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Biomedical subjects

D Weissman

Publications and source records attributed to D Weissman.

At least 19 recordsLinked to original sources
PubMed2006

Engineering and public health at CDC.

Engineering is the application of scientific and technical knowledge to solve human problems. Using imagination, judgment, and reasoning to apply science, technology, mathematics, and practical experience, engineers develop the design, production, and operation of useful objects or processes. During the 1940s, engineers dominated the ranks of CDC scientists. In fact, the first CDC director, Assistant Surgeon General Mark Hollis, was an engineer. CDC engineers were involved in malaria control through the elimination of standing water. Eventually the CDC mission expanded to include prevention and control of dengue, typhus, and other communicable diseases. The development of chlorination, water filtration, and sewage treatment were crucial to preventing waterborne illness. Beginning in the 1950s, CDC engineers began their work to improve public health while developing the fields of environmental health, industrial hygiene, and control of air pollution. Engineering disciplines represented at CDC today include biomedical, civil, chemical, electrical, industrial, mechanical, mining, and safety engineering. Most CDC engineers are located in the National Institute for Occupational Safety and Health (NIOSH) and the Agency for Toxic Substances and Disease Registry (ATSDR). Engineering research at CDC has a broad stakeholder base. With the cooperation of industry, labor, trade associations, and other stakeholders and partners, current work includes studies of air contaminants, mining, safety, physical agents, ergonomics, and environmental hazards. Engineering solutions remain a cornerstone of the traditional "hierarchy of controls" approach to reducing public health hazards.

Centers for Disease Control and Prevention, U.S.↗
PubMed2003

Fucosylated lactosamines participate in adhesion of HIV-1 envelope glycoprotein to dendritic cells.

Carbohydrates expressed on HIV-1 gp160 are purported to bind to several receptor types that affect virus pathophysiology. Here, we define a potential role for fucosylated glycans involved in the adhesion of cells expressing anchored HIV-1 glycoprotein or HIV virions to human dendritic cells (DCs). We observe that a monoclonal antibody (FH6), with reactivity toward an extended dimeric form of a fucosyl lactosamine, binds to gp120 transfectants, blocking adhesion of these cells and virus particles to human DCs. We observe that serum antibodies induced by peptide mimetic of fucosylated carbohydrate core structures emulate the monoclonal antibody reactivity pattern, showing enhanced reactivity to HIV-1 envelope-expressing cell line and blocking the adhesion of these cells to human DCs. These results suggest a potential role for initial adherence of virally infected cells or virions mediated by fucosylated lactosamines expressed on the envelope protein. As these carbohydrates function as adhesion molecules associated with homing and dissemination processes, such interactions may contribute to the HIV infection process.

Animals↗
PubMed2002

Kinetics of changes in lymphocyte sub-populations in mouse lungs after intrapulmonary infection with M. bovis (Bacillus Calmette-Guerin) and identity of cells responsible for IFNgamma responses.

Gamma interferon (IFNgamma) plays a key role in host defense against pulmonary mycobacterial infections. A variety of lymphocyte subsets may participate in producing pulmonary IFNgamma responses, but their relative contributions after mycobacterial infection have not been clearly elucidated. To address this question, C57Bl/6 female mice were infected by intrapulmonary instillation of 2.5 x 104 BCG (Mycobacterium bovis Bacillus Calmette-Guerin). Lymphocyte populations in lung interstitium were examined at different time points after the infection. BCG load in lungs peaked between 4 and 6 weeks post-infection and declined to very low levels by the 12th week of infection. Recovery of lung interstitial lymphocytes doubled by 4-6 weeks after infection and declined thereafter. Flow cytometric analysis of the lung-derived lymphocytes revealed that about 5% of the these cells made IFNgamma in control mice, and this baseline IFNgamma production involved T (CD3+NK1.1-), NK (CD3-NK1.1+) and NKT (CD3+NK1.1+) cells. As the BCG lung infection peaked, the total number of CD3+ T cells in the lungs increased threefold at 5-6 weeks post-infection. There was a marked increase (sixfold) in the number of T cells secreting IFNgamma 5-6 weeks post-infection. Some increase was also noted in the NKT cells making IFNgamma, but the numbers of NK cells making IFNgamma in BCG-infected lungs remained unaltered. Our results suggest that whereas NK and NKT cells contribute to baseline IFNgamma secretion in control lungs, expansion in the IFNgamma-producing T-cell population was essentially responsible for the augmented response seen in lungs of BCG-infected mice.

Animals↗
PubMed2001

A membrane-proximal basic domain and cysteine cluster in the C-terminal tail of CCR5 constitute a bipartite motif critical for cell surface expression.

We examined the structural requirements for cell surface expression, signaling, and human immunodeficiency virus co-receptor activity for the chemokine receptor, CCR5. Serial C-terminal truncation of CCR5 resulted in progressive loss of cell surface expression; mutants truncated at the 317th position and shorter were not detected at the cell surface. Alanine substitution of basic residues in the membrane-proximal domain (residues 314-322) in the context of a full-length C-tail resulted in severe reduction in surface expression. C-terminal truncation that excised the three cysteines in this domain reduced surface expression, but further truncation of upstream basic residue(s) abolished surface expression. Substituting the carboxyl-terminal domain of CXCR4 for that of CCR5 failed to rectify the trafficking defect of the tailless CCR5. In contrast, tailless CXCR4 or a CXCR4 chimera that exchanged the native cytoplasmic domain for that of wild type CCR5 was expressed at the cell surface. Deletion mutants that expressed at the cell surface responded to chemokine stimulation and mediated human immunodeficiency virus entry. Substitution of all serine and threonine residues in the C-terminal tail of CCR5 abolished chemokine-mediated receptor phosphorylation but preserved downstream signaling (Ca(2+) flux), while substitutions of tyrosine residues in the C-tail affected neither phenotype. CCR5 mutants that failed to traffic to the plasma membrane did not exhibit obvious changes in metabolic turnover and were retained in the Golgi or pre-Golgi compartments(s). Thus, the basic domain (-KHIAKRF-) and the cysteine cluster (-CKCC-) in the C-terminal tail of CCR5 function cooperatively for optimal surface expression.

Amino Acid Motifs↗
PubMed2001

Chronic inflammation with increased human immunodeficiency virus (HIV) RNA expression in the vaginal epithelium of HIV-infected Thai women.

Thai residents have a greater risk of heterosexual transmission of human immunodeficiency virus (HIV) than do US residents. To analyze host factors associated with heterosexual transmission, vaginal epithelial biopsies from HIV-seropositive Thai and US women were evaluated for tissue virus load and histologic makeup. In all, 84% of Thai and 14% of US women exhibited a chronic inflammatory T cell infiltrate in the vaginal epithelium. In Thai tissue, the infiltrate was associated with elevated levels of HIV RNA in the epidermis. Uninfected Thai women also had vaginal epithelial inflammation. Inflammation did not correlate with sexually transmitted diseases or HIV disease stage. The higher rates and increased risk of heterosexual transmission in Thailand may be due to chronic inflammation at the site where the virus is transmitted, which leads to the accumulation of activated T cells. Such cells might act as targets for initial viral infection and subsequently as reservoirs that support efficient transmission.

Adult↗
PubMed2001

Nonproliferating bystander CD4+ T cells lacking activation markers support HIV replication during immune activation.

HIV replicates primarily in lymphoid tissue and immune activation is a major stimulus in vivo. To determine the cells responsible for HIV replication during Ag-driven T cell activation, we used a novel in vitro model employing dendritic cell presentation of superantigen to CD4(+) T cells. Dendritic cells and CD4(+) T cells are the major constituents of the paracortical region of lymphoid organs, the main site of Ag-specific activation and HIV replication. Unexpectedly, replication occurred in nonproliferating bystander CD4(+) T cells that lacked activation markers. In contrast, activated Ag-specific cells were relatively protected from infection, which was associated with CCR5 and CXC chemokine receptor 4 down-regulation. The finding that HIV replication is not restricted to highly activated Ag-specific CD4(+) T cells has implications for therapy, efforts to eradicate viral reservoirs, immune control of HIV, and Ag-specific immune defects.

Antigen Presentation↗
PubMed2001

A map of human genome sequence variation containing 1.42 million single nucleotide polymorphisms.

We describe a map of 1.42 million single nucleotide polymorphisms (SNPs) distributed throughout the human genome, providing an average density on available sequence of one SNP every 1.9 kilobases. These SNPs were primarily discovered by two projects: The SNP Consortium and the analysis of clone overlaps by the International Human Genome Sequencing Consortium. The map integrates all publicly available SNPs with described genes and other genomic features. We estimate that 60,000 SNPs fall within exon (coding and untranslated regions), and 85% of exons are within 5 kb of the nearest SNP. Nucleotide diversity varies greatly across the genome, in a manner broadly consistent with a standard population genetic model of human history. This high-density SNP map provides a public resource for defining haplotype variation across the genome, and should help to identify biomedically important genes for diagnosis and therapy.

Chromosome Mapping↗
PubMed2001

In vivo identification of Langerhans and related dendritic cells infected with HIV-1 subtype E in vaginal mucosa of asymptomatic patients.

In Thailand, the predominant HIV subtype is E, rather than Subtype B as in North America and Europe, and the predominant mode of transmission is heterosexual contact. Subtype E has the ability to replicate in vitro in Langerhans cells. We hypothesized that this cell type might constitute a reservoir for the HIV virus in vaginal mucosa of asymptomatic carriers. To examine this hypothesis, we compared vaginal tissue histology in HIV-1-seropositive cases with seronegative cases and determined the immunophenotype of HIV-1-infected cells, their numbers, and their distribution in vaginal mucosa. Vaginal biopsies were performed at four different sites from six asymptomatic HIV-1 Subtype E-infected persons and from six seronegative cases at necropsy and examined histologically. Immunophenotyping was performed using immunoperoxidase for Gag p24 HIV, CD3, CD20, CD68, CD1a, S-100 and p55 antigens and by double labeling, combining immunoperoxidase with alkaline phosphatase using pairs of the above antigens. Twenty of twenty-four vaginal biopsies (83.3%) from HIV-seropositive cases showed definite inflammation compared to five of twenty-four vaginal necropsies (20.8%) from HIV-seronegative cases. One third of HIV-seropositive biopsies (8/24) demonstrated p24-positive cells in the epithelium, whereas three-fourths (18/24) of the biopsies revealed p24-positive cells in the lamina propria. All seropositive patients showed positive cells in at least one biopsy, but not all biopsies contained positive cells. Infected cells were more frequently observed at sites of greater inflammation. The dendritic cell count in HIV-seropositive vaginal epithelium was significantly higher than that observed in the seronegative cases (P =.004). The majority of p24-positive cells in the vaginal epithelium were Langerhans cells (CD1a+/S-100+), whereas in the lamina propria, about half of p24-positive cells were Langerhans-related dendritic cells (p55+ and S-100+) and half were T lymphocytes. In conclusion, the increased propensity for heterosexual transmission of Subtype E may be related to vaginal inflammation, leading to the accumulation of Langerhans cells and related dendritic cells which, once infected with HIV, can act as a reservoir for further virus transmission.

Acquired Immunodeficiency Syndrome↗
PubMed2000

HIV gag mRNA transfection of dendritic cells (DC) delivers encoded antigen to MHC class I and II molecules, causes DC maturation, and induces a potent human in vitro primary immune response.

Dendritic cells (DC) are the major APCs involved in naive T cell activation making them prime targets of vaccine research. We observed that mRNA was efficiently transfected, resulting in superior translation in DC compared with other professional APCs. A single stimulation of T cells by HIV gag-encoded mRNA-transfected DC in vitro resulted in primary CD4(+) and CD8(+) T cell immune responses at frequencies of Ag-specific cells (5-12.5%) similar to primary immune responses observed in vivo in murine models. Additionally, mRNA transfection also delivered a maturation signal to DC. Our results demonstrated that mRNA-mediated delivery of encoded Ag to DC induced potent primary T cell responses in vitro. mRNA transfection of DC, which mediated efficient delivery of antigenic peptides to MHC class I and II molecules, as well as delivering a maturation signal to DC, has the potential to be a potent and effective anti-HIV T cell-activating vaccine.

Antigen Presentation↗
PubMed2000

Interleukin-2 up-regulates expression of the human immunodeficiency virus fusion coreceptor CCR5 by CD4+ lymphocytes in vivo.

Intermittent interleukin-2 (IL-2) therapy can substantially increase CD4+ T cell counts of human immunodeficiency virus (HIV)-infected subjects. Administration of IL-2 led to transient up-regulation of CCR5 on CD4+ T cells; up to 87% of CD4+ cells expressed CCR5 after a 5-day cycle, with return to baseline levels within 2 weeks. Unlike in vitro studies, CCR5 was coexpressed with CD45RA and CXCR4 on CD4+ T cells after IL-2 therapy. The observed increase in coreceptor expression was not associated with detectable increases in viral replication. IL-2 therapy induced CCR5 expression in >90% of circulating memory CD4+ T cells, determined to be a long-term reservoir of HIV, suggesting significant activation of these cells. These studies demonstrate that levels of expression of HIV coreceptors alone do not always correlate with HIV replication in vivo and that IL-2 therapy activates a majority of memory T cells in the circulation and likely throughout the immune system.

CD4-Positive T-Lymphocytes↗
PubMed1999

Quantification of CD4, CCR5, and CXCR4 levels on lymphocyte subsets, dendritic cells, and differentially conditioned monocyte-derived macrophages.

CCR5 and CXCR4 are the major HIV-1 coreceptors for R5 and X4 HIV-1 strains, respectively, and a threshold number of CD4 and chemokine receptor molecules is required to support virus infection. Therefore, we used a quantitative fluorescence-activated cell sorting assay to determine the number of CD4, CCR5, and CXCR4 antibody-binding sites (ABS) on various T cell lines, T cell subsets, peripheral blood dendritic cells (PBDC), and monocyte-derived macrophages by using four-color fluorescence-activated cell sorting analysis on fresh whole blood. Receptor levels varied dramatically among the various subsets examined and typically varied from 2- to 5-fold between individuals. CCR5 was expressed at much higher levels in CD4+/CD45RO+/CD62L-true memory cells compared with CD4+/CD45RO+/CD62L+ cells. Fresh PBDC had the highest number of CCR5 ABS among the leukocyte subsets examined but had few CXCR4 ABS, affording a strategy for sort-purifying PBDC. In vitro maturation of PBDC resulted in median 3- and 41-fold increases in CCR5 and CXCR4 ABS, respectively. We found that macrophage colony-stimulating factor caused the greatest up-regulation of both CCR5 and CXCR4 on macrophage maturation (from approximately 5,000 to approximately 50, 000 ABS) whereas granulocyte-macrophage colony-stimulating factor caused a marked decrease of CXCR4 (from approximately 5,000 ABS to <500) while up-regulating CCR5 expression (from approximately 5,000 to approximately 20,000 ABS). Absolute ABS for CD4 and the major HIV-1 coreceptors serve as a more quantitative measure of cell surface expression, and we propose that this be used for future studies looking at the modulation of CD4 or chemokine receptor expression by cytokines, HIV-1 infection, or receptor polymorphisms.

CD4 Antigens↗
PubMed1999

Reduced interleukin-8 production by cystic fibrosis airway epithelial cells.

The acquisition of Pseudomonas aeruginosa in the airways of patients with cystic fibrosis (CF) is the initial event leading to bronchiectasis and lung disease. Although the host factors that permit initial airway colonization are largely unknown, recent studies suggest that secretion of interleukin (IL)-8 by airway epithelia and local recruitment of neutrophils is the final pathway in a pulmonary cytokine network. To determine whether differences in cytokine production exist between normal and CF airway epithelia, secretion of immunoreactive IL-8 and IL-10 as well as specific messenger RNA (mRNA) abundance were compared in airway epithelia expressing normal and mutant CF transmembrane regulator. After induction with IL-1beta, a CF airway cell line engineered to express the wild-type CF gene (CFT1-LCFSN) secreted significantly more immunoreactive IL-8 than did its isogenic parent that expressed the mutant CF gene (CFT1) or an isogenic vector control line (CFT1-LC3). Further studies with the three related cell lines demonstrated that expression of CFT1-LCFSN was associated with a significant increase in uninduced secretion of immunoreactive IL-8 as well as a 10- to 20-fold increase in IL-8 mRNA abundance when compared with the isogenic lines expressing the mutant gene. IL-1beta induction and intracellular accumulation of IL-8 appeared to be unaffected by CF genotype. These studies suggest that IL-8 secretion by CF airway epithelial cells is defective and may contribute to Pseudomonas persistence in the CF airway. Further studies are needed to confirm this difference in other cell lines and determine the linkage between IL-8 production and CF gene expression.

Bronchi↗
PubMed1998

The role of dendritic cells in the infection of CD4+ T cells with the human immunodeficiency virus: use of dendritic cells from individuals homozygous for the delta32CCR5 allele as a model.

Despite exposure to multiple strains of both macrophage (M)-tropic and T cell (T)-tropic HIV, primary infection is largely restricted to relatively homogeneous M-tropic virus. Since dendritic cells (DCs) play a pivotal role in the early events of HIV infection, several studies have focused on the role of DCs in this restriction. It has been proposed that DCs are more efficiently infected with M-tropic versus T-tropic viruses; however, the infectability of DCs and the relevance of their infectability for inducing productive infection is controversial. It has also been suggested that variability in DC expression of coreceptors for M-tropic versus T-tropic virus could explain the restriction in the transmitting virus. Using HIV-pulsed DCs from individuals with a homozygous deletion in the CCR5 gene as a human "knockout" model, we demonstrate that infection of DCs per se is not necessary to promulgate infection in CD4+ T cells. The data also suggest that transmission of HIV to CD4+ T cells is not dependent on DC coreceptor expression.

CD4-Positive T-Lymphocytes↗
PubMed1998

Dendritic cells express multiple chemokine receptors used as coreceptors for HIV entry.

Cells of the dendritic lineage are thought to be among the first cells infected after mucosal exposure to HIV. In this study, we have identified the presence of multiple chemokine receptors on dendritic cells (DC) that may function as coreceptors for HIV entry. DC effectively used CCR5 for entry of macrophage (M)-tropic isolates. CCR3, the eotaxin receptor, initially identified on eosinophils, is expressed on DC and may be used as an entry coreceptor by certain dual-tropic strains. CXCR4 was not expressed on DC, although SDF-1 induced a calcium flux and DC could be infected by T cell line (T)-tropic HIV. Our findings provide evidence for the presence of a non-CXCR4 SDF-1 receptor on DC that is used mainly by T-tropic strains of HIV. DC from individuals homozygous for a 32-bp deletion of the CCR5 gene are also infectable with M-tropic strains of HIV-1, and this infection is inhibited by stromal cell-derived factor (SDF)1, suggesting that this receptor can also be used by M-tropic HIV for entry. Delineation of the spectrum of coreceptor usage on DC may offer new approaches to interfere with the initiation and propagation of HIV infection.

Base Sequence↗
PubMed1998

Radiotherapy residents' knowledge of and attitudes toward management of cancer pain.

PURPOSE: To evaluate the fund of knowledge of and attitudes toward cancer pain management of radiotherapy residents across the nation. METHODS: Radiotherapy (XRT) residents who had completed at least a year of training were surveyed by questionnaire. Residents (n = 10) from a training program who had been given instructional resources in cancer pain management skills were compared with residents from across the nation (n = 61). A validated survey used in national Cancer Pain Initiative Role Model Programs was administered by mail. The survey contained 30 questions that evaluated attitude alone (A), knowledge alone (K), and how attitude affects the application of knowledge (A/K). RESULTS: The residents from the training program scored significantly higher in K (p < 0.005) and A/K (p < 0.04) than did the residents across the nation. No difference in scores evaluating A were detected (p = 0.26). Compared with the baseline knowledge of physicians in practice who had attended a workshop on cancer pain management, the national XRT residents had significantly lower scores in A (p < 0.006) and K (p < 0.001); however, no difference was found in A/K scores. After the workshop, the physicians in practice had significant gains in cancer pain management skills (p < 0.006). When the post-instruction survey was compared with the national XRT resident scores, there were marked differences in A (p < 0.00001), K (p < 0.00001) and A/K (p < 0.01). CONCLUSIONS: XRT residents in the United States are empathetic, but knowledge of cancer pain management is lacking. Instruction in the principles of cancer pain management can make a profound difference in knowledge and attitude. There is a need to recognize cancer pain management as a significant aspect of radiotherapeutic practice.

Attitude of Health Personnel↗
PubMed1998

The in vitro induction of human immunodeficiency virus (HIV) replication in purified protein derivative-positive HIV-infected persons by recall antigen response to Mycobacterium tuberculosis is the result of a balance of the effects of endogenous interleukin-2 and proinflammatory and antiinflammatory cytokines.

Coinfection with Mycobacterium tuberculosis and human immunodeficiency virus (HIV) is a serious problem, particularly in developing countries. Recently, M. tuberculosis and purified protein derivative (PPD) were demonstrated to induce HIV replication in CD8 T cell-depleted peripheral blood mononuclear cells from HIV-positive, PPD-positive persons but not in cells from PPD-negative persons. The role of endogenous and exogenous cytokines in modulating M. tuberculosis-induced HIV replication was evaluated. M. tuberculosis-induced HIV replication decreased following simultaneous inhibition of endogenous interleukin (IL)-2, IL-1beta, and tumor necrosis factor-alpha by the addition of soluble receptors and receptor antagonists or following exogenous IL-10 and transforming growth factor (TGF)-beta. In contrast, neutralization of endogenous IL-10 and TGF-beta augmented M. tuberculosis-induced HIV replication by increasing cellular activation. Thus, the balance between IL-2 and proinflammatory and antiinflammatory cytokines plays a major role in M. tuberculosis-induced replication of HIV.

CD8-Positive T-Lymphocytes↗
PubMed1997

Macrophage-tropic HIV and SIV envelope proteins induce a signal through the CCR5 chemokine receptor.

Human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) enter target cells by forming a complex between the viral envelope protein and two cell-surface membrane receptors: CD4 and a 7-span transmembrane chemokine receptor. Isolates of HIV that differ in cellular tropism use different subsets of chemokine receptors as entry cofactors: macrophage-tropic HIVs primarily use CCR5, whereas T-cell-tropic and dual-tropic isolates use CXCR4 receptors. HIV-mediated signal transduction through CCR5 is not required for efficient fusion and entry of HIV in vitro. Here we show that recombinant envelope proteins from macrophage-tropic HIV and SIV induce a signal through CCR5 on CD4+ T cells and that envelope-mediated signal transduction through CCR5 induces chemotaxis of T cells. This chemotactic response may contribute to the pathogenesis of HIV in vivo by chemo-attracting activated CD4+ cells to sites of viral replication. HIV-mediated signalling through CCR5 may also enhance viral replication in vivo by increasing the activation state of target cells. Alternatively, envelope-mediated CCR5 signal transduction may influence viral-associated cytopathicity or apoptosis.

CD4 Antigens↗