7 results on '"Stuart Imlach"'
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2. Jaagsiekte sheep retrovirus infects multiple cell types in the ovine lung
- Author
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Mark P. Dagleish, Stuart Imlach, David J. Griffiths, Henny M. Martineau, and Chris Cousens
- Subjects
Cell type ,Immunology ,Cell ,Microbiology ,Transformation and Oncogenesis ,Virology ,medicine ,Animals ,Lung cancer ,Lung ,Microscopy ,Sheep ,biology ,Histocytochemistry ,Stem Cells ,Epithelial Cells ,respiratory system ,Jaagsiekte sheep retrovirus ,biology.organism_classification ,medicine.disease ,Immunohistochemistry ,medicine.anatomical_structure ,Pulmonary Adenomatosis, Ovine ,Insect Science ,biology.protein ,Antibody ,Stem cell ,Betaretrovirus ,Biomarkers - Abstract
Ovine pulmonary adenocarcinoma (OPA) is a transmissible lung cancer of sheep caused by Jaagsiekte sheep retrovirus (JSRV). The details of early events in the pathogenesis of OPA are not fully understood. For example, the identity of the JSRV target cell in the lung has not yet been determined. Mature OPA tumors express surfactant protein-C (SP-C) or Clara cell-specific protein (CCSP), which are specific markers of type II pneumocytes or Clara cells, respectively. However, it is unclear whether these are the cell types initially infected and transformed by JSRV or whether the virus targets stem cells in the lung that subsequently acquire a differentiated phenotype during tumor growth. To examine this question, JSRV-infected lung tissue from experimentally infected lambs was studied at early time points after infection. Single JSRV-infected cells were detectable 10 days postinfection in bronchiolar and alveolar regions. These infected cells were labeled with anti-SP-C or anti-CCSP antibodies, indicating that differentiated epithelial cells are early targets for JSRV infection in the ovine lung. In addition, undifferentiated cells that expressed neither SP-C nor CCSP were also found to express the JSRV Env protein. These results enhance the understanding of OPA pathogenesis and may have comparative relevance to human lung cancer, for which samples representing early stages of tumor growth are difficult to obtain.
- Published
- 2011
3. High Levels of Human Immunodeficiency Virus Infection of CD8 Lymphocytes Expressing CD4 In Vivo
- Author
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Gordon Scott, Peter Simmonds, Stuart Imlach, Clifford Leen, Alexandra Cochrane, and Dermot Kennedy
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Lymphocyte ,Immunology ,HIV Infections ,CD8-Positive T-Lymphocytes ,Microbiology ,Models, Biological ,Virus ,Antigens, CD4 ,Acquired immunodeficiency syndrome (AIDS) ,In vivo ,T-Lymphocyte Subsets ,Virology ,medicine ,Humans ,HIV Long Terminal Repeat ,biology ,Base Sequence ,HIV ,Cell Differentiation ,Middle Aged ,biology.organism_classification ,medicine.disease ,medicine.anatomical_structure ,Phenotype ,Insect Science ,Lentivirus ,CD4 Antigens ,DNA, Viral ,Pathogenesis and Immunity ,Viral disease ,CD8 - Abstract
Human immunodeficiency virus (HIV)-infected CD8 lymphocytes have been reported in vivo, but the mechanism of infection remains unclear. Experiments using the thy/hu mouse model support export of intrathymically infected CD8 precursors, while recent in vitro data suggest that mature CD8 lymphocytes upregulate CD4 upon activation (generating a CD8brightCD4dimphenotype) and are susceptible to HIV infection. To determine whether these mechanisms operate in vivo and to assess their relative importance in the generation of circulating HIV-infected CD8 lymphocytes, we quantified HIV long terminal repeat (LTR) DNA in CD8+CD4−and CD8brightCD4dimlymphocytes isolated from HIV-infected individuals by fluorescence-activated cell sorting. HIV infection of CD8 lymphocytes was demonstrated in 17 of 19 subjects, with a significant inverse relationship between level of infection and CD4 lymphocyte count (R= −0.73;P< 0.001). The level of HIV infection of CD8brightCD4dimlymphocytes was significantly higher (median, 1,730 HIV LTR copies/106cells;n= 9) than that of CD8+CD4−lymphocytes (undetectable in seven of nine individuals;P< 0.01) and approached that of CD4 lymphocytes from the same individuals (median, 3,660 HIV LTR copies/106cells). CD8brightCD4dimlymphocytes represented 0.8 to 3.3% of total CD8 lymphocytes and were most prevalent in the memory subset. Thus, HIV-infected CD8 lymphocytes commonly circulate in HIV-infected individuals and are generated through infection of activated CD8 lymphocytes rather than through export of intrathymically infected precursors. The high level of infection of CD8brightCD4dimlymphocytes could have a direct role in the decline in CD8 lymphocyte function that accompanies HIV disease progression.
- Published
- 2004
4. Phenotypic analysis of peripheral blood gammadelta T lymphocytes and their targeting by human immunodeficiency virus type 1 in vivo
- Author
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Peter Simmonds, Clifford Leen, Jeanne E. Bell, and Stuart Imlach
- Subjects
Adult ,Male ,Receptors, CXCR4 ,Receptors, CCR5 ,medicine.drug_class ,CD8 Antigens ,Biology ,Antigens, CD8 ,Monoclonal antibody ,CXCR4 ,Flow cytometry ,Antigens, CD4 ,Immunophenotyping ,Chemokine receptor ,Immune system ,Proviruses ,T-Lymphocyte Subsets ,Virology ,medicine ,Humans ,Infectivity ,medicine.diagnostic_test ,Receptors, Antigen, T-Cell, gamma-delta ,Middle Aged ,Viral Load ,CD4 Antigens ,Immunology ,HIV-1 ,Female ,CD8 - Abstract
There is increasing evidence that a wider range of lymphoid cell types other than CD4(+) T helper lymphocytes are infected with HIV-1 in vivo, including CD8 lymphocytes, natural killer cells, and reticulodendritic cells. Each potentially contributes to the reservoir of infected cells that resist antiviral treatment and to the impairment of immune responses in AIDS. By quantitative PCR for HIV proviral sequences we have now obtained evidence for substantial infection of gammadelta lymphocytes, contributing 3-45% of the proviral load in peripheral blood. A large proportion of gammadelta lymphocytes constitutively expressed the chemokine receptors CCR5 and CXCR4, with evidence for marked up-regulation of CD8 in samples from HIV-infected individuals, corresponding to an activated phenotype. That gammadelta lymphocytes might be susceptible to HIV infection was investigated using in vitro infectivity assays of recombinant HIV-expressing green fluorescent protein, followed by flow cytometry. gammadelta, CD4, and CD8 lymphocytes were each productively infected, with gammadelta lymphocytes showing the greatest susceptibility. For each cell type, blocking assays with an anti-CD4 monoclonal antibody indicated that entry was CD4-dependent.
- Published
- 2003
5. Activated peripheral CD8 lymphocytes express CD4 in vivo and are targets for infection by human immunodeficiency virus type 1
- Author
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Jeanne E. Bell, Stuart Imlach, Peter Simmonds, Clifford Leen, T. Shirafuji, and S. McBreen
- Subjects
Adult ,CD4-Positive T-Lymphocytes ,Male ,Immunology ,Population ,Human leukocyte antigen ,Biology ,CD8-Positive T-Lymphocytes ,Microbiology ,Peripheral blood mononuclear cell ,Antigens, CD4 ,Immunophenotyping ,Immune system ,Antigen ,Proviruses ,T-Lymphocyte Subsets ,Virology ,Cytotoxic T cell ,Humans ,education ,DNA Primers ,Protein Tyrosine Phosphatase, Non-Receptor Type 1 ,education.field_of_study ,Base Sequence ,Immunomagnetic Separation ,Antigens, CD45 ,Middle Aged ,Viral Load ,HIV Antigens ,Insect Science ,Case-Control Studies ,CD4 Antigens ,HIV-1 ,Pathogenesis and Immunity ,Leukocyte Common Antigens ,Female ,CD8 - Abstract
There is increasing evidence that CD8 lymphocytes may represent targets for infection by human immunodeficiency virus type 1 (HIV-1) in vivo whose destruction may contribute to the loss of immune function underlying AIDS. HIV-1 may infect thymic precursor cells destined to become CD4 and CD8 lymphocytes and contribute to the numerical decline in both subsets on disease progression. There is also evidence for the induction of CD4 expression and susceptibility to infection by HIV-1 of CD8 lymphocytes activated in vitro. To investigate the relationship between CD8 activation and infection by HIV-1 in vivo, activated subsets of CD8 lymphocytes in peripheral blood mononuclear cells (PBMCs) of HIV-seropositive individuals were investigated for CD4 expression and HIV infection. Activated CD8 lymphocytes were identified by expression of CD69, CD71, and the human leukocyte antigen (HLA) class II, the β-chain of CD8, and the RO isoform of CD45. CD4+and CD4−CD8 lymphocytes, CD4 lymphocytes, other T cells, and non-T cells were purified using paramagnetic beads, and proviral sequences were quantified by PCR using primers from the long terminal repeat region. Frequencies of activated CD8 lymphocytes were higher in HIV-infected study subjects than in seronegative controls, and they frequently coexpressed CD4 (mean frequencies on CD69+, CD71+, and HLA class II+cells of 23, 37, and 8%, respectively, compared with 1 to 2% for nonactivated CD8 lymphocytes). The level of CD4 expression of the double-positive population approached that of mature CD4 lymphocytes. That CD4 expression renders CD8 cell susceptible to infection was indicated by their high frequency of infection in vivo; infected CD4+CD8 lymphocytes accounted for between 3 and 72% of the total proviral load in PBMCs from five of the eight study subjects investigated, despite these cells representing a small component of the PBMC population (
- Published
- 2001
6. Infection of the CD45RA+ (naive) subset of peripheral CD8+ lymphocytes by human immunodeficiency virus type 1 in vivo
- Author
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Jeanne E. Bell, Peter Simmonds, Stuart Imlach, T. Shirafuji, Gordon Scott, S. McBreen, and Clifford Leen
- Subjects
CD4-Positive T-Lymphocytes ,Chemokine ,Lymphocyte ,CD3 ,Immunology ,Population ,Molecular Sequence Data ,HIV Infections ,Biology ,CD8-Positive T-Lymphocytes ,Microbiology ,CXCR4 ,Proviruses ,Virology ,medicine ,Humans ,Amino Acid Sequence ,education ,Immunodeficiency ,HIV Long Terminal Repeat ,Protein Tyrosine Phosphatase, Non-Receptor Type 1 ,education.field_of_study ,Base Sequence ,Antigens, CD45 ,medicine.disease ,Long terminal repeat ,medicine.anatomical_structure ,Insect Science ,DNA, Viral ,biology.protein ,HIV-1 ,Leukocyte Common Antigens ,Pathogenesis and Immunity ,Immunologic Memory ,CD8 - Abstract
To investigate the mechanism and functional significance of infection of CD8+lymphocytes by human immunodeficiency virus type 1 (HIV-1) in vivo, we determined frequencies of infection, proviral conformation, and genetic relationships between HIV-1 variants infecting naive (CD45RA+) and memory (CD45RO+) peripheral blood CD4+and CD8+lymphocytes. Infection of CD3+CD8+CD45RA+cells was detected in 9 of 16 study subjects at frequencies ranging from 30 to 1,400 proviral copies/106cells, more frequently than CD3+CD8+lymphocytes expressing the RO isoform of CD45 (n= 2, 70 and 260 copies /106cells). In agreement with previous studies, there was no evidence for a similar preferential infection of CD4+naive lymphocytes. Proviral sequences in both CD4+and CD8+lymphocyte subsets were complete, as assessed by quantitation using primers from the long terminal repeat region spanning the tRNA primer binding site. In six of the seven study subjects investigated, variants infecting CD8+lymphocytes were partially or completely genetically distinct in the V3 region from those recovered from CD4+lymphocytes and showed a greater degree of compartmentalization than observed between naive and memory subsets of CD4+lymphocytes. In two study subjects, arginine substitutions at position 306, associated with use of the chemokine coreceptor CXCR4, were preferentially found in CD4 lymphocytes. These population differences may have originated through different times of infection rather than necessarily indicating a difference in their biological properties. The preferential distribution of HIV-1 in naive CD8+lymphocytes indeed suggests that infection occurred early in T-lymphocyte ontogeny, such as during maturation in the thymus. Destruction of cells destined to become CD8+lymphocytes may be a major factor in the decline in CD8+lymphocyte frequencies and function on disease progression and may contribute directly to the observed immunodeficiency in AIDS.
- Published
- 2001
7. Infection of CD8 Lymphocytes with HIV in vivo
- Author
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Clifford Leen, Gordon Scott, Alexandra Cochrane, Ray Brettle, Stuart Imlach, and Peter Simmonds
- Subjects
Thymic Tissue ,medicine.anatomical_structure ,Immune system ,In vivo ,Lymphocyte ,Immunology ,Cell ,medicine ,General Medicine ,Biology ,Provirus ,Virus ,CD8 - Abstract
Although the major cellular target of HIV is the CD4 lymphocyte, the virus has been shown to infect numerous other cells of the immune system including macrophages, dendritic cells and CD8 lymphocytes. In vivo it is likely that infection of CD8 lymphocytes with HIV occurs at times when CD4 is expressed on the cell surface. This occurs during CD8 lymphocyte development in the thymus and during activation in the periphery. Evidence supporting infection in the thymus comes from post-mortem examination of thymic tissue from HIV infected patients and from experimental infection of thymocytes in the Thy-hu mouse model. Support for infection during activation is provided by the observation that a greater proportion of activated than non-activated CD8 lymphocytes carry the HIV provirus.
- Published
- 2003
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