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

The current knowledge of CD4 function is limited to its role as a necessary coreceptor in TCR-initiated signaling. We have investigated whether CD4 regulates additional T cell functions. Using human primary resting CD4+ T cells, we demonstrate that CD4 activation is sufficient to induce lymphocyte death. Immediately after CD4 cross-linking, CD4+ T cells are rendered susceptible to apoptosis mediated by TNF or FasL. This, together with the concomitant induction of FasL within the same population, results in significant CD4+ T cell death in vitro. The CD4-dependent induction of susceptibility to apoptosis that is mediated by TNF or FasL is protein synthesis independent but phosphorylation dependent. After CD4 activation, PKC regulates susceptibility to apoptosis mediated by FasL but not the induction of susceptibility to TNF-dependent apoptosis. Moreover, significant differences between CD3 and CD4 activation were observed with regards to the kinetics of induction of CD4+ T cell susceptibility to FasL- and TNF-mediated apoptosis. Altogether, these results provide a model with which to study the molecular mechanisms regulating lymphocyte survival after CD4 activation, and highlight the potential role of CD4 in controlling lymphocyte apoptosis under physiological conditions or in disease states such as HIV infection.
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PMID:CD4 regulates susceptibility to Fas ligand- and tumor necrosis factor-mediated apoptosis. 948 Sep 81

Antigen derived peptides bound on MHC class II molecules on presenting cells stimulate specific CD4 lymphocytes that are in a naive state if antigen is given for the first time, or in a memory state if antigen has been previously encountered. In order to compare clonal heterogeneity of the human CD4+ T helper repertoire in primary vs. recall responses, we have generated T cell lines in vitro by repeated stimulation of peripheral lymphocytes with primary or with recall antigens. Clonal heterogeneity was broad in the case of recall response to tetanus toxoid or PPD, with a high frequency of specific precursors (> 100 cells/10(6) lymphocytes). In contrast, T cell lines responsive to primary antigens (HIV gp120 or HIV p66) were oligoclonal as defined by TCR V beta gene usage and by spectratyping, and the precursor frequency was low (< 2 cells/10(6) lymphocytes). Primary T cell lines generated from blood samples drawn at different times from the same donor showed that clones with identical TCR CDR3 region coding sequences were expanded, suggesting that in these individuals a large progeny derived from one single precursor is present, even though a previous encounter with the antigen was not documented. Assuming an even in vivo distribution of such cells, the presence of one precursor every 10(6) CD4 lymphocytes (within the CD4 T repertoire that comprises roughly 10(11) CD4 T cells) indicates that approximately 10(5) identical T cells from the same clonal precursor account for the primary response against the model antigens we have studied.
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PMID:Repertoire breadth of human CD4+ T cells specific for HIV gp120 and p66 (primary antigens) or for PPD and tetanus toxoid (secondary antigens) 954 73

Cross-linking of cell surface CD4 molecules by anti-CD4 mAb or HIV-1 gp120/anti-gp120 Ab primes resting T lymphocytes for activation-induced cell death (AICD) triggered via the CD3/TCR complex. In striking contrast, we demonstrate here that preincubation of activated human CD4+ T cells with anti-CD4 mAb consistently inhibited AICD triggered via anti-CD3 mAb or Staphylococcus aureus enterotoxin A superantigen. Inhibition of AICD of CD4+ T cell clones was also observed with F(ab')2, but not with Fab, of anti-CD4 mAb. Moreover, soluble HIV-1 gp120, but not rIL-16, inhibited AICD stimulated by S. aureus enterotoxin A. In susceptible clones, CD4 ligation prevented the up-regulation of Fas ligand mRNA and cell surface expression in response to anti-CD3 mAb or superantigen stimulation. CD3/TCR-dependent protein tyrosine phosphorylation and cytokine production were also prevented by preceding CD4 ligation. The inhibition of AICD due to the prevention of Fas ligand upregulation reveals a novel immunoregulatory consequence of CD4 ligation that might play a role in HIV infection and in the therapeutic application of anti-CD4 mAb.
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PMID:Ligation of cell surface CD4 inhibits activation-induced death of human T lymphocytes at the level of Fas ligand expression. 954 19

Viral, bacterial, protozoal, and cancer-associated Ags elicit strong responses in human gammadelta T lymphocytes. The majority of these cells in the peripheral blood express the Vgamma9Vdelta2-encoded TCR and recognize nonpeptidic phosphoantigens without an apparent MHC restriction. We have shown that Vgamma9Vdelta2 T cells express the inhibitory CD94/NKG2 receptor for HLA class I molecules. The anti-CD94 mAb inhibits 1) the Vgamma9Vdelta2 T cell proliferation in response mycobacterial phosphoantigens and 2) the HIV-induced Vgamma9Vdelta2 T cell expansion. Vgamma9Vdelta2 T cells stimulated with nonpeptidic mycobacterial antigens produce IFN-gamma and TNF-alpha. Signaling through the CD94/NKG2 receptor interferes with the synthesis of these cytokines. The CD94/HLA class I interaction is also involved in the cytotoxic activity of Vgamma9Vdelta2 T cells. The Vgamma9Vdelta2 T cell regulation through the CD94 receptor may be important for the potentially dual function in innate immunity, i.e., 1) NK-like and 2) TCR ligand-induced cytolytic activities.
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PMID:CD94/NKG2 inhibitory receptor complex modulates both anti-viral and anti-tumoral responses of polyclonal phosphoantigen-reactive V gamma 9V delta 2 T lymphocytes. 955 Mar 99

Listeria monocytogenes is a facultative intracellular pathogen which, following uptake by macrophages, escapes from the phagosome and replicates in the cytoplasm. This property has been exploited using recombinant L. monocytogenes as a carrier for the intracytoplasmic expression of antigens when MHC class I-restricted cytotoxic T lymphocyte responses are required. Much less is known of the ability of these bacteria to trigger MHC class II-restricted responses. Here, we demonstrate that after ingestion of L. monocytogenes expressing a T helper epitope from the gp120 envelope glycoprotein of HIV, human adherent macrophages and dendritic cells can process and present the epitope to a specific CD4+ T cell line in the context of MHC class II molecules. No significant differences were observed when the attenuated strains were trapped in the phagolysosome or impaired in the capacity to spread intracellularly or from cell to cell. Similar results were obtained using carrier proteins that were either secreted, associated with the bacterial surface, or restricted to the bacterial cytoplasm. A dominant expression of the TCR Vbeta 22 gene subfamily was observed in specific T cell lines generated after stimulation with the recombinant strains or with soluble gp120. Our data show that in this in vitro system L. monocytogenes can efficiently deliver antigens to the MHC class II pathway, in addition to the well-established MHC class I pathway. The eukaryotic cell compartment in which the antigen is synthesized, and the mode of display seem to play a minor role in the overall efficiency of epitope processing and presentation.
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PMID:Attenuated Listeria monocytogenes carrier strains can deliver an HIV-1 gp120 T helper epitope to MHC class II-restricted human CD4+ T cells. 964 61

Intracellular expression of genes that inhibit key steps in the human immunodeficiency virus (HIV-1) replicative cycle could offer an alternative therapy for AIDS treatment. One of these approaches involves the inhibition of env protein maturation through the expression of CD4 molecules with added exogenous sequences that promote their retention in the endoplasmic reticulum (ER). We have tested this strategy using a CD4 chimera (CD4epsilon10) containing an ER retention sequence derived from the TCR CD3-epsilon chain. Transfection of CD4epsilon10 in the human T cell line Jurkat made it resistant to infection with two different HIV-1 isolates, which was evaluated by measuring p24 antigen production, induction of apoptosis, and syncytia formation. Furthermore, polymerase chain reaction (PCR) analysis of genomic DNA showed no traces of the proviral HIV-1 genome in CD4epsilon10-transfected cells, suggesting it was not maintained latently in these cells. To facilitate the delivery of the CD4epsilon10 chimera to primary cells from AIDS patients, a Moloney-based retroviral vector was constructed that expresses CD4epsilon10 under the transcriptional control of the HIV-1 long terminal repeat (LTR) promoter. Transduction of the MT-2 human T cell line with this vector rendered it resistant to infection with HIV-1 by a process that involved the inhibition of gp160 proteolytic processing. Finally, transduction of the CD4epsilon10 chimera into T lymphoblasts derived from asymptomatic HIV-infected individuals demonstrated a protective effect, resulting in both an increased cellular proliferation rate and an increased percentage of CD4+ cells. These results suggest that it is feasible to use retroviral transduction of CD4epsilon10 as a gene therapy approach for AIDS treatment.
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PMID:Retroviral vector-mediated expression in primary human T cells of an endoplasmic reticulum-retained CD4 chimera inhibits human immunodeficiency virus type-1 replication. 965 Jun 19

During the course of infection with HIV-1, striking alterations in the subset distribution of peripheral blood gammadelta T cells are observed. While TCR Vdelta2 expression dominates among peripheral blood gammadelta T cells in healthy adults, there is a clear preponderance of Vdelta1 cells in HIV-1-infected persons. In this study, we present the first flow cytometry (FCM) analysis of the complete TCR Vgamma gene repertoire in HIV-1-infected individuals using a panel of mAb against all expressed Vgamma genes. The quantitative analysis of TCR Vgamma transcripts after amplification of cDNA by inverse PCR suggested that Vgamma5 usage is increased in HIV-1+ donors. This was confirmed by FCM with a new anti-Vgamma5 mAb. In addition, all members of the TCR VgammaI gene family (i.e. Vgamma2, 3, 4, 5 and 8) were expressed on significantly higher percentages of gammadelta T cells in HIV+ as compared to HIV- donors, whereas VgammaII (Vgamma9) expression was drastically reduced. No preferential association of the expanded Vdelta1+ cells with a particular Vgamma gene was observed in HIV-1 + donors. These results indicate that the increase in Vgamma1+ cells during HIV-1 infection occurs independently of the Vgamma gene usage and support the hypothesis that a Vdelta1-selective ligand might be involved.
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PMID:Analysis of the TCR Vgamma repertoire in healthy donors and HIV-1-infected individuals. 972 92

Thymocyte infection with HIV-1 is associated with thymic involution and impaired thymopoiesis, particularly in pediatric patients. To define mechanisms of thymocyte infection, we examined human thymocytes for expression and function of CXCR4 and CCR5, the major cell entry coreceptors for T cell line-tropic (T-tropic) and macrophage-tropic (M-tropic) strains of HIV-1, respectively. CXCR4 was detected on the surface of all thymocytes. CXCR4 expression on mature, high level TCR thymocytes was similar to that on peripheral blood T cells, but was much lower than that on immature thymocytes, including CD34+ thymic progenitors. Consistent with this, stroma-derived factor-1 (SDF-1) induced calcium flux primarily in immature thymocytes, with CD34+ progenitors giving the strongest response. In addition, SDF-1 mRNA was detected in thymic-derived stromal cells, and SDF-1 induced chemotaxis of thymocytes, suggesting that CXCR4 may play a role in thymocyte migration. Infection of immature thymocytes by the T-tropic HIV-1 strain LAI was 10-fold more efficient than that in mature thymocytes, consistent with their relative CXCR4 surface expression. Anti-CXCR4 antiserum or SDF-1 blocked fusion of thymocytes with cells expressing the LAI envelope. In contrast to CXCR4, CCR5 was detected at low levels on thymocytes, and CCR5 agonists did not induce calcium flux or chemotaxis in thymocytes. However, CD4+ mature thymocytes were productively infected with the CCR5-tropic strain Ba-L, and this infection was specifically inhibited with the CCR5 agonist, macrophage inflammatory protein-1beta. Our data provide strong evidence that CXCR4 and CCR5 function as coreceptors for HIV-1 infection of human thymocytes.
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PMID:CXCR4 and CCR5 on human thymocytes: biological function and role in HIV-1 infection. 974 77

Vaccination can elicit CD8(+) cytotoxic T lymphocytes (CTL) that recognize peptides presented by class I MHC molecules. Relatively little is known, however, about the genetic factors that shape the repertoire of T cell clonotypes responding to any given epitope. We report here that H-2(b) mice immunized with a plasmid DNA vaccine or vaccinia virus encoding for HIV-1SF2p55gag elicit CD8(+) CTL against the H-2Db-restricted immunodominant epitope (pgagb). This response involved three different T cell populations based on their recognition of alloantigens: one that cross-reacted with the alloantigen H-2Ld, one that cross-reacted with H-2Kd, and one that did not cross-react with either H-2(d) or H-2(k) molecules. Using the TAP-deficient cell line T2-Ld, we showed that pgagb-specific CTL cross-react with H-2Ld and a yet unidentified self-peptide. In mice expressing H-2(b) and H-2(d) allotypes, we investigated whether tolerance to H-2(d) influenced the HIVp55gag-specific CTL repertoire as a consequence of thymic deletion of the cross-reactive CTL repertoire. In (H-2(dxb))F1 mice heterogygosity at the MHC-I level prevented maturation of some but not all TCR combinations specific for H-2Db+pgagb, illustrating the concept that self-tolerance can influence the repertoire of antiviral T cells.
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PMID:The T cell repertoire primed by antiviral vaccination is influenced by self-tolerance. 974 60

Binding of the HIV envelope glycoprotein gp120 to CD4 inhibits T cell activation. We have used a murine T cell clone transfected with either wild-type human CD4 or mutated forms of CD4 to characterize the pathways involved in this inhibitory effect of gp120. Ag-induced proliferation of T cell clones transfected with human CD4 was completely inhibited in the presence of gp120, even though stimulation of this clone is independent of a CD4/MHC class II interaction. In addition, our results demonstrate that the inhibition by gp120 is not due to the sequestration of lck from TCR and does not require activation of lck by gp120. This suggests that CD4 can regulate the initiation of T cell activation independently of its interaction with lck. Moreover, we demonstrate that the nonresponsiveness induced by gp120 can be reversed by soluble CD4 when added early after onset of stimulation and that gp120 exerts its inhibitory effect when cells are in the G0 > or = 1 phase of the cell cycle.
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PMID:lck-independent inhibition of T cell antigen response by the HIV gp120. 975 76


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