Treatment of acquired immune deficiency syndrome (AIDS)-related pneumonitis with foscarnet: a double-blind placebo controlled study.

A double-blind placebo controlled trial of foscarnet was conducted in 32 Human Immunodeficiency Virus (HIV) antibody positive male homosexuals with a presumed AIDS pneumonia. The study was designed to evaluate the importance of treating cytomegalovirus (CMV) as a possible lung pathogen of these patients and as a toxicity study of foscarnet. Trial subjects were randomised to receive either foscarnet or placebo as a continuous intravenous infusion for 2 weeks along with conventional therapy against Pneumocystis carinii (PC) pneumonia. Bronchoscopy or post-mortem showed PC to be present in 24 patients and the bronchoalveolar lavage fluid had early antigen foci of CMV in nine, five of these being double infections. The incidence of CMV infection in this group of patients was not sufficiently high to prove or disprove that treatment of CMV speeds recovery or improves prognosis in AIDS pneumonias. Overall however foscarnet was well tolerated with a slight increase in adverse reactions in the treated groups. This agent is therefore a relatively non-toxic drug to use in the treatment of established CMV disease.

Remoxipride and haloperidol in the acute phase of schizophrenia: a double-blind comparison.

The efficacy and safety of remoxipride in the treatment of schizophrenia were compared with those of haloperidol in a multicentre double-blind 6-week study which was randomized with a parallel group design and was preceded by a washout period. Eighty-nine consecutively admitted men and women meeting the Research Diagnostic Criteria for schizophrenia in an acute phase of the illness were treated with remoxipride 75-300 mg twice daily or haloperidol 5-20 mg twice daily. The efficacy assessments were the Brief Psychiatric Rating Scale, Krawiecka Rating Scale, and Clinical Global Impression. Both antipsychotic drugs produced clinical improvement with no significant differences between the efficacy of the two drugs. There were relatively few side effects. There were significantly fewer extrapyramidal symptoms and instances of blurred vision with remoxipride and less constipation with haloperidol. The results indicate that remoxipride is as effective an antipsychotic as haloperidol. Remoxipride has an advantage over haloperidol in respect to extrapyramidal side effects.

Foscarnet therapy in chronic hepatitis B virus E antigen carriers.

Foscarnet (trisodium phosphonoformate) is a novel antiviral agent that inhibits viral-specific DNA polymerase. In the present study, eight males with chronic HBV carriage (HBeAg and HBV-DNA seropositivity greater than 12 months) showing chronic persistent hepatitis (CPH) or chronic active hepatitis (CAH) on liver biopsy received either a continuous infusion of foscarnet at 0.15 mg/kg/min for 7 days or 180 mg/kg/day divided into three daily boluses for 2 weeks. In all eight, HBV-DNA levels fell during therapy (median, 401 pg/40 microliters serum; range, 4-3, 100) vs. pretreatment levels (median, 533 pg/40 microliters; range, 30-4, 175), but in none was HBV-DNA undetectable at any stage. Within 1 month, the HBV-DNA had risen to pretreatment levels in all but one patient (with the lowest pretreatment level), who cleared HBeAg and developed anti-HBe within 3 months. Two further patients were anti-HBe positive at 6 months, but their pretreatment serum HBV-DNA levels were already low, suggesting a high probability of spontaneous seroconversion. Toxicity was not evident with the continuous infusion, but for those receiving IV bolus therapy, serum creatinine and phosphate levels rose in three of four patients, necessitating a 25% dose reduction. There was no difference in the effect on serum HBV-DNA between the two regimes. We conclude that foscarnet has only modest antiviral activity in chronic HBV carriers.

Restriction of sensitivity of HIV-1-antigen ELISA by serum anti-core antibodies.

Addition of varying concentrations of HIV-1-seropositive plasma to purified virus particles and soluble viral antigen preparation inhibited the detection of HIV-1-antigen by ELISA. The degree of inhibition on p24 antigen ELISA depended on the relative concentrations of viral antigen and anti-p24 antibodies in the mixtures. The relevance of these observations to clinical specimens was demonstrated when serial plasma samples from nine AIDS-related complex (ARC) patients in a clinical trial of foscarnet therapy were assayed for p24 antigen. Six (66.6%) out of nine patients were negative on screening. However, when their plasma was centrifuged through a sucrose solution, virus particles were pelleted that were depleted of anti-p24 and virus-specific p24 antigen was detected in resuspended pellets obtained from samples from all six patients. Eight serial samples collected from a male homosexual over 50 weeks following seroconversion were also subjected to the separation procedure. HIV-1-antigen was detected in all eight samples. In the light of these observations, the application of the separation technique in monitoring the efficacy of zidovudine or other anti-retroviral therapy should reveal more precise antigen levels in patients who otherwise appear to be antigen-negative in HIV-antigen assays. We propose that the natural history of HIV infections follows a pattern of chronic viral infection with continuous shedding of virus particles circulating as immune complexes.

Localization of an arenavirus protein in the nuclei of infected cells.

Host cell nuclear involvement in an arenavirus infection was examined by immunofluorescence. Both polyclonal antisera and monoclonal antibodies specific for the major nucleocapsid (N) polypeptide revealed virus-specific nuclear inclusions in Pichinde virus-infected Vero cells. Immunoprecipitation of infected cell extracts with the anti-N monoclonal antibodies and subsequent analysis by SDS-PAGE, identified two N-related proteins with mol. wt. of 36,000 (p36) and 28,000 (p28) in addition to the N polypeptide. Only those monoclonal antibodies which precipitated p28 as well as N and p36 were found to produce nuclear as well as cytoplasmic fluorescence. These findings suggest that either the p28 protein itself or a conformational variant of N was the nuclear antigen detected.

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.

Phosphonoformate (foscarnet): a pilot study in AIDS and AIDS related complex.

Phosphonoformate (PFA; a pyrophosphate analogue) is an effective inhibitor of the reverse transcriptase enzyme in many animal retroviruses. In vitro studies have shown that PFA is also an effective inhibitor of HIV (HTLV III/LAV) at doses readily attainable in vitro. A pilot study was therefore performed with a 3-week intravenous infusion of PFA in 11 patients with AIDS and AIDS-related complex (ARC). Viral isolations were performed before and at regular intervals up to 3 months post-infusion on treated patients, as well as on four untreated control patients. Virus isolation was negative after therapy in eight patients, six of whom were negative throughout the follow-up period. Virus was isolated on 70% of attempts from the four control subjects and on 20% of attempts from treated subjects. Three patients showed an improvement in delayed hypersensitivity responses. No obvious improvement was seen in patients' OKT4 positive lymphocyte counts. Treatment was not limited by side-effects with the exception of one patient who developed an axillary vein thrombosis within 4 days of treatment via a subclavian line. Treatment was therefore discontinued following administration of only one dose and the patient was excluded from further study. A further patient had reversible renal dysfunction. Other side-effects were minor, consisting of headache or thrombophlebitis at the site of infusion. These results suggest that a further trial with PFA administered over a longer period and with a longer follow-up period in AIDS and ARC patients may be warranted, particularly if an oral preparation becomes available.(ABSTRACT TRUNCATED AT 250 WORDS)

Monoclonal immunoglobulin M antibody to Japanese encephalitis virus that can react with a nuclear antigen in mammalian cells.

An immunoglobulin M (IgM) class monoclonal antibody raised against Japanese encephalitis virus reacted with an epitope on the nonstructural virus protein P74 (NV4 in the old nomenclature) of several flaviviruses and also with an antigen present in the nuclei of a variety of mammalian cell types. This antigen had a characteristic granular distribution by immunofluorescence and may correspond to a polypeptide of molecular weight 56,000 seen in nitrocellulose transfers of sodium dodecyl sulfate-polyacrylamide gels. Cross-reactivity with nuclear antigen was also occasionally observed in the IgM antibody fraction of mice early after infection with Japanese encephalitis virus and also in acute sera from some clinical cases of encephalitis containing IgM antibody to Japanese encephalitis virus.

Conformational changes in Sindbis virus E1 glycoprotein induced by monoclonal antibody binding.

A monoclonal antibody (30.2) raised against Sindbis virus is able to precipitate both E1 and PE2 from [35S]methionine-labelled infected cells solubilized with non-ionic detergent. Addition of SDS to the lysate abolishes the precipitation of PE2 without affecting that of E1, thus demonstrating that the antibody is specific for E1. Other Sindbis E1-specific monoclonal antibodies (30.11 and 30.12) precipitate only E1, even from lysates containing only non-ionic detergent, and their presence in such a lysate prevents precipitation of PE2 by antibody 30.2. These data indicate that E1-PE2 complexes stable in the presence of non-ionic detergent can be precipitated as such by one antibody, but that binding of the other antibodies induces dissociation of E1 and PE2. Competition experiments using 125I-labelled antibodies indicate that all three antibodies bind to distinct antigenic sites on the E1 molecule. Antibodies 30.11 and 30.12 stimulate each other's binding in such experiments, which suggests that binding of either of these antibodies alters the conformation of E1 in such a way as to increase its affinity for the other, and at the same time to release PE2. Antibody 30.2 also enhances binding of the other two antibodies, but this stimulation is only weakly reciprocated.

Immunofluorescence studies on the antigenic interrelationships of the Hughes virus serogroup (genus Nairovirus) and identification of a new strain.

Titrations of hyperimmune antisera by indirect immunofluorescence using each virus of the Hughes serogroup (Hughes, Zirqa, Punta Salinas, Soldado and Farallon) demonstrated their individual antigenic identities. Furthermore, an antigenically related virus, designated Puffin Island (PI) virus, was shown both by indirect immunofluorescence and by neutralization in XTC cells to be distinguishable from the other viruses. These viruses readily established persistent infections in Vero cells after producing only moderate cytopathic effects. Treatment of persistently infected cultures with either fluorodeoxyuridine or bromodeoxyuridine made no significant difference to the percentage of immunofluorescent cells. Attempts to demonstrate haemagglutination by Zirqa virus were unsuccessful.

The interaction of monoclonal antibodies directed against envelope glycoprotein E1 of Sindbis virus with virus-infected cells.

Two monoclonal antibodies specific for the Sindbis virus envelope glycoprotein E1 were evaluated for their ability to maintain long-term infection when present in the medium of virus-infected cells. One of them, previously shown to have neutralizing activity and to inhibit haemagglutination, caused suppression of both virus expression at the cell surface and prolonged intracellular virus presence. The other monoclonal antibody which lacked neutralizing activity but inhibited virus-specific haemolysis caused redistribution of viral antigens on the cell surface but only slightly prolonged cell survival. Both epitopes were located on the surface of the virus. By electron microscopy it was demonstrated that the determinant associated with haemolytic activity resided near the virus membrane while the haemagglutination inhibition antibody attached near the apex of the virus spikes.

Monoclonal antibodies to Sindbis virus glycoprotein E1 can neutralize, enhance infectivity, and independently inhibit haemagglutination or haemolysis.

Two monoclonal antibodies raised against Sindbis virus were shown to be specific for the envelope glycoprotein E1 by radioimmunoprecipitation (RIP). They had a number of contrasting biological properties. One of them was capable of neutralizing virus infectivity and inhibiting haemagglutination, while the other had no significant neutralizing or haemagglutination-inhibiting capability, but did inhibit virus-mediated haemolysis. Both monoclonal antibodies could enhance virus infectivity of Fc receptor-bearing macrophage-like cells when present at suitable dilutions.

A seroepidemiological survey in the Gezira, Sudan, with special reference to arboviruses.

A serological survey in the Gezira area of the Sudan confirmed that malaria and schistosomiasis were highly endemic. Of other parasitic infections amoebiasis was common but Toxoplasma was less than found in a previous survey. Poliomyelitis and measles infection were universal and there was an extremely high incidence of infection with hepatitis B. Of arboviruses infection with flaviviruses was frequent and more than with alphaviruses.

Arbovirus isolations from ixodid ticks infesting livestock, Kano Plain, Kenya.

In a study conducted on the Kano Plain, Kenya, virus isolation attempts were made on ixodid ticks collected, over a 14-month period, from livestock held in family enclosures (bomas) before releasing the animals for daily foraging. 8735 Amblyomma variegatum (Fabricius) were tested, 98.6% of which were taken from cattle, yielding 36 strains of Dugbe (DUG), four strains of Nairobi sheep disease (NSD), three strains of Bhanja (BHA), one strain of Thogoto (THO) and five strains of virus which could not be characterized. 6549 Rhipicephalus spp. ticks were collected (60.3% from cattle). NSD, DUG and BHA viruses were each isolated twice from ticks taken from cattle. One BHA virus strain was recovered from ticks from a sheep. One strain recovered from ticks on cattle could not be characterized.

Evaluation of plaque size reduction as a method for the detection of Pichinde virus antibody.

The reaction between Pichinde virus and homologous antisera has been studied using a plaque size reduction method. The incorporation of antiserum in the overlay of infected Vero cell monolayers revealed a pattern of virus-cell interactions which were manifested by both a significant reduction in the diameter of virus plaques, and regeneration of cells in the centre of each. Electron microscopy demonstrated that antibody molecules were bound to virus particles budding from the surface of infected cells resulting in the formation of extracellular virus-antibody complexes. These aggregates were subsequently detected in vacuoles of freshly-infected cells. In the absence of virus neutralization, reaction of Pichinde virus with homologous antiserum leads to the formation of infectious aggregates which due to their larger size restrict the rate of plaque development.

Investigation of the ecology of Soldado virus on Puffin Island, North Wales.

The prevalence of Soldado (SOL) virus and SOL virus antibodies was investigated on immature sea birds and the argasid tick Ornithodoros (Alectorobius) maritimus collected on Puffin Island, North Wales. No SOL virus was recovered from 133 bird sera, but 2 of the birds exhibited neutralizing antibodies against SOL virus. Nine of 27 tick pools (226 individuals) and 34 of 173 ticks tested individually proved to be infected with SOL virus.