Biomedical subjects
Publications and source records attributed to A G Dalgleish.
The past year has seen the discovery of new isolates which do not readily fit into the established categories HIV-1, HIV-2 and SIV, as well as the availability of new assays including the use of the polymerase chain reaction. New combination enzyme-linked immunosorbent assays can detect viruses from two or more groups where specific enzyme-linked immunosorbent assays have been developed using peptides and monoclonal antibodies.
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Anti-idiotypic antibodies to anti-CD4 monoclonal antibodies (MAbs) have been reported to bind to the human immunodeficiency virus (HIV) envelope glycoprotein gp120. To establish whether HIV-infected patients can mount an anti-idiotypic response to murine MAb, four individuals with symptoms of AIDS-related complex (ARC) were immunized over 10 weeks with six intramuscular injections of anti-Leu 3a (1 mg). Despite their immunocompromised state, all patients made anti-constant region and anti-idiotypic antibodies, although the amplitude of the responses varied between individuals. No significant toxic or allergic reactions were seen, and there were no changes in clinical status during the 6 months after immunization. No increase in serum HIV-neutralization titers was seen, and purified anti-idiotypic antibodies did not bind gp120.
The fact that viruses can cause cancer in animals has been appreciated since the turn of the century. The widely held belief that viruses had little to do with cancer in humans has only recently been dispelled. Two classes of human retrovirus (HTLV and HIV) have been discovered in the last decade and the malignant potential of hepatitis B virus, Epstein Barr Virus and the human papilloma virus have been documented not only by confirming their association with disease by large scale epidemological studies but also at the molecular level. Indeed detailed investigation of the way viruses can cause cancer can reveal new insights into 'final common pathways' and hopefully provide new approaches for treatment over and above the real possibility that virus associated cancers can potentially be vaccinated against.
A case of rapidly progressive cerebellar degeneration with bilateral sixth nerve palsies is described in whom investigation revealed the presence of unsuspected coeliac disease. In spite of treatment with a gluten free diet, rapid fatal deterioration occurred. Coeliac disease should be considered in patients with encephalopathy of obscure origin.
Idiotype studies have been important in our study of the HIV/CD4 interaction. They have predicted the binding site on CD4 and showed that it is the same amongst all HIV-I isolates, and therefore a formidable candidate for the design of effective therapeutic and vaccine strategies against HIV. Future research could implicate an anti-idiotype approach to a prophylactic vaccine. It is important to note that an anti-idiotype response may be needed to prime an immune response against a viral epitope which may be used as a secondary component. The use of anti-idiotype responses in infected persons may be able to tip the balance of the immune system so that the body is able to control HIV infection. Until recently the use of anti-idiotypic approaches in the design of HIV vaccines has been sadly neglected.
Twenty six patients with sarcoidosis of recent onset or with severe progressive disease were studied for evidence of retroviral infection. Peripheral blood mononuclear cells (PBMC) were cultured in vitro and stimulated with phytohaemagglutinin and interleukin-2. Induction of syncytia (SI) and production of reverse transcriptase (RT) were sought as indicators of possible retroviral infection. PBMC from two patients showed syncytia formation and in one of these two there was associated production of low levels of reverse transcriptase. The remaining patients showed neither RT nor SI activity. The predominantly negative results of this study indicate that sarcoidosis is unlikely to be of retroviral aetiology; however, cell populations from sites of active disease should be studied before drawing this conclusion.
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Specific T cells stimulated by antigen presenting cells (APC) pulsed with antigen in the presence of HIV were no longer detectable with a functional assay, which suggests that HIV has been transferred from APC to the specific activated T cell via an antigen-dependent mechanism to exert its cytopathic effect on activated T cells. In contrast soluble gp120 inhibited antigen-driven proliferation, but this action was reversible and could be blocked by soluble CD4. Thus the chief mechanism of HIV pathogenesis may be gp120/CD4 interaction and HIV may be pathogenic mainly as a producer of gp120.
OBJECTIVE: To compare the prevalence of antibody to and proviral DNA of the retrovirus HTLV-I in relatives of 11 British patients with tropical spastic paraparesis who had migrated from Jamaica before they developed symptoms, and to examine factors possibly related to transmission of HTLV-I. DESIGN: Migrant, family study. Antibody state was determined by several methods and confirmed by western blotting; the polymerase chain reaction was used to detect proviral DNA. SETTING: Britain and Jamaica. SUBJECTS: All available first degree relatives: those born and still resident in Jamaica (group 1); those born in Jamaica who migrated to Britain (group 2); and index patients' children who were born and resident in Britain (group 3). All had been breast fed and none had had blood transfusions. RESULTS: Of the 66 living relatives, 60 were traced. Seroprevalence among those born in Jamaica (irrespective of current residence) was 22% (10/46; 95% confidence limits 9 to 34%) compared with zero among British born offspring (0/14) and was higher in group 2 at 33% (7/21; 12 to 55%) than in group 1 at 12% (3/25; 0 to 25%). (Patients in group 1 had the greatest mean age.) Proviral DNA was not detected in any subject negative for HTLV-I antibody, making prolonged viral incubation in those negative for the antibody unlikely. CONCLUSION: In this sample factors related to place of birth and early residence were more important in transmission of HTLV-I than maternal or age effects. In areas with a low to moderate prevalence policies of preventing mothers who are carriers of the virus from breast feeding would be premature.
The immune deficiency induced by HIV has its origin in the interaction of the outer envelope glycoprotein gp120/gp41 with receptors present on human immunocytes. Virus binding to cells, virus entry and subsequent compartmentalization resulting in productive infection depends on the interaction of gp120/gp41 with CD4 and other accessory molecules. Gp120 and HIV are markedly immunosuppressive of T-cell responses and, in addition, HIV can functionally delete antigen responsiveness of T cells. Abolition of CD4 binding, by denaturation of gp120, allows study of T-cell epitopes in gp120 and shows the denatured molecule is highly immunogenic even in naive subjects (F. Manca, unpublished). The gp120-binding site of CD4 is shared with MHC class II molecules and the reaction of antibodies within this region of CD4 induces conformational changes that may be significant for virus entry into cells or for syncytial formation. The HIV envelope contains sites of sequence homology with monomorphic human MHC class II sites that do not appear to be naturally immunogenic in humans. In addition to the properties of gp120, it is hypothesized that HIV envelope may also represent an 'alloepitope' of class II to the human T-cell repertoire, and is therefore able to induce a chronic allogeneic response not dissimilar to experimentally induced GVHD. These features are of potential importance both for primary vaccination against HIV, and for the long-term treatment of HIV seropositive patients. Induction of effective T-cell responses to gp120 require use of a denatured or otherwise modified product lacking CD4-binding capacity. The potential distortion of the TCR repertoire by the class-II-homologous and CD4-interactive sequences must be assessed.(ABSTRACT TRUNCATED AT 250 WORDS)
Using a quantitative suspension test method, the antiviral activity of sodium hypochlorite (NaOCl) and sodium dichloroisocyanurate (NaDCC) against human immunodeficiency virus (HIV) was investigated. Viral suspensions were prepared containing 10(4)-10(5) syncitial forming units ml-1 in 0.9% saline or 0.9% saline containing 10% v/v plasma to simulate clean and dirty conditions. A syncitial inhibition assay on C8166 lymphoblastoid line was used to determine viral titre. Results indicate that satisfactory disinfection (3-4 log reduction in 2 min) can be achieved using NaDCC and NaOCl at concentrations of 50 ppm and 2500 ppm available chlorine (AvCl2) for clean and soiled conditions respectively. For treatment of blood spillages, the addition of NaDCC and NaOCl solutions (10,000 ppm) to equal volumes of contaminated blood (giving a final AvCl2 concentration of 5000 ppm of blood) was sufficient to produce total kill within 2 min. For treatment of spillage material, chlorine-releasing powder formulations--which produce higher AVCl2 concentrations and achieve containment of spillage material--offer an effective alternative.
The cell-surface antigen CD4 is the major receptor for HIV. Anti-CD4 autoantibodies and anti-idiotypic antibodies to murine monoclonal anti-CD4 antibodies have been described in HIV-infected people. Ninety-seven sera from HIV-infected people at all stages of disease were examined for the presence of anti-idiotypic antibodies to three anti-CD4 monoclonal antibodies. None were found. The same sera were screened for antibodies reactive with soluble CD4, and five (5.2%) were positive. These antibodies did not recognize native CD4, and it is thought unlikely that they arise as anti-idiotypes to anti-gp120 antibodies.
To establish the phenotype of human T-cell leukemia virus type 1 (HTLV-1)-infected cells in peripheral blood, the polymerase chain reaction was used to detect and quantitate viral DNA in subpopulations of leukocytes obtained from patients with tropical spastic paraparesis and asymptomatic carriers. HTLV-1 could not be detected in peripheral blood mononuclear cells thoroughly depleted of T lymphocytes (E- CD3-), nor could it be detected in highly enriched populations of B lymphocytes (E- CD19+), monocytes (E- CD14+), or natural killer cells (E- CD16+). T lymphocytes were strongly positive for HTLV-1, and fractionation of this population revealed that 90 to 99% of the HTLV-1 DNA segregated with the CD4+ CD8- and CD45RO+ subsets. No difference between the cell type distribution of HTLV-1 in the asymptomatic carrier and the subjects with tropical spastic paraparesis was evident. Southern hybridization of genomic DNA prepared from the peripheral blood of HTLV-1 carriers indicated that up to 10% of circulating leukocytes may carry the HTLV-1 provirus.
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The CD4 antigen has been subverted as a receptor by the human and simian immunodeficiency viruses (HIV-1, HIV-2 and SIV). Several groups have reported that recombinant, soluble forms of the CD4 molecule (sCD4) block the infection of T lymphocytes by HIV-1, as CD4 binds the HIV envelope glycoprotein, gp120, with high affinity. We now report that sCD4 blocks diverse strains of HIV-1, HIV-2 and SIV, but is less effective for HIV-2. The blocking effect is apparent even after adsorption of virions to CD4 cells. Soluble CD4 prevents HIV infection of T-lymphocytic and myelomonocytic cell lines, but neither sCD4 nor anti-CD4 antibodies inhibit infection of glioma and rhabdomyosarcoma cell lines.
1-(3-Cyano-2,3-dideoxy-beta-D-erythro-pentofuranosyl)thymine (cyanothymidine) (3a) has been prepared by an unambiguous route starting from D-xylose. The relative and absolute stereochemistry of 3a and its anomeric isomer 9 have been confirmed by NOE experiments and by X-ray diffraction analysis. In antiviral tests vs HIV 3a was shown to be inactive, a surprising result in view of a preliminary disclosure claiming potent anti-HIV activity. The activity previously assigned to 3a is believed to be due to contamination of that sample with the known antiviral nucleoside analogue 5b.
Twenty-one patients with tropical spastic paraparesis (TSP), all of whom were born in the Caribbean and who had migrated to the United Kingdom, are described. All had a progressive spastic paraparesis developing many years after immigration and all 19 tested had antibodies to the human T cell lymphotropic retrovirus type 1 (HTLV1). The clinical and laboratory features and visual, auditory and somatosensory evoked potentials are described. Details of magnetic resonance scanning of the brain and, in a few cases, the spinal cord are compared with those found in multiple sclerosis. The antibody titres to HTLV1 assessed by particle agglutination, Western blot, antibody-directed cell mediated cytotoxicity and pseudotype neutralization were higher than in asymptomatic infected relatives and in patients with adult T cell leukaemia. Some, but not all, of the IgG oligoclonal bands in the CSF were directed against HTLV1. IgM oligoclonal bands directed against HTLV1 were found in 2 patients. Sixty of the 64 first degree relatives of 11 Jamaican patients with TSP were traced in the UK and the Caribbean; 20-30% of those born in the Caribbean had antibodies to HTLV1, irrespective of their present place of residence, whilst none of those born in the UK, who were the children of the patients, had antibodies. The original pathological material obtained from the Caribbean by Montgomery et al. (1964) is reviewed. These results are discussed in relation to animal retroviral neurological diseases, particularly visna in sheep which has clinical and pathological features closely similar to TSP. It is proposed that TSP is due to a HTLV1 infected lymphocyte/macrophage immune-mediated inflammatory response in the spinal cord.