-positive subset. However, there was no overall effect on lymphocyte proliferation, perhaps as a consequence of the differential effect of alpha-interferons on the early T-cell activation marker. At higher concentration, however, the enhancement of T-cell activation was less clear, indicating that the concentration range that supports T-cell activation is narrow. Such subtle differential effects on T-cell activation may be accompanied by more profound effects on immune function and this may be one way in which alpha-interferons are of value in chronic HBV infection.

Adult↗
PubMed1988

Abnormal T-cell activation in chronic hepatitis B viral infection: a consequence of monocyte dysfunction?

The process of T-cell activation in chronic hepatitis B virus (HBV) carriers has been investigated by measurement of membrane expression of lymphocyte-activation markers in response to a variety of mitogenic stimuli in order to delineate further the abnormality of T-cell-mediated immunity present in such patients. A substantial proportion of unstimulated T cells from the peripheral blood of patients but not controls expressed HLA-DR; in contrast the IL-2 and transferrin receptors were rarely expressed spontaneously in either group and there was no difference in spontaneous lymphocyte transformation. After stimulation with monocyte-dependent T-cell mitogens, phytohaemagglutinin (PHA) or anti-T3, patients had significantly reduced expression of the IL-2 and transferrin receptors and of HLA-DR in association with impaired lymphocyte transformations compared to controls. In contrast, lymphocyte activation was normal in response to the monocyte-independent T-cell mitogen phorbol-myristate-acetate (PMA). These data confirm that the process of T-cell activation is abnormal in chronic HBV carriers but suggest that the T cell is intrinsically normal. In allogeneic co-cultures, monocytes from patients inhibited the transformation of normal and patients' lymphocytes in response to PHA, suggesting that defects of T-cell-mediated immunity in chronic HBV carriers may be a consequence of monocyte dysfunction.

Antigens, Surface↗
PubMed1987

Suramin treatment for chronic active hepatitis B--toxic and ineffective.

Suramin has recently been shown to inhibit the activity of the duck hepatitis B virus DNA polymerase (DHBV DNAp) in vitro. However, we found no demonstrable in vivo suppression of human hepatitis B virus DNA polymerase (HBV DNAp) activity in three male patients with severe chronic active hepatitis. Suramin treatment resulted in prolongation of the prothrombin time in all cases and a rise in bilirubin in two and it may have led to haemorrhage from oesophageal varices in one patient and to hepatic encephalopathy in another. Its use in chronic hepatitis is not recommended.

Esophageal and Gastric Varices↗
PubMed1987

Treatment of cytomegalovirus pneumonitis with foscarnet (trisodium phosphonoformate) in patients with AIDS.

Foscarnet was administered to eight AIDS patients for suspected cytomegalovirus (CMV) pneumonitis as a continuous intravenous infusion for a minimum of 8 days. All the patients improved, three showing complete resolution of symptoms. Evidence of CMV infection from bronchoalveolar lavage samples was lacking in two patients. Adverse drug experiences consisted of thrombophlebitis, transient decreases in haemoglobin concentration, and reversible rises in serum creatinine levels.

Acquired Immunodeficiency Syndrome↗
PubMed1987

Randomised controlled trial of lymphoblastoid interferon for chronic active hepatitis B.

Thirty male patients (27 homosexual) with biopsy proven chronic active hepatitis B were randomised to receive lymphoblastoid interferon (Wellferon) or no treatment. All patients were HBeAg positive and had continuing viral replication. Patients receiving treatment were given a single daily intramuscular injection of interferon for 28 days at a starting dose of 2.5 MU/m2 increasing to a maximum of 7.5 MU/m2/day. Transient side effects of malaise and influenza like symptoms occurred in all patients and resolved rapidly after treatment. Hepatitis B viral replication was suppressed during interferon treatment in all patients but the effect was limited to the period of therapy. After one year there was no appreciable difference in viral markers between the two groups of patients and this treatment schedule appears less effective than the thrice weekly, three month regimes recently reported from other centres.

Adult↗
PubMed1986

Strategy for lymph node biopsy in homosexual men suspected of having LAV/HTLV-III related disease.

Since January 1985 we have changed our policy regarding lymph node biopsy in male homosexuals presenting with lymphadenopathy. Before that date all such patients underwent biopsy if there was no apparent cause. We no longer perform biopsy in male homosexuals presenting with uncomplicated persistent generalized lymphadenopathy (enlargement to more than 1 cm of lymph nodes in more than one extra-inguinal site for more than 3 months with no apparent cause) provided that the patient is positive for the antibody to lymphadenopathy associated virus/human T-lymphotropic virus type III. Such a policy should reduce the need for open biopsy procedures in this group of patients.

Adult↗
PubMed1986

Hepatitis B virus DNA in the hepatocyte. A series of 160 biopsies.

DNA-DNA hybridisation was used to examine 160 liver biopsies for the presence of the hepatitis B virus genome. HBeAg-positive HBsAg carriers were found to have replicating viral DNA in the hepatocytes and, very occasionally, HBV DNA was also integrated into the chromosomes. A high proportion of the anti-HBe-positive HBsAg carriers also have replicating HBV DNA and in the remainder integrated sequences are often, but not always, seen. No evidence was found, however, to implicate HBV in HBsAg-negative patients with alcoholic liver disease, nor in patients with a variety of other liver diseases including non-A, non-B hepatitis.

Base Sequence↗
PubMed1986

Randomised controlled trial of lymphoblastoid interferon for chronic active hepatitis B.

Thirty male patients (28 homosexual or bisexual) with biopsy proven chronic active hepatitis B were randomised to receive lymphoblastoid interferon (Wellferon) or no treatment. All patients were HBeAg-positive and had continuing viral replication. Interferon was given as a single daily i.m. injection for 28 days at a starting dose of 2.5 megaunits/m2 increasing to a maximum of 7.5 megaunits/m2/day. Transient side-effects occurred in all patients. Hepatitis B viral replication was suppressed during interferon treatment in all patients but the effect was limited to the period of therapy. After 1 year there was no appreciable difference in viral markers between the two groups of patients and this treatment schedule appears less effective than the thrice weekly, 3-month regimes reported from other centres.

Clinical Trials as Topic↗