Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although steady progress has been made in transducing human T lymphocytes by Moloney murine leukemia virus (Mo-MuLV)-based vectors, few studies have been done to define ex vivo gene transfer protocols to transduce rhesus macaque primary T lymphocytes. Given the fact that simian immunodeficiency virus (SIV) infection in rhesus macaque is a well-characterized model for human immunodeficiency virus (HIV), it is of great interest to develop an efficient protocol to transduce rhesus macaque primary T cells. In this study, we have used MuLV-10A1-pseudotyped retrovirus expressing enhanced green fluorescent protein (EGFP) to evaluate a number of ex vivo gene transfer protocols in rhesus macaque primary T lymphocytes. Our objectives in designing these protocols were (1) to test whether higher efficiency gene transfer could be obtained by combining two previously defined protocols, centrifugation at 32 degrees C and the CH-296-coated plate; and (2) to study the effect of an ex vivo gene transfer protocol on the expression of lymphocyte homing receptors L-selectin and alpha 4 beta 7 and alpha 4 beta 1 integrins. From seven independent experiments we demonstrate by flow cytometry analyses of EGFP expression that whereas centrifugation at 32 degrees C or the fibronectin fragment CH-296-coated plate protocol alone yielded 10-14% transduction efficiency, combining these two protocols resulted in 28.1-51.2% transduction efficiency. EGFP in transduced cells was expressed highly throughout the 14 days of posttransduction expansion. Our results also demonstrate that whereas the transduction procedure per se did not significantly alter the expression of lymphocyte homing receptors, anti-CD3 and anti-CD28 antibody stimulation profoundly reduced the expression of L-selectin. The selective reduction of L-selectin may result in significant in vivo consequences if transduced cells are infused.
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PMID:High-efficiency gene transfer into rhesus macaque primary T lymphocytes by combining 32 degrees C centrifugation and CH-296-coated plates: effect of gene transfer protocol on T cell homing receptor expression. 1158 27

HIV infection causes an acquired immunodeficiency, principally because of depletion of CD4 lymphocytes. The mechanism by which the virus depletes these cells, however, is not clearly understood. Since the virus predominantly infects CD4 lymphocytes in vivo, some have assumed that HIV replication directly kills the infected cells or that the anti-HIV immune response destroys them. However, a large number of studies do not support this concept. Rather, the data strongly indicate that CD4 lymphocyte depletion is by an indirect mechanism. Several theories on various direct and indirect mechanisms are reviewed. The most plausible mechanism, which is backed by in vivo data, involves the consequences of HIV contact with resting CD4 lymphocytes, which cannot support virus replication. HIV binding to, and signaling through, CD4 and chemokine receptor molecules on resting CD4 lymphocytes and other cell types [which extensively occurs as the rare, productively infected cells (ie: infected cells producing virus) migrate among other cells through the lymphoid tissues back into the blood] induces upregulation of L-selectin and Fas. When these resting, HIV-signaled CD4 cells return to the blood, they home very rapidly back to peripheral lymph nodes and axial bone marrow, and their disappearance from the blood is likely due to their leaving the circulatory system. Approximately one-half of these cells that have been induced by HIV to home to lymph nodes are subsequently induced into apoptosis during the process of trans-endothelial migration when secondary signals are received through various homing receptors. These cells are not making HIV, which would explain the observation that CD4 cells not making HIV are the predominant cells dying in the lymph nodes of HIV+ subjects. These studies indicate that the principal mechanism of CD4 T-cell depletion by HIV is due to its use of CD4 as its primary receptor and the signaling induced through this receptor on nonpermissive (resting) T-lymphocytes. This unique mechanism of viral pathogenesis, if correct, leads to the possibility that HIV might not cause depletion of CD4 lymphocytes if it used some other receptor to infect CD4 lymphocytes.
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PMID:How does HIV cause depletion of CD4 lymphocytes? A mechanism involving virus signaling through its cellular receptors. 1189 30

Venezuelan equine encephalitis (VEE) virus-replicon particles (VRP) were used to generate feline immunodeficiency virus (FIV) Gag- and ENV-expressing vaccine vectors. Serum and mucosal FIV-specific antibody was detected in cats immunized subcutaneously, once monthly for 5 months, with FIV-expressing VRP. Expansion of the CD8+ L-selectin negative phenotype and transient CD8+ noncytolytic suppressor activity were seen in cats immunized with FIV-expressing or control VRP. Despite induction of FIV-specific immune responses and nonspecific suppressor responses, all cats became infected following vaginal challenge with high dose, pathogenic cell-associated FIV-NCSU(1) although relative early maintenance of CD4+ cells was seen in FIV-immunized cats.
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PMID:Evaluation of FIV protein-expressing VEE-replicon vaccine vectors in cats. 1245 Jul 1

The chemokine receptor, CXCR4, serves as the primary coreceptor for entry of T-cell tropic human immunodeficiency virus (HIV). Binding of either the CXC-chemokine, stromal-derived factor 1 alpha (SDF-1 alpha), or a CXCR4 antagonist, AMD3100, to CXCR4 inhibits infection of CD4(+) T cells by T-tropic HIV-1, although only SDF-1 alpha triggers T-cell signaling cascades. We have previously demonstrated that ligation of CD4 by T-cell tropic HIV-1 NL4-3 induces metalloproteinase-dependent L-selectin (CD62L) shedding on resting CD4(+) T cells. However, the role of CXCR4 in HIV-induced L-selectin shedding is unclear. Here, we show that L-selectin shedding induced by HIV-1 NL4-3 is completely reversed by AMD3100, but not SDF-1 alpha, although SDF-1 alpha alone does not induce L-selectin shedding. These results indicate that engagement of both CD4 and CXCR4 is required for HIV-induced shedding of L-selectin on primary resting CD4(+) T cells.
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PMID:CXCR4 engagement is required for HIV-1-induced L-selectin shedding. 1457 59

Patients with disseminated cryptococcosis typically have measurable levels of cryptococcal polysaccharide in serum samples but minimal leukocyte infiltration into infected tissues. In vitro data have shown that cryptococcal polysaccharide induces L-selectin (CD62L) shedding from leukocytes. To assess shedding in vivo, we compared leukocyte L-selectin levels in human immunodeficiency virus (HIV) type 1-negative and -positive subjects with and without circulating cryptococcal polysaccharide. Results showed that subjects with cryptococcal polysaccharide in serum samples have significantly lower percentages of neutrophils, monocytes, and CD3+ T cells with L-selectin on their surfaces than do healthy subjects, regardless of HIV status. There was significantly more soluble L-selectin in serum samples from subjects with cryptococcosis than in those from uninfected subjects. Reduced L-selectin levels on leukocytes in subjects with circulating cryptococcal polysaccharide and increased serum levels of soluble L-selectin indicates that surface L-selectin shedding is a mechanism that likely explains reduced leukocyte extravasation into infected tissues of patients with disseminated cryptococcosis.
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PMID:Levels of L-selectin (CD62L) on human leukocytes in disseminated cryptococcosis with and without associated HIV-1 infection. 1577 84

The Ras-guanyl nucleotide exchange factor RasGRP1 is an important link between TCR-mediated signaling and the activation of Ras and its downstream effectors. RasGRP1 is especially critical for the survival and differentiation of developing thymocytes whereas negative selection of thymocytes bearing an autoreactive TCR appears to be RasGRP1 independent. Despite apparently normal central tolerance, RasGRP1(-/-) mice spontaneously acquire an acutely activated and proliferating CD4 T cell population that exhibits characteristics of T cell exhaustion, including strong expression of programmed cell death-1. To elucidate the basis for RasGRP1(-/-) CD4 T cell immune activation, we initiated a series of adoptive transfer experiments. Remarkably, the copious amounts of cytokines and self-Ags present in hosts made lymphopenic through irradiation failed to induce the majority of RasGRP1(-/-) CD4 T cells to enter cell cycle. However, their infusion into either congenitally T cell- or T/B cell-deficient recipients resulted in robust proliferation and L-selectin down-regulation. These findings imply that the activation and proliferation of RasGRP1(-/-) CD4 T cells may be dependent on their residence in a chronically immunocompromised environment. Accordingly, bacterial and viral challenge experiments revealed that RasGRP1(-/-) mice possess a weakened immune system, exhibiting a T cell-autonomous defect in generating pathogen-specific T cells and delayed pathogen clearance. Collectively, our study suggests that chronic T cell immunodeficiency in RasGRP1(-/-) mice may be responsible for CD4 T cell activation, proliferation, and exhaustion.
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PMID:Chronic immunodeficiency in mice lacking RasGRP1 results in CD4 T cell immune activation and exhaustion. 1767 73

Previous studies have identified several host-derived cell-surface proteins incorporated within emerging human immunodeficiency virus type 1 (HIV-1) particles. Some of these molecules play a role in different steps of the virus life cycle and are often advantageous for the virus. We report here that the leukocyte L-selectin (also called CD62L) remains functional when inserted within the envelope of HIV-1. Indeed, we demonstrate that adsorption of virions to endothelial cells is enhanced upon acquisition of host-derived CD62L. The more important binding of CD62L-bearing HIV-1 particles resulted in a more efficient virus transmission to CD4(+) T lymphocytes. Capture and eventual transfer of such CD62L-bearing virions by the endothelium could play a role in the pathogenesis of HIV-1 infection.
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PMID:Virus-associated host CD62L increases attachment of human immunodeficiency virus type 1 to endothelial cells and enhances trans infection of CD4+ T lymphocytes. 1769 68

Glycoproteins secreted into plasma from T cells infected with human immunodeficiency virus (HIV) latent infection may provide insight into understanding the host response to HIV infection in vivo. Glycoproteomics, which evaluates the level of the glycoproteome, remains a novel approach to study this host response to HIV. In order to identify human glycoproteins secreted from T cells with latent HIV infection, the medium from cultured HIV replication-competent T cells was compared with the medium from cultured parental A3.01 cells via solid phase extraction of glycopeptides (SPEG) and high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). Using these methods, 59 human glycoproteins were identified as having significantly different abundance levels between the media from these two cell lines. The relevance of these 59 proteins to HIV infection in vivo was assessed in plasma from HIV+ and HIV- subjects. Comparison between T cell and plasma revealed that six glycoproteins (galectin-3-binding protein, L-selectin, neogenin, adenosine deaminase CECR1, ICOS ligand and phospholipid transfer protein) were significantly elevated in the HIV+ T cells and plasma studies. These findings suggest that the response of T cells harboring latent HIV infection contributed, in part, to the glycoprotein changes in HIV+ plasma. These proteins, once validated, could provide insight into host-HIV interaction.
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PMID:Glycoproteomic analysis identifies human glycoproteins secreted from HIV latently infected T cells and reveals their presence in HIV+ plasma. 2459 96


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