Neutralization and receptor recognition of human T-lymphotropic retroviruses.
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Antibodies, Viral↗
Biomedical subjects
R A Weiss
Publications and source records attributed to R A Weiss.
Human immunodeficiency virus infection of monocytic and T-lymphocytic cells: receptor modulation and differentiation induced by phorbol ester.
The monocytic leukemic cell line U937 can be infected with human immunodeficiency virus type 1 (HIV-1) to become permanently infected virus producers. Uninfected U937 cells express T4 (CD4) antigen and form syncytia when mixed with HIV-1 producing cells. Anti-T4 monoclonal antibodies block syncytium formation indicating that the HIV-1 receptors on U937 cells include T4 antigen. The promyelocytic leukemic cell line HL60, while expressing only low amounts of surface T4 and not forming syncytia on exposure to HIV-1, can be infected by HIV-1 at lower efficiency than U937 and T-cell lines. 12-O-Tetradecanoylphorbol-13-acetate (TPA) treatment induces the differentiation of U937 cells into macrophages. HIV-infected U937 cells retain the ability to differentiate, though less efficiently, as shown by the appearance of monocyte/macrophage surface markers. T4 antigen on both U937 and T-cell lines is down regulated by TPA treatment. Functional receptors for HIV-1, assayed by syncytium induction and pseudotype plating, are lost concomitantly with T4 antigen following TPA treatment of U937 cells and T cells.
Antigens, Differentiation, T-Lymphocyte↗
Detection of HIV envelope specific antibodies by immunoelectron microscopy and correlation with antibody titer and virus neutralizing activity.
Human antisera positive for HIV were evaluated on HTLV-IIIB producing cells by two different immunoelectron microscopic (IEM) techniques. In preembedding immunoferritin IEM a heavy label was observed with early budding HIV. Under the same conditions cell released 'mature' particles were almost negative, which could be explained by the direct observation that most of the surface glycoprotein knobs are lost spontaneously during virus maturation. Using freshly infected cultures after agarose embedding, immunogold labelling of ultrathin cryosections allowed us to detect and differentiate internal core as well as virus envelope antigens. A good qualitative correlation between neutralization titers and IEM labelling intensity was observed. This type of immunocryoultramicrotomy appears to be useful for the detection of antigens in and on the virion. It might turn out valuable for the characterization of the env gp120 epitopes of HIV.
AIDS-Related Complex↗
Ultrastructure and immunoelectron microscopy of human T-cell leukaemia virus type I-producing lymphoid and non-lymphoid human tumour cells.
The ultrastructure and distribution of some viral and cellular antigens was examined in lymphoid C91/PL and fibroblastic HOS/PL cells infected with human T-cell leukaemia virus type I. Tubuloreticular structures in the endoplasmic reticulum, characteristic of virus-infected or interferon-treated cells, were found in both cell types. Virions were observed particularly in the HOS/PL cells in budding and mature forms and in coated pits, coated vesicles and lysosomes, indicative of receptor-mediated endocytosis. Using immunogold indirect labelling, viral antigens, recognized by sera of infected patients and by monoclonal antibody, were detected in patches on the cell surface and in material loosely attached to the envelope of some virions. Beta 2-microglobulin was associated with virion envelopes from C91/PL and HOS/PL cells, but major histocompatibility complex class 1 (HLA) antigens were not associated with virions even when produced by HLA-positive HOS/PL cells.
Antigens, Surface↗
Characterization of monoclonal antibodies against the human immunodeficiency virus (HIV) gag products and their use in monitoring HIV isolate variation.
Monoclonal antibodies were raised against the gag proteins of a British isolate of the human immunodeficiency virus (HIV), CBL-1. Seven of the monoclonal antibodies recognized HIV gag-coded proteins of 55,000 mol. wt. (p55) and 24,000 mol. wt. (p24), three recognized p55/p18 and three p18 alone. Cross-competition assays suggested that at least two independent epitopes exist on the p24 cleaved from the p55 precursor, whereas a cluster of closely related epitopes was recognized by the p55/p18 and p18 antibodies. The panel of monoclonal antibodies was then used to compare by immunofluorescence the expression of gag-encoded antigenic determinants on HIV isolates from different geographical locations. Minor changes in epitope expression were observed in isolates from the U.S.A. and Haiti with the most notable changes being detected in isolates from Zaire, Tanzania and Uganda.
Africa↗
Retroviruses and human disease.
Over the past 25 years animal retroviruses have been favoured subjects of research by virologists, oncologists, and molecular biologists. Retroviruses have given us reverse transcriptase, oncogenes, and cloning vectors that may one day be exploited for human gene therapy. They have also given us leukaemia and the acquired immune deficiency syndrome (AIDS). Kawasaki disease and tropical spastic paraparesis are thought to be associated with retrovirus infection, and other diseases such as de Quervain's thyroiditis, multiple sclerosis, acquired hypogammaglobulinaemia, and certain forms of non-A, non-B hepatitis have come under passing suspicion of a retroviral aetiology. With AIDS threatening to become pandemic, and a second AIDS virus appearing in West Africa, human retroviruses are under intensive study for new antiviral drugs targeted to their unique mode of replication, and for the development of vaccines.
Acquired Immunodeficiency Syndrome↗
Advanced diagnostic imaging techniques in ophthalmology.
Diagnostic imaging techniques continue to gain tremendous importance in the evaluation of ocular and orbital disease as technical developments and refinements are made. This article presents key diagnostic imaging methods, with special focus directed toward the advanced modalities important in evaluation of the traumatized eye and orbit. The text has been prepared specifically for the clinical ophthalmologist. Each of the diagnostic modalities discussed is presented in terms of its basic biophysical mechanism, indications, and advantages and disadvantages. The techniques described include simple plain film roentgenography (and its contrast-related applications: dacryocystography, orbital venography, and angiography), axial hypocycloidal tomography, computed tomography, ultrasonography, and magnetic resonance imaging.
Diagnostic Imaging↗
Epitopes of the CD4 antigen and HIV infection.
The CD4 (or T4) surface antigen of human T lymphocytes is an important part of the receptor for the human immunodeficiency virus (HIV). After binding to the receptor, the HIV may enter the T cell and induce the formation of syncytia. In an attempt to identify the receptor site more closely, monoclonal antibodies (Mab's) to CD4 were tested for their ability to block HIV infection in a syncytium formation assay, and the CD4 epitopes so identified were mapped by antibody cross-blocking. The antibodies that showed strong inhibition of HIV fell into two main families while a third group of Mab's blocked syncytia formation weakly or not at all. Several different isolates of HIV as well as the laboratory strain CBL1 grown in CEM cells were used to induce the syncytia. The data indicate that only some epitopes of CD4 are important for virus binding and imply that the virus-binding site for CD4 is conserved in different isolates of HIV with substantially divergent env gene sequences. Preliminary studies of patients suggest that polymorphism of these epitopes does not play a role in determining susceptibility to infection.
Acquired Immunodeficiency Syndrome↗
Evidence for heterosexual transmission and clinical manifestations of human immunodeficiency virus infection and related conditions in Lusaka, Zambia.
In a hospital-based survey in Lusaka, Zambia, 189 (17.5%) of 1078 subjects had antibodies against the human immunodeficiency virus (HIV). The prevalence of antibodies was low in subjects aged less than 20 or greater than 60 years; in men the peak prevalence (32.9%) occurred in those aged 30-35 years, and in women (24.4%) it occurred in the 20-25 year age-group. There was no significant difference in prevalence by sex after adjusting for age. High educational level was independently associated with HIV seropositivity; the antibody against HIV was found in 18.4% of blood donors and in 19.0% of hospital workers. Among patients the antibody prevalence ranged from 8.7% in antenatal women and 9.3% in orthopaedic patients to 29.2% in those attending sexually transmitted disease (STD) clinics (the prevalence being 37.3% in previous attenders and 22.8% in first-time attenders). Seropositivity rates were higher in patients with an infectious problem (23.4%) than in those without (11.4%, p = 0.0002). Herpes zoster, oral thrush, diarrhoea, tuberculosis, and weight loss were independently correlated with seropositivity. The data strongly suggest that HIV infection is prevalent in Africa and is transmitted heterosexually. The restricted distribution of seropositivity to the sexually active age-groups indicates that the epidemic, at least in this part of Africa, is newly introduced; this has substantial implications for prevention.
Acquired Immunodeficiency Syndrome↗
The T4 gene encodes the AIDS virus receptor and is expressed in the immune system and the brain.
The isolation of clones encoding the human surface protein T4, and the expression of the T4 gene in new cellular environments, have enabled us to examine the role of this protein in the pathogenesis of AIDS. Our studies support a mechanism of AIDS virus infection that initially involves the specific interaction of the AIDS virus with T4 molecules on the cell surface. This association can be demonstrated on T4+ transformed T and B lymphocytes as well as epithelial cells. Furthermore, the presence of T4 on the surface of all human cells examined is sufficient to render these cells susceptible to AIDS virus infection. Our data suggest that the T4-AIDS virus complex is then internalized by receptor-mediated endocytosis. Finally, we find that the T4 gene is expressed in the brain as well as in lymphoid cells, providing an explanation for the dual neurotropic and lymphotropic character of the AIDS virus. In this manner, a T lymphocyte surface protein important in mediating effector cell-target cell interactions has been exploited by a human retrovirus to specifically target the AIDS virus to populations of T4+ cells.
Ammonium Chloride↗
Studies in healthy human T-cell-leukemia lymphoma virus (HTLV-I) carriers from the Caribbean.
Six healthy relatives of 3 adult T-cell leukemia lymphoma (ATLL) patients and 6 members of a Caribbean family immigrant to the UK have been investigated for the presence of HTLV-I and expression of interleukin 2 (IL-2) receptors. Serum antibodies to HTLV-I were detected in all but 4 samples. Four to 10% of circulating cells from 3/4 seropositive donors studied displayed IL-2 receptors (anti-Tac+) and were shown to be convoluted lymphocytes by light microscopy morphology and immunoelectronmicroscopy. After 5 to 28 days in culture, cells from 4 seropositive donors reacted with monoclonal antibodies (MAbs) against the HTLV-I core proteins, p19 and p24, and released retrovirus particles. Similar experiments with blood from 3 seronegative donors from the same families and 4 normal controls proved negative. Our findings indicate that seropositive individuals harbour the virus in a population of T-lymphocytes which may then acquire receptors for IL-2. These individuals are at risk of developing ATLL.
Antibodies, Viral↗
Isolation of retroviruses from two patients with "common variable" hypogammaglobulinaemia.
Retroviruses related to human T-lymphotropic virus III/lymphadenopathy-associated virus (HTLV-III/LAV) have been isolated from peripheral-blood mononuclear cells of two patients with "common variable" hypogammaglobulinaemia who were being treated with intravenous gammaglobulin. One has had three different opportunistic infections. In both patients hypogammaglobulinaemia developed within 6 years of a longlasting undiagnosed viral-like illness in adolescence, and it is suggested that the virus causing that illness also gave rise to the hypogammaglobulinaemia. However, iatrogenic infection from intravenous gammaglobulin cannot be ruled out.
Adolescent↗
Fc receptor function on sheep alveolar macrophages.
We have examined the binding to sheep alveolar macrophages (AM) and peripheral blood polymorphonuclear leukocytes (PMN) of sheep immunoglobulin G subclasses or rabbit IgG immune complexes formed between rabbit anti-DNP IgG and DNP-bovine serum albumin. Binding studies using 125I-rabbit IgG immune complexes demonstrated 6.6 +/- 3.5 X 10(4) receptors per alveolar macrophage; these receptors bound immune complexes with an average association constant of 3.3 X 10(7) M-1. Saturation binding was achieved by 90 minutes at 4 degrees C with 6 X 10(-8) M IgG. Binding of subclasses of sheep IgG was examined by immunofluorescence. Only 10% of alveolar macrophages bound monomeric IgG1 and no binding of sheep IgG2 monomer could be demonstrated. In contrast, most peripheral blood PMN (93.0 +/- 9.5%) bound IgG2, but not IgG1. No binding to adult peripheral blood PMN of rabbit IgG immune complexes could be demonstrated. To study further the development of pulmonary host defense, we examined the expression of receptors for IgG immune complexes (Fc gamma R) on alveolar macrophages obtained from animals aged 8 through 180 days. At 8 and 21 days of age, the number of Fc gamma R varied considerably (75,000-192,000 sites per cell) and equalled or even exceeded that of adult sheep. Fc gamma R number declined by 42 and 90 days of age, where a nadir was reached (37,000 +/- 6,000 and 25,000 +/- 6,000 sites, respectively). By 180 days of age, the number of receptors had approached those of normal adult sheep (70,000 +/- 20,000 sites per cell). These studies parallel previous observations that revealed age-related differences in the phagocytic capacity of ovine alveolar macrophages.
Age Factors↗
Endocrine evaluation of forty female-to-male transsexuals: increased frequency of polycystic ovarian disease in female transsexualism.
A retrospective study of 40 female-to-male transsexuals was performed to investigate the frequency of endocrine dysfunction prior to hormonal treatment with testosterone. Two patients had laparoscopic evidence of polycystic ovarian disease (PCOD) prior to androgen treatment. Nine additional subjects had clinical evidence of PCOD, including ultrasonographic evidence of multicystic and enlarged ovaries in three patients and/or evidence of hirsutism and oligomenorrhea associated with increased androgen levels and/or an increased plasma luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratio. Two subjects had evidence of gonadal dysgenesis. Plasma levels of testosterone, prolactin, LH/FSH ratio, and dehydroepiandrosterone sulfate were significantly increased in 30 female transsexuals prior to testosterone treatment when compared to normal adult female controls studied in the early follicular phase of the menstrual cycle. These data indicate that female transsexuals have an increased incidence of endocrine dysfunction (32.5%) which should be investigated prior to hormonal treatment.
Adolescent↗
Introduction to diagnostic imaging techniques in ophthalmology.
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Eye Diseases↗
The T4 glycoprotein is a cell-surface receptor for the AIDS virus.
Taken together, our studies suggest a mechanism of AIDS virus infection that initially involves the specific association of the AIDS virus with T4 molecules on the cell surface. This association does not require additional T-cell-specific molecules and can be demonstrated on both B lymphocytes and epithelial cell lines. The T4-AIDS virus complex is likely to be internalized in endosomes via receptor-mediated endocytosis. The virus can then fuse with the vacuolar membrane, releasing the viral nucleocapsid into the cytoplasm to undergo uncoating. Viral replication does not appear to require the environment of a T lymphocyte because active infection is also observed in human T4+ B lymphocytes and epithelial cell lines. Moreover, the T4 gene is expressed in the brain as well as in lymphocytes, providing an explanation for the dual neurotropic and lymphotropic character of the virus. In this manner, a T-lymphocyte surface protein thought to be important in mediating effector cell-target cell interactions has been exploited by a human lymphotropic virus to target the AIDS virus specifically to populations of T4+ cells.
Acquired Immunodeficiency Syndrome↗
Postnatal maturation of pulmonary antimicrobial defense mechanisms in conventional and germ-free lambs.
The phagocytic and bactericidal capacities of ovine bronchoalveolar lavage (BAL) cells were investigated as a function of postnatal age. In addition, age-related changes in the elaboration by alveolar macrophages of chemotaxins for neutrophils, concentrations of BAL fluid and serum immunoglobulins, and serum opsonic capacity were determined. BAL cells exhibited major changes in morphology, composition, and in vitro proliferation during the 1st postnatal wk. Studies in germ-free lambs indicated that the antigenic burden of the ambient environment markedly influenced the concentration of BAL neutrophils but had no effect on the influx, phagocytic, and proliferative activities of alveolar macrophages. Phagocytic and bactericidal functions of BAL cells improved rapidly during the 1st postnatal wk, then declined, and did not reattain adult levels until day 180. The capacity of alveolar macrophages to elaborate chemotaxins for neutrophils was deficient at day 8, but not at subsequent ages. The concentration of BAL IgG1 increased until day 8, fell at day 21, and then continued to increase gradually. IgA was not detected in BAL until day 21 and increased rapidly thereafter. Serum opsonic capacity at days 1 and 4 was comparable to that of adult serum, but sera from days 8 to 42 showed a marked reduction in opsonic capacity. Pulmonary antimicrobial defenses in neonatal sheep were thus found to be deficient to some degree throughout the first 3 months of life. It was not until day 180 that the parameters investigated in this study approximated those of adult sheep.
Age Factors↗
AIDS and the spectrum of HTLV-III/LAV infection.
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Acquired Immunodeficiency Syndrome↗