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Biomedical subjects

J Laurence

Publications and source records attributed to J Laurence.

At least 109 records · Page 6Linked to original sources
PubMed1995

Role of glucocorticoid receptor binding sites in the human immunodeficiency virus type 1 long terminal repeat in steroid-mediated suppression of HIV gene expression.

Dexamethasone inhibited human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR)-directed gene expression in cells of T and B lymphoblastoid lineages, but not in monocytic cells. Suppression required an intact glucocorticoid receptor (GR), as it was amplified by transfection of lymphocytes with a plasmid encoding the human GR and blocked by the receptor antagonist RU486. These results were in direct contrast to the effects of dexamethasone on a murine leukemia retrovirus promoter where, consistent with the findings of others, activation of gene expression was obtained. Potential regions of the HIV-1 LTR mediating these effects were sought, with sequence homologies predicting two new glucocorticoid response element half-sites, GRE-II (nucleotides -6 to -1) and GRE-III (+ 15 to + 20), downstream from a previously identified GR DNA binding domain, GRE-I (-264 to -259). Mutational analyses documented the loss of inhibitory activity attendant on changes in GRE-III and the independence of steroid-mediated effects from GRE-I and GRE-II. Consistent with these findings, electrophoretic mobility shift assays revealed a difference in binding of cellular factors to GRE-III in cells of T and B lymphocyte vs. monocytic lineages. Binding sites for the cellular transcription factor leader binding protein (LBP-1) were found to overlap with GRE-III, and LBP-1 interacted with this element in the HIV LTR only in T and B lymphocytic extracts. We hypothesize that GRE-III sequence-specific effects, including modulation of LBP-GR interactions, underlie the negative regulatory effect of glucocorticoids on HIV-1 gene expression, with some specificity for cell type.

Base Sequence↗
PubMed1995

Immunodominant epitope regions of HIV-1 reverse transcriptase: correlations with HIV-1+ serum IgG inhibitory to polymerase activity and with disease progression.

Anti-HIV-1 polymerase antibodies are present in high titer throughout the course of HIV disease. The possibility that a subset of these immunoglobulins might represent an adaptive immune response was suggested by several studies, from this laboratory and others, identifying IgGs capable of inhibiting the catalytic activity of reverse transcriptase (RT) in asymptomatic HIV+ individuals, which were absent from most AIDS patients. We have now determined the dominant B-cell epitope segments of RT recognized during natural HIV-1 infection, with one epitope region, amino acids 244-269, recognized by the majority of HIV-1 positive sera. We have also correlated IgG RT inhibitor activity with amino acids 157-178, corresponding to sequences previously identified by monoclonal antibody mapping and site-directed mutagenesis as necessary for the maintenance of polymerase function. Absence of reactivity to synthetic peptides prepared from this latter region correlated with both advanced HIV disease in a cross-sectional survey of 57 HIV-1+ individuals, and progression of clinical symptoms in a small cohort followed longitudinally. Given current interest in examining diverse components of HIV in development of peptide-based protective vaccines and specific active immunotherapies, these segments of RT might be considered as potential candidates.

Amino Acid Sequence↗
PubMed1995

Neutrophils from human immunodeficiency virus (HIV)-seronegative donors induce HIV replication from HIV-infected patients' mononuclear cells and cell lines: an in vitro model of HIV transmission facilitated by Chlamydia trachomatis.

Infection with a sexually transmitted disease (STD) increases the risk for human immunodeficiency virus (HIV) infection. Polymorphonuclear leukocytes (PMNs) are recruited into the genital tract by STD pathogens, such as Chlamydia trachomatis. Semen of HIV-infected men contains HIV associated with mononuclear cells. This study investigated the interaction among PMNs from HIV-uninfected persons, C. trachomatis, and HIV-infected cells and examined the mechanisms for enhanced HIV replication. We demonstrated that PMNs from HIV-seronegative donors induced HIV replication in mononuclear cells from 17 HIV-infected patients in medium without exogenous IL-2. HIV in the cell-free supernatants from cocultures of PMNs and patients' peripheral blood mononuclear cells (PBMCs) was replication competent, as indicated by their capacity to propagate HIV in a second round of culture using PBMCs from HIV-seronegative individuals and by the fact that proviral DNA was found in these cells. PMNs from HIV-seronegative donors increased HIV replication over 100-fold in chronically HIV-infected cell lines of the monocytic, T, and B cell lineages. Moreover, PMNs increased U1 cells' production of p24 antigen by as much as ninefold when compared with U1 cells cocultured with PBMCs. The addition of C. trachomatis to PMN and U1 coculture increased HIV replication by an additional ninefold at 24 h, whereas C. trachomatis alone had no effect on p24 antigen production by U1 cells. Thus, C. trachomatis serves not only to recruit PMNs, but also to interact with PMNs to increase HIV replication. HIV replication is triggered by contact of HIV-infected cells with PMNs, by the generation of reactive oxygen intermediates (ROIs), and by soluble factors such as TNF-alpha and IL-6. This is based on the findings that production of p24 antigen, IL-6, and TNF-alpha induced by PMNs is abrogated by disrupting or partitioning PMNs from HIV-infected cells; is inhibited by superoxide dismutase and catalase, enzymes that destroy ROIs; is enhanced by differentiated HL60 cells capable of producing ROIs; and is induced by PMNs tested negative for CMV. Furthermore, the production of ROIs is independent of HIV infection of mononuclear cells, since PMNs cocultured with HIV-uninfected parental monocytic and T cell lines generated ROIs. Therefore, the increased risk for acquiring HIV infection associated with chlamydia cervicitis may be related to the local recruitment of PMNs by C. trachomatis and the induction of infectious virus from mononuclear cells present in semen. These observations provide a rationale for strategies to reduce HIV transmission by control of STD.

B-Lymphocytes↗
PubMed1995

Growth hormone in HIV/AIDS: current uses and future prospects.

Recombinant human growth hormone (rhGH) and its primary induced product, insulin-like growth factor-I (IGF-I), have beneficial effects on a myriad of syndromes associated with catabolic metabolism in children and in adults. Their ability to promote nitrogen retention and protein synthesis and to enhance lipolysis has translated into significant increases in body weight, lean body mass, and sense of well-being among HIV+ individuals with wasting syndromes. These changes, first observed in limited phase I studies, have now been confirmed by two large, controlled clinical trials. The alterations are consistent with the low GH and/or IGF-I levels observed in HIV infection, as well as the relative resistance to GH. Whether long-term outcome in HIV disease is altered by such therapies remains to be determined, however. The ability of GH to augment cellular immune function and modulate T lymphocyte trafficking in animal models of immune suppression has also led to examination of its impact on CD4+ T cell counts and viral load in HIV infection. There is currently little evidence that short-term rhGH administration has any lasting impact on T cell biology in the setting of HIV disease. However, preliminary reports that, in vitro, GH alters immune cell apoptosis and enhances the efficacy of Zidovidine (AZT), similar to changes observed with granulocyte-macrophage colony-stimulating factor, may lead to additional uses for GH. Studies to define the mechanism of action of GH and IGF-I on normal and abnormal immune homeostasis in children and adults should enhance our ability to design effective treatments for those with acquired immune deficiency syndrome (AIDS) and perhaps other wasting and immune suppressive disorders.

Adult↗
PubMed1994

Identification of a novel cell-type and context specific enhancer within the negative regulatory element of the human immunodeficiency virus type 1 long terminal repeat.

One segment of the negative regulatory region of the human immunodeficiency virus long terminal repeat (HIV-LTR), nucleotides -273 to -255, is homologous to positive response elements for interleukin-2 and glucocorticoids. We demonstrate that this sequence, referred to as purine-rich response element (PRRE), acts as a classic enhancer in the context of a heterologous promoter, but serves as a functional repressor in the intact provirus, binding (a) cellular factor(s). These data suggest that certain DNA response elements in the HIV LTR serve as negative regulators only in the context of the intact LTR, presumably through interactions with other transcriptional factors, a phenomenon that might be exploited to interfere with viral gene transcription.

Base Sequence↗
PubMed1994

HIV-induced T-lymphocyte depletion.

A fundamental paradox of HIV disease is the progressive diminution in CD4+ lymphocytes despite the fact that only a small fraction of cells are infected. The mechanisms of T-cell depletion in HIV disease are divers. These include immune and autoimmune destruction of infected and uninfected cells, signaling derangements inducing clonal anergy and apoptosis, and direct cytotoxic effects of viral particles. These phenomena are reviewed as they pertain to the different clinical stages of HIV infection.

Acquired Immunodeficiency Syndrome↗
PubMed1993

T-cell subsets in health, infectious disease, and idiopathic CD4+ T lymphocytopenia.

PURPOSE: To update our knowledge about normal absolute values for CD4+ and CD8+ peripheral T-lymphocyte subsets and to show how these values are influenced by infectious disease. These data are discussed in the context of a newly identified syndrome, idiopathic CD4+ T lymphocytopenia and severe unexplained human immunodeficiency virus (HIV)-negative immune suppression (ICL/SUHIS). DATA IDENTIFICATION: Studies done after 1978, when T-lymphocyte subset analysis using monoclonal antibodies was introduced, identified from a MEDLARS computer search and from personal files. STUDY SELECTION: All English-language articles that included the number of patients studied; the criteria for patient selection; and the means, ranges, and standard deviations for absolute counts of peripheral T-cell subsets. RESULTS OF DATA ANALYSIS: The effects of certain bacterial, viral, parasitic, and fungal infections; analytic variance; and biologic factors on T-lymphocyte subsets must be considered in assessing such values in health and disease. Quantitative T-cell abnormalities secondary to advanced HIV infection may be dissociated from physiologic changes, congenital disorders, and most other conditions by documentation of absolute CD4 counts of less than 400/mm3, a progressive depletion of CD4 cells, and a CD4:CD8 ratio of less than 1.0. Designation of ICL/SUHIS as a new syndrome, dependent solely on CD4 cell count, raises the possibility that persons with an extraordinary diversity of conditions, including those with stable, "physiologic" CD4 lymphopenia, will be given the diagnosis. CONCLUSIONS: Persons with a CD4 count of less than 300 to 400/mm3, a progressive decline in absolute CD4 count, and a CD4:CD8 ratio of less than 1.0 should be aggressively investigated for HIV infection as well as for other causes of immune deficiency, regardless of intercurrent infections. The search for potential novel infectious causes in syndromes such as ICL/SUHIS may be most productive among such a subset of all persons with CD4 counts less than normal levels.

CD4-Positive T-Lymphocytes↗