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ABSTRACT: Patients with HIV-1 often present with a wide range of hematopoietic abnormalities, some of which may be due to the presence of opportunistic infections and to therapeutic drug treatments. However, many of these abnormalities are directly related to HIV-1 replication in the bone marrow (BM). Although the most primitive hematopoietic progenitor cells (HPCs) are resistant to HIV-1 infection, once these cells begin to differentiate and become committed HPCs they become increasingly susceptible to HIV-1 infection and permissive to viral gene expression and infectious virus production. Trafficking of BM-derived HIV-1-infected monocytes has been shown to be involved in the dissemination of HIV-1 into the central nervous system (CNS), and it is possible that HIV-1 replication in the BM and infection of BM HPCs may be involved in the early steps leading to the development of HIV-1-associated dementia (HAD) as an end result of this cellular trafficking process. In addition, the growth and development of HPCs in the BM of patients with HIV-1 has also been shown to be impaired due to the presence of HIV-1 proteins and changes in the cytokine milieu, potentially leading to an altered maturation process and to increased cell death within one or more BM cell lineages. Changes in the growth and differentiation process of HPCs may be involved in the generation of monocyte populations that are more susceptible and/or permissive to HIV-1, and have potentially altered trafficking profiles to several organs, including the CNS. A monocyte subpopulation with these features has been shown to expand during the course of HIV-1 disease, particularly in HAD patients, and is characterized by low CD14 expression and the presence of cell surface CD16.
PLoS Pathogens 01/2009; 4(12):e1000215. · 9.13 Impact Factor
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ABSTRACT: A major obstacle in human immunodeficiency virus type 1 (HIV-1) eradication is the ability of the virus to remain latent in a subpopulation of the cells it infects. Latently infected cells can escape the viral immune response and persist for long periods of time, despite the presence of successful highly active antiretroviral therapy (HAART). Given the appropriate stimulus, latently infected cells can reactivate and start producing infectious virions. The susceptibility of these cell populations to HIV-1, their life span, their proliferative capacity, and their ability to periodically produce infectious virus subsequent to alterations in cellular physiology and/or immunologic controls are critical issues which determine the contribution of these cells to viral persistence. Memory CD4+ T cells due to the long life span, which may be several years, and their ability to reactivate upon encounter with their cognate antigen or other stimulation, are considered a critical reservoir for maintenance of latent HIV-1 proviral DNA. Cells of the monocyte-macrophage lineage, which originate in the bone marrow (BM), are of particular importance in HIV-1 persistence due to their ability to cross the blood-brain barrier (BBB) and spread HIV-1 infection in the immunoprivileged central nervous system (CNS). Hematopoietic progenitor cells (HPCs) are also a potential HIV-1 reservoir, as several studies have shown that CD34+ HPCs carrying proviral DNA can be found in vivo in a subpopulation of HIV-1-infected patients. The ability of HPCs to proliferate and potentially generate clonal populations of infected cells of the monocyte-macrophage lineage may be crucial in HIV-1 dissemination. The contribution of these and other cell populations in HIV-1 persistence, as well as the possible strategies to eliminate latently infected cells are critically examined in this review.
Current HIV research 10/2008; 6(5):388-400. · 1.98 Impact Factor
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ABSTRACT: Cells of the monocyte-macrophage lineage play an important role in human immunodeficiency virus type 1 (HIV-1)-associated disease. Infected myeloid precursor cells of the bone marrow are thought to be a viral reservoir that may repopulate the peripheral blood, central nervous system (CNS), and other organ systems throughout the course of disease. To model select aspects of HIV-1 infection of the bone marrow compartment in vitro, the erythro-myeloid precursor cell line, TF-1, was used. Phorbol 12-myristate 13-acetate (PMA) was found to induce the TF-1 cell line to differentiate through the myeloid lineage and become activated, as demonstrated by cellular morphologic changes and surface expression of differentiation and activation markers. Herein we demonstrate that HIV-1 long terminal repeats (LTRs) from T-, M-, and dual-tropic molecular clones have similar basal LTR activity in TF-1 cells and that differentiation of these cells by PMA resulted in increased LTR activity. Examination of specific cis-acting elements involved in basal and PMA-induced LTR activity demonstrated that the transcription factor families nuclear factor-kappa B (NF-kappaB) and specificity protein (Sp) contributed to the LTR activity of TF-1 cells, the Sp family being the most critical. These studies elucidate the impact of infected bone marrow monocytic cell differentiation on LTR activity and its potential impact on HIV-1-associated disease.
DNA and Cell Biology 07/2007; 26(6):387-94. · 2.07 Impact Factor
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ABSTRACT: Human T cell leukemia virus type 1 (HTLV-1) has previously been shown to infect antigen-presenting cells and their precursors in vivo. However, the role these important cell populations play in the pathogenesis of HTLV-1-associated myelopathy/tropical spastic paraparesis or adult T cell leukemia remains unresolved. To better understand how HTLV-1 infection of these important cell populations may potentially impact disease progression, the regulation of HTLV-1 viral gene expression in established monocytic cell lines was examined. U-937 promonocytic cells transiently transfected with a HTLV-1 long-terminal repeat (LTR) luciferase construct were treated with phorbol 12-myristate 13-acetate (PMA) to induce cellular differentiation. PMA-induced cellular differentiation resulted in activation of basal and Tax-mediated transactivation of the HTLV-1 LTR. In addition, electrophoretic mobility shift analyses demonstrated that PMA-induced cellular differentiation induced DNA-binding activity of cellular transcription factors to Tax-responsive element 1 (TRE-1) repeat II. Supershift analyses revealed that factors belonging to the activator protein 1 (AP-1) family of basic region/leucine zipper proteins (Fra-1, Fra-2, JunB, and JunD) were induced to bind to TRE-1 repeat II during cellular differentiation. Inhibition of AP-1 DNA-binding activity by overexpression of a dominant-negative c-Fos mutant (A-Fos) in transient expression analyses resulted in severely decreased levels of HTLV-1 LTR activation in PMA-induced U-937 cells. These results have suggested that following infection of peripheral blood monocytes, HTLV-1 viral gene expression may become up-regulated by AP-1 during differentiation into macrophages or dendritic cells.
Journal of Leukocyte Biology 10/2006; 80(3):640-50. · 4.99 Impact Factor
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Retrovirology. 01/2005;
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Retrovirology. 01/2005;
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Retrovirology. 01/2005;
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ABSTRACT: There is growing evidence that dietary fatty acids and/or dietary cholesterol could have a direct role on inflammatory diseases such as atherosclerosis. F(1)B Golden Syrian hamsters (Mesocricetus auratus), in 2 groups of 72, were fed for 10 wk a semipurified diet containing either 20 g/100 g hydrogenated coconut oil without cholesterol or cocoa butter (20 g/100 g) with cholesterol (0.15 g/100 g). After the 10-wk treatment period, plasma was collected from food-deprived hamsters (16 h) for plasma lipid measurements. Hamsters were then ranked according to their plasma VLDL and LDL cholesterol (non-HDL-C) concentrations with 1.86 mmol/L as the cut-off point between low (Low; n = 36) and medium (Med; n = 36) concentrations for each treatment. Hamsters in the Low and Medium groups fed cholesterol (Low-chol) had significantly lower plasma total cholesterol (TC) concentrations than hamsters in the Low group fed coconut oil (Low-CO). However, this difference for the Medium group was reflected in significantly lower plasma HDL cholesterol (HDL-C) concentrations. Hamsters in the Low-CO group had significantly higher aortic total and esterified cholesterol concentrations than hamsters in the Low-chol group. Hamsters in the Low-chol group had significantly higher aortic tumor necrosis factor-alpha concentrations than hamsters in the Low-CO group. Hamsters in the Med-CO group had significantly higher aortic interleukin-1beta concentrations than hamsters in the Med-chol group. In conclusion, the present study suggests that dietary cholesterol and saturated fatty acids could have an effect on atherosclerosis not only beyond their role in affecting plasma lipoproteins but also through increased production of inflammatory cytokines in the arterial wall.
Journal of Nutrition 03/2004; 134(2):410-5. · 3.92 Impact Factor
