Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Dendritic cells (DC), the most potent antigen-presenting cells (APC), have been implicated as the initial targets of HIV infection in skin and mucosal surfaces. DC can be generated in vitro from blood-isolated CD14(+) monocytes or CD34(+) hematopoietic progenitor cells in the presence of various cytokines. In this study, we investigated whether monocytes obtained from placental cord blood are capable of differentiation into dendritic cells when cultured with a combination of cytokines - granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-4 (IL-4), and tumor necrosis factor-alpha (TNF-alpha). We then examined HIV infection, HIV receptor (CD4, CCR5) expression, and beta-chemokine [macrophage inflammatory protein-1alpha and -1beta (MIP-1alpha, MIP-1beta)] production by placental cord monocyte-derived dendritic cells (MDDC) as compared to that of autologous cord monocyte-derived macrophages (MDM). Monocytes isolated from placental cord blood differentiate into DC after 7 days in culture with the mixture of cytokines, as demonstrated by development of characteristic DC morphology, loss of CD14 expression, and gain of CD83, a marker for mature DC. Mature cord MDDC had significantly lower susceptibility to M-tropic ADA (CCR5-dependent) envelope-pseudotyped HIV infection in comparison to autologous placental cord MDM, whereas there was no significant difference in virus replication in cord MDDC and MDM infected with murine leukemia virus envelope-pseudotyped HIV (HIV receptor-independent). This limited susceptibility of cord MDDC to M-tropic HIV infection may be due to lower expression of CD4 and CCR5 on the cell membrane and higher production of MIP-1alpha and MIP-1beta. These data provide important information toward our understanding of the biological properties of cord MDDC in relation to HIV infection.
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PMID:HIV-1 infection of placental cord blood monocyte-derived dendritic cells. 1167 7

Increases in circulating CD14+/CD16+ monocytes have been associated with HIV dementia; trafficking of these cells into the CNS has been proposed to play an important role in the pathogenesis of HIV-induced neurological disorders. This model suggests that events outside the CNS leading to monocyte activation initiate the process leading to HIV dementia. To investigate the role of this activated monocyte subset in the pathogenesis of HIV dementia, we examined brain specimens from patients with HIV encephalopathy (HIVE), HIV without encephalopathy, and seronegative controls. An accumulation of perivascular macrophages was observed in HIVE. The majority of these cells identified in microglial nodules and in the perivascular infiltrate were CD14+/CD16+. P24 antigen colocalized with both CD14 and CD16 suggesting that the CD14+/CD16+ macrophage is a major reservoir of HIV-1 infection in CNS. Using CD45/LCA staining, the perivascular macrophage was distinguished from resident microglia. In addition to perivascular and nodular localizations, CD16 also stained ramified cells throughout the white matter. These cells were more ramified and abundant than cells positive for CD14 in white matter. Double staining for p24 and CD16 suggests that these cells were often infected with HIV-1. The prominent distribution of CD14+ cells in HIVE prompted our analysis of soluble CD14 levels in cerebrospinal fluid. Higher levels of soluble CD14 (sCD14) were observed in patients with moderate-to-severe HIV dementia, suggesting the utility of sCD14 as a surrogate marker. CD14+/CD16+ monocytes may play a role in other neurological disorders and sCD14 may be useful for evaluating these conditions.
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PMID:CNS invasion by CD14+/CD16+ peripheral blood-derived monocytes in HIV dementia: perivascular accumulation and reservoir of HIV infection. 1170 85

In vitro studies show that human immunodeficiency virus type 1 (HIV-1) does not replicate in freshly isolated monocytes unless monocytes differentiate to monocyte-derived macrophages. Similarly, HIV-1 may replicate in macrophages in vivo, whereas it is unclear whether blood monocytes are permissive to productive infection with HIV-1. We investigated HIV-1 replication in CD14(+) monocytes and resting and activated CD4(+) T cells by measuring the levels of cell-associated viral DNA and mRNA and the genetic evolution of HIV-1 in seven acutely infected patients whose plasma viremia had been <100 copies/ml for 803 to 1,544 days during highly active antiretroviral therapy (HAART). HIV-1 DNA was detected in CD14(+) monocytes as well as in activated and resting CD4(+) T cells throughout the course of study. While significant variation in the decay slopes of HIV-1 DNA was seen among individual patients, viral decay in CD14(+) monocytes was on average slower than that in activated and resting CD4(+) T cells. Measurements of HIV-1 sequence evolution and the concentrations of unspliced and multiply spliced mRNA provided evidence of ongoing HIV-1 replication, more pronounced in CD14(+) monocytes than in resting CD4(+) T cells. Phylogenetic analyses of HIV-1 sequences indicated that after prolonged HAART, viral populations related or identical to those found only in CD14(+) monocytes were seen in plasma from three of the seven patients. In the other four patients, HIV-1 sequences in plasma and the three cell populations were identical. CD14(+) monocytes appear to be one of the potential in vivo sources of HIV-1 in patients receiving HAART.
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PMID:Evidence for human immunodeficiency virus type 1 replication in vivo in CD14(+) monocytes and its potential role as a source of virus in patients on highly active antiretroviral therapy. 1175 61

Whereas T-cell activation parameters of HIV disease have been extensively studied, the activation status of circulating monocytes has received less attention. Sixty-one subjects with primary HIV infection were evaluated by fluorescent-activated cell sorter (FACS) analysis at baseline (pretreatment) for CD4 T-cell count, CD4 T-cell apoptosis, and immune activation. A subset of 15 subjects with marked elevated (3 standard deviations above normal) monocyte DR expression had significantly reduced CD4 T-cell counts at baseline (p <.01) when compared with 46 subjects without monocyte activation. Ten subjects who presented with elevated levels of both CD14/DR, and CD4/CD38, had higher CD4 T-cell apoptosis (p <.001), and lower CD4 T-cell counts (p <.001) and higher baseline plasma HIV RNA (p <.01) than 21 subjects without elevated CD14/DR and CD4/CD38 coexpression. Fifty subjects were subsequently evaluated for immune cell activation over 24 weeks postinitiation of highly active antiretroviral therapy (HAART). A subgroup of 5 subjects who had persistent CD14/DR activation showed continuous depression of CD4 T-cell counts persisting for up to 2 years. The CD4 T-cell counts of this subgroup were significantly lower, at all time points, in comparison to 35 subjects who lacked any persistent expression of monocyte or CD4 T-cell activation (at 24 weeks, p <.002). We conclude that monocyte activation as defined by elevation of CD14/DR expression correlates to CD4 T-cell depletion in primary HIV infection, and is predictive of a poor CD4 T-cell response to HAART in a subset of patients.
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PMID:Increased HLA-DR expression on peripheral blood monocytes in subsets of subjects with primary HIV infection is associated with elevated CD4 T-cell apoptosis and CD4 T-cell depletion. 1204 76

The dendritic cell (DC)-specific molecule DC-SIGN is a receptor for the HIV-1 envelope glycoprotein gp120 and is essential for the dissemination of HIV-1. DC-SIGN is expressed by DCs, both monocyte-derived DCs and DCs in several tissues, including mucosa and lymph nodes. To identify a DC-SIGN(+) DC in blood that may be involved in HIV-1 infection through blood, we have analyzed the expression of DC-SIGN in human blood cells. Here we describe the characterization of a subset of DCs in human blood, isolated from T-/NK-/B-cell-depleted peripheral blood mononuclear cells (PBMCs) on the basis of expression of DC-SIGN. This subset coexpresses CD14, CD16, and CD33 and is thus of myeloid origin. In contrast to CD14(+) monocytes, DC-SIGN(+) blood cells display a DC-like morphology and express markers of antigen-presenting cells, including CD1c, CD11b, CD11c, CD86, and high levels of major histocompatibility complex (MHC) class I and II molecules. This DC population differs from other described CD14(-) blood DC subsets. Functionally, DC-SIGN(+) blood DCs are able to stimulate proliferation of allogeneic T cells and can produce tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) upon activation with lipopolysaccharide (LPS). When they encounter HIV-1, low amounts of these blood DC-SIGN(+) DCs enhance infection of T lymphocytes in trans, whereas blood monocytes and CD14(-) blood DCs are not capable of transmitting HIV-1. Therefore DC-SIGN(+) blood DCs can be the first target for HIV-1 upon transmission via blood; they can capture minute amounts of HIV-1 through DC-SIGN and transfer HIV-1 to infect target T cells in trans.
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PMID:Subset of DC-SIGN(+) dendritic cells in human blood transmits HIV-1 to T lymphocytes. 1217

The ability of HIV-1 to use dendritic cells (DCs) for transport and to transfer virus to activated T cells in the lymph node may be crucial in early HIV-1 pathogenesis. We have characterized primary DCs for the receptors involved in viral envelope attachment and observed that C-type lectin receptor (CLR) binding was predominant in skin DCs, whereas binding to emigrating and tonsil DCs was CD4-dependent. No one CLR was solely responsible for envelope binding on all skin DC subsets. DC-SIGN (DC-specific ICAM-3-grabbing nonintegrin) was only expressed by CD14(+)CDla(lo) dermal DCs. The mannose receptor was expressed by CD1a(hi) and CD14(+)CDla(lo) dermal DCs, and langerin was expressed by Langerhans cells. The diversity of CLRs able to bind HIV-1 in skin DCs may reflect their ability to bind a range of microbial glycoproteins.
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PMID:Diversity of receptors binding HIV on dendritic cell subsets. 1235 61

Microglia are endogenous brain macrophages that show distinct phenotypes such as expression of myeloid antigens, ramified morphology, and presence within the neural parenchyma. They play significant roles in a number of human CNS diseases including AIDS dementia. Together with monocyte-derived (perivascular) macrophages, microglia represent a major target of HIV-1 infection. However, a recent report challenged this notion based on findings in SIV encephalitis. This study concluded that perivascular macrophages can be distinguished from parenchymal microglial cells by their expression of CD14 and CD45, and that macrophages, but not microglia, are productively infected in SIV and HIV encephalitis. To address whether parenchymal microglia are productively infected in HIV encephalitis, we analyzed expression of CD14, CD45 and HIV-1 p24 in human brain. Microglia were identified based on their characteristic ramified morphology and location in the neural parenchyma. We found that parenchymal microglia are CD14+ (activated), CD45+ (resting and activated), and constitute approximately two thirds of the p24+ cells in HIV encephalitis cases. These results demonstrate that microglia are major targets of infection by HIV-1, and delineate possible differences between HIVE and SIVE. Because productively infected tissue macrophages serve as the major viral reservoir, these findings have important implications for AIDS.
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PMID:Human brain parenchymal microglia express CD14 and CD45 and are productively infected by HIV-1 in HIV-1 encephalitis. 1274 76

We investigated the expression of membrane-bound CD14 (mCD14) on monocytes and soluble CD14 (sCD14) released into the culture supernatants of peripheral blood lymphocytes (PBMC) from human immunodeficiency virus (HIV)-infected individuals. Monocytes from HIV-positive individuals exhibited both enhanced mCD14 expression and sCD14 production in the PBMC culture supernatants compared to the levels of mCD14 and sCD14 in HIV-negative individuals. This enhanced mCD14 expression and sCD14 production in HIV-infected individuals may be due to the effects of cytokines, the bacterial product lipopolysaccharide (LPS), and/or the HIV regulatory antigens Tat and Nef. Interleukin-10 (IL-10), an immunoregulatory cytokine, as well as LPS enhanced mCD14 expression and the release of sCD14 in the culture supernatants. HIV-Nef, unlike Tat, enhanced mCD14 expression on monocytes but did not induce the release of sCD14 into the culture supernatants. Studies conducted to investigate the mechanism underlying HIV-Nef-induced mCD14 expression revealed that HIV-Nef upregulated mCD14 expression via a mechanism that does not involve endogenously produced IL-10. In contrast, LPS upregulated the expression of mCD14 and increased the release of sCD14 via a mechanism that involves, at least in part, endogenously produced IL-10. Furthermore, dexamethasone, an anti-inflammatory and immunosuppressive agent, inhibited HIV-Nef-induced CD14 expression in an IL-10-independent manner. In contrast, dexamethasone inhibited IL-10-dependent LPS-induced CD14 expression by interfering with IL-10-induced signals but not by blocking IL-10 production. These results suggest that HIV-Nef and IL-10 constitute biologically important modulators of CD14 expression which may influence immunobiological responses to bacterial infections in HIV disease.
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PMID:Nef protein of human immunodeficiency virus and lipopolysaccharide induce expression of CD14 on human monocytes through differential utilization of interleukin-10. 1241 52

The ligation of programmed death-ligand 1 (B7-H1) to T cells results in the preferential production of interleukin 10 (IL-10). We investigated if B7-H1 would be up-regulated in HIV infection, a disease characterized by increased IL-10 production, by measuring B7-H1, B7-1 (CD80), and B7-2 (CD86) expression and mRNA in 36 HIV-infected patients and in 22 healthy controls (HCs). Results showed that (1) B7-H1 expression and mRNA are augmented in cells of HIV patients; (2) increased IL-10 production in these patients is largely induced by B7-H1-expressing CD14(+) cells; (3) an inverse correlation is detected between B7-H1 expression and CD4 counts, whereas the up-regulation of B7-H1 is directly associated with HIV plasma viremia; (4) antiviral therapy results in the parallel down modulation of IL-10 production and B7-H1 expression/synthesis; and (5) B7-H1/CD80 and B7-H1/CD86 mRNA ratios are increased in peripheral blood mononuclear cells (PBMCs) of HIV patients compared with HCs. B7-H1 synthesis and expression are up-regulated in HIV infection, and the degree of dysregulation correlates with the severity of disease. Aberrant antigen presentation by antigen-presenting cells (APCs) that exhibit increased B7-H1 expression and IL-10 production in HIV infection could be responsible for T-lymphocyte unresponsiveness and loss of protective immunity. B7-H1 is a surrogate marker potentially involved in AIDS disease progression.
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PMID:B7-H1 is up-regulated in HIV infection and is a novel surrogate marker of disease progression. 1246 26

Effective suppression of HIV-1 replication requires inhibition of critical viral target molecules. Tat and Rev are indispensable regulatory factors for HIV-1 replication, whereas Env mediates virus entry by direct interaction with surface receptor CD4 and coreceptor CCR5 or CXCR4. Anti-HIV-1 tat-rev and env ribozymes and Rev aptamers were previously demonstrated to provide relatively long-term protection against HIV-1 infection in vitro. However, further improvements in these constructs for clinical application in a stem-cell-based gene therapy setting requires in vivo characterization. Toward this end, we introduced these constructs into CD34(+) hematopoietic progenitor cells by retrovirus-mediated gene transduction. Ribozyme- and aptamer-transduced CD34(+) cells differentiated normally into multiple lineages of erythroid and myeloid progenies in a colony-forming unit assay. Macrophages that differentiated from the transduced CD34(+) cells expressed anti-tat-rev and -env ribozymes and Rev aptamers and displayed their normal characteristic surface markers CD14, CD4, and CCR5. Using the SCID-hu mouse in vivo human thymopoiesis model, we demonstrated that ribozyme- and aptamer-transduced CD34(+) cells retained their normal capacity to reconstitute human fetal thymus and liver tissue (thy/liv) grafts. Reconstitution by ribozyme- and aptamer-transduced CD34(+) cells reached levels of up to 87% based on HLA surface marker staining. Differentiated thymocytes derived from reconstituted grafts expressed anti-tat-rev and -env ribozymes and Rev aptamers and showed significant resistance to HIV-1 infection upon challenge. Analysis of reconstituted thymocytes by hybridization revealed an average of 0.4 to 2 copies of vector sequences per cell. Southern analysis of proviral integration junctions in progeny thymocytes demonstrated that the human thy/liv grafts were reconstituted by a few primitive hematopoietic stem cells. These results highlight the utility of RNA-based anti-HIV-1 gene therapeutic approaches and their preclinical testing in a surrogate animal model harboring human tissue.
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PMID:RNA-based anti-HIV-1 gene therapeutic constructs in SCID-hu mouse model. 1249 73


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