UMLS:C0019693 - FACTA Search

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Query: UMLS:C0019693 (HIV)
170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HIV-1 Tat has been shown to have an inhibitory effect on the Ag-specific responsiveness of human peripheral T cells. We have previously demonstrated that this retroviral protein binds to and partially inhibits the enzymatic activity of dipeptidyl aminopeptidase type IV (DP IV), also known as CD26, which is expressed on a variety of mammalian tissue, including T lymphocytes. A number of studies have implicated a role for DP IV in the activation of T lymphocytes. By utilizing HIV-1 Tat, as well as ProboroPro, a potent and specific boronic acid analog inhibitor of DP IV, we show here that blocking DP IV partially inactivates Ag and anti-CD3-mediated T cell proliferation. Neither mitogen nor anti-CD2 mediated proliferation of T lymphocytes, however, is impaired by blocking DP IV. The target molecule for the inhibition induced by both compounds was confirmed by the finding that soluble DP IV neutralized the reduced Ag responsiveness. The Ag-specific inhibition could be overcome by the addition of exogenous IL-2, suggesting that blocking or inactivation of DP IV results in a state of anergy, probably by interfering with the delivery or amplification of a signal necessary for IL-2 production. This is further substantiated by the finding that costimulation of human PBMC via the CD28 molecule, which initiates a non-TCR-dependent signaling pathway, overcomes the reduced Ag responsiveness induced by Tat and ProboroPro. The fact that ProboroPro has no impact on stimulation of T cells with PMA and ionomycin implies that blocking DP IV is influencing events before the activation of protein kinase C and Ca2+ flux. These results suggest that DP IV is necessary for amplification of signals generated by the engagement of the TCR-CD3 complex by nominal Ag.
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PMID:Mechanism of HIV-1 Tat induced inhibition of antigen-specific T cell responsiveness. 809 14

Viral superantigens (SAg) were shown in mice to induce anergy and deletion of T cells bearing specific T cell receptor V beta subsets, these perturbations being mainly restricted to CD4+ T cells. In accordance with this model, a putative HIV-associated SAg could contribute to the pathogenesis of HIV-1 infection and AIDS. To reveal the presence of this putative molecule, three study protocols were designed that relied on the fact that similarity of the expressed V beta repertoire of a given pair of individuals is proportional to the relative likeness of their MHC background: (1) by using a quantitative PCR technique that allows simultaneous typing of 24 V beta families, the V beta repertoires of HIV-discordant monozygotic twins were compared; (2) the V beta repertoire found in lymph nodes of HIV-infected subjects was contrasted to that found in peripheral blood of the same individuals; (3) the V beta repertoire of a cohort of HIV-infected mothers was compared with that of their HIV-infected and uninfected children. Results from these approaches revealed that significant perturbations of the TCR V beta repertoire were taking place in HIV-infected subjects, and that these alterations were restricted to T cells expressing specific V beta s. These results are consistent with the presence of an HIV-associated SAg in HIV-1 infection.
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PMID:The T cell receptor V beta repertoire in HIV-1 infection and disease. 810 62

Immediately after infection of the targeted cell by HIV-1, proviral gene expression is limited to the three regulatory proteins, Tat, Rev, and Nef, with the nef transcript representing nearly 80% of total expression. Additionally, simian immunodeficiency virus Nef has been shown to be essential for high in vivo titer and the development of immunodeficiency. Recent findings demonstrate that the negative effects of Nef expression, as first defined in transformed T cell lines, are not present when Nef is expressed in primary human T cells or in T cells from transgenic mice, in which one sees moderate positive enhancements of HIV replication and the T cell activation process, respectively. We find that Nef expression in an Ag-specific murine T cell hybridoma results in both the down-modulation of CD4, as seen in primary cells and human T cell lines, and a positive enhancement of the TCR response to stimuli. Examination of a CD4- cell demonstrated that the positive enhancement is independent of CD4 expression or modulation. CD4 down-modulation is shown to be caused by a post-Golgi, acid-dependent process, which dramatically decreases the lifespan of the CD4 molecule. The TCR, Thy Ag, and CD45 remained unchanged in their surface expression. These findings suggest that Nef alters the normal routing and residencies of the CD4 molecule and that the positive effect of Nef on T cell activation is independent of this modulation.
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PMID:HIV-1 Nef activity in murine T cells. CD4 modulation and positive enhancement. 817 29

A cross-sectional PCR analysis of the TCR V beta repertoires in HIV-1 seronegative controls and HIV-1 infected individuals with either clinically or immunologically defined AIDS [1] was performed to examine the proposed superantigen model for HIV-1 pathogenesis. In contrast to previous reports, we find neither uniform specific losses nor uniform clonal expansions of particular TCR V beta gene families in subjects with AIDS. Instead our study, which was designed specifically to qualitatively determine the presence or absence of TCR V beta families in both subject populations, indicates an overall diminution in the expression of TCR V beta gene families in HIV-1 infected individuals with AIDS compared with controls. This is commensurate with the decrease in CD4 T cells in the AIDS population. Our data are therefore not directly suggestive of a common superantigen model of HIV-1 induced T cell clonal depletion or anergy, but instead emphasize a broad decrease in signals throughout the TCR V beta repertoire in AIDS versus control groups. This random depletion in the TCR V beta repertoire is most likely caused by aspects of HIV-1 pathogenesis other than virus-encoded superantigens.
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PMID:Random depletion of T cells that bear specific T cell receptor V beta sequences in AIDS patients. 822 26

The ability of activated T lymphocytes to extravasate and reach inflammatory and malignant foci in the tissues is a basic function of cellular immunity. Recent evidence strongly suggests that the urokinase receptor (uPAR) holds a central position in the development of human two-chain urokinase-mediated pericellular proteolysis and matrix degradation, an important element in cell migration. In this report we establish uPAR as a pan T cell activation Ag. As determined by FACS analysis, CD3+ lymphocytes from healthy donors exhibited no significant uPAR expression. In contrast, patients (e.g., HIV-positive donors) showed distinct uPAR expression, confined to HLA-DR+ cells, in up to 80% of all T cells. In vitro activation by PMA caused a rapid up-regulation of membrane uPAR in all healthy donor T cells and was accompanied by enhanced receptor synthesis and elevated uPAR mRNA levels. A similar induction resulted from activation via the TCR/CD3 complex using mitogens (PHA, and Con A), anti-CD3 antibodies, and alloantigen. Receptor expression at single cell level was also modulated by a number of cytokines. IL-2, IL-4 and IL-7 increased uPAR presentation on 20 to 50% of the T cell population, and combined stimulation of bulk cultures demonstrated an additive effect of IL-2 and IL-7, whereas the response to each of the two was inhibited by IL-4. In addition, TGF-beta 1 substantially reduced the uPAR expression in T cell cultures responding to PHA, IL-2, and IL-7. Irrespective of the activating reagent, the T cells appeared to produce the same molecular uPAR species, but the affinity of uPAR expressed in PMA blasts was decreased, presumably because of a differential location at the cell surface. All activated cultures showed co-expression of uPAR and CD25. The finding that the urokinase receptor is an activation Ag may suggest that cell-associated plasminogen activation is involved in extravasation and migration of activated T cells.
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PMID:Urokinase receptor. An activation antigen in human T lymphocytes. 828 34

In this study the frequency of gamma delta+ cells and their subsets has been assessed in bronchoalveolar lavage (BAL) cell populations recovered from 51 patients at various clinical stages of HIV-1 infection. Thirteen out of the 51 HIV-1-infected patients showed an increase in the percentage of TCR delta 1+ BAL T cells (25.5%). BAL lymphocytes bearing pan-gamma delta antigens were also quantitatively increased in 10 patients (19.6%). A strict correlation was observed between the degree of CD8 alveolitis and the increase of gamma delta T cells. Phenotypic study of BAL gamma delta cells revealed that (a) V delta 2-related BB3+ cells accounted for the majority of lung gamma delta T cells; (b) these cells were CD45RO+ memory cells and expressed a series of adhesion molecules; and (c) 29% of BAL gamma delta T cells expressed CD8 surface molecules. We also compared the distribution of V delta 2 and V delta 1 subsets in paired samples of peripheral blood and BAL fluid. Patients who showed an increased number of BB3+ cells in the BAL fluid presented a reversal of the V delta 2 to V delta 1 cell ratio in the peripheral blood. By contrast, in the lung of normal subjects pulmonary BB3+ and A13+ cells were present in approximately the same proportions found in the peripheral blood. Taken together these data demonstrate that a redistribution of T cells expressing V delta 2 TCR takes place in the lung of a subset of patients with HIV-1 infection and CD8 alveolitis. In the pulmonary microenvironment these cells might play a role in the local immune response against HIV-1 and/or opportunistic infections.
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PMID:Gamma delta T cell receptor subsets in the lung of patients with HIV-1 infection. 828 89

Studies to assess the possibility that the HIV may encode a superantigen that plays a role in the depletion of functional CD4+ lymphocytes in the infected individual have yielded discrepant results. The problem in performing conclusive examinations of this issue may be attributed, at least in part, to the difficulty of prospectively studying individuals from before their infection until the time of profound CD4+ lymphocyte loss. To determine whether the AIDS virus deletes particular subpopulations of V beta-expressing lymphocytes, we have employed an animal model of AIDS, the simian immunodeficiency virus (SIV)-infected macaque monkey. Rhesus monkeys were experimentally infected with SIVmac and studied prospectively. A PCR-based quantitative method for assessing TCR repertoire was employed to analyze the expression of 24 V beta and 30 V alpha gene families in the monkeys. Although circulating PBL were increased in number by 3 wk after SIVmac infection, the expanded lymphocyte populations exhibited no significant perturbation in their TCR V beta repertoires. PBL obtained from monkeys before and 0.5 to 3 years after infection displayed no significant change in V beta and V alpha gene family expression. Finally, no deletion of V beta-expressing cell subpopulations could be demonstrated in purified CD4+ lymphocytes from infected monkeys. This was true even for monkeys whose blood contained less than 200 CD4+ lymphocytes/microliters. These results indicate that the TCR repertoire is conserved in SIVmac-infected rhesus monkeys and suggests that mechanisms other than superantigen-induced deletion must be responsible for CD4+ lymphocyte loss in these animals.
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PMID:Conserved T-cell receptor repertoire in simian immunodeficiency virus-infected rhesus monkeys. 839 99

In the past few years, there has been a virtual explosion of information on the viral and bacterial molecules now known as superantigens. Some structures have been defined and the mechanism by which they interact with MHC class II and the V beta region of the T cell receptor is being clarified. Data are accumulating regarding the importance of virally encoded superantigens in infectivity, viral replication, and the life cycle of the virus. In the case of MMTV, evidence also suggests that superantigens encoded by a provirus may be maintained by the host to protect against future exogenous MMTV infection. Experiments in animals have also begun to elucidate the dramatic and variable effects of superantigens on responding T cells and other immune processes. Finally, the role of superantigens in certain human diseases such as toxic shock syndrome, some autoimmune diseases like Kawasaki syndrome, and perhaps some immunodeficiency disease such as that secondary to HIV infection is being addressed and mechanisms are being defined. Still, numerous important questions remain. For example, it is not clear how superantigens with such different structures, for example, SEB, TSST-1, and MMTV vSAG, can interact with MHC and a similar region of the TCR in such basically similar ways. It remains to be determined whether there are human equivalents of the endogenous murine MMTV superantigens. The functional role of bacterial superantigens also remains to be explained. Serious infection and serious consequences from toxin-producing bacteria are relatively rare events, and it is questionable whether such events are involved in the selection pressure to maintain production of a functional superantigen. Hypotheses to explain these molecules, which can differ greatly in structure, include T cell stimulation-mediated suppression of host responses or enhancement of environments for bacterial growth and replication, but substantiating data for these ideas are mostly absent. It also seems likely that only the tip of the iceberg has been uncovered in terms of the role of superantigens in human disease. Unlike toxic shock syndrome, other associations, especially with viral superantigens, may be quite subtle and defined only after considerable effort. The definition of these molecules and mechanisms of disease may result in new therapeutic strategies. Finally, it is apparent that superantigens have dramatic effects on the immune system. One wonders whether these molecules or modifications of them can be used as specific modulators of the immune system to treat disease.
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PMID:Superantigens and their potential role in human disease. 839 79

Using a flow cytometric method, CD4+, CD8+, alpha beta TCR+ and TCR variable region gene product (TVRGP)-specific T cells were analysed in healthy heterosexual males (HHeM), HIV-seronegative homosexual males (SNHM), asymptomatic seropositive homosexual males (ASPH) and homosexual males with AIDS who were either well (AIDS-A), or unwell in hospital (AIDS-B). Total CD4+ and CD8+ T cell numbers were similar in HHeM and SNHM. CD4+ T cells were significantly reduced in ASPH relative to both HHeM and SNHM and in AIDS-A and AIDS-B relative to SNHM. TVRGP-specific T cells expressed as a percentage of TCR alpha beta + cells showed no significant difference in HHeM, SNHM and AIDS-B. The proportion of alpha beta + cells expressing the V beta 5.1, V beta 12 and V alpha 2 gene product (GP) was, however, significantly reduced in ASPH and AIDS-B relative to HHeM, SNHM and AIDS-A. Possible causes of TVRGP-specific T cell deletion are discussed.
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PMID:HIV induces deletion of T cell receptor variable gene product-specific T cells. 840 2

Studies by several groups have suggested that HIV infection in vivo results in a BV-specific alteration of the TCR repertoire and that this might play a role in the pathogenesis of AIDS. Our earlier studies demonstrated that both a crude extract of HIV451 as well as purified gp 160 from HIV451 could specifically activate, in vitro, T cells expressing a common set of TCRBV segments (TCRBV3, 12, 14, 15, and sometimes BV17 and 20) in individuals of disparate HLA type. Furthermore, purified gp120 from HIV451 was shown to have a similar ability to activate T cells, although with a slightly different TCRBV-specific pattern. In order to determine whether gp120 from other HIV strains could similarly activate T cells in a TCRBV-specific pattern, PBMC from HIV seronegative individuals of disparate HLA type were stimulated with gp120 from three strains of HIV (451, IIIB, and MN). The authors found that gp120 from all three strains activate T cells bearing TCRBV2 and BV3 in nearly every individual. T cells expressing other BV segments are also activated, but this is more variable and appears to be unique to each individual. Furthermore, gp120(451) and gp120 from HIVIIIB and HIVMN differ in their ability to activate T cells expressing these other TCRBV segments. These observations suggest that variation in the structure of gp120 and in the genetic and/or environmental background of the individual play an important role in determining which TCRBV segments are 'triggered' by gp120. Furthermore, these observations may have important implications for the rate of disease progression in HIV-infected individuals.
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PMID:Differential patterns of T-cell receptor BV-specific activation of T cells by gp120 from different HIV strains. 855 83

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