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

Although several peptides have been found to bind to both class I and class II molecules, the basis for this binding of the same peptide to two classes of MHC molecules has not been compared previously. We have analyzed one such peptide, P18 from the V3 loop of HIV-1 gp160, which we have previously shown to be recognized by CD8+ CTL with the class I molecule H-2Dd, and by CD4+ Th cells with the class II molecule I-Ad. With the use of truncated and substituted peptides, we found that the minimal core peptides are very similar, that the residues required for class I binding precisely fit the recently identified consensus motif for peptides binding to Dd (XGPX[R/K/H]XXX(X) [L/I/F]), and that at least three of the same residues are involved in binding to class II I-Ad. In addition, several of the same residues are involved in TCR interaction when the peptide is presented by class I and class II molecules. Modeling shows results to be consistent with the crystal structure of a peptide-class II MHC complex. Thus, the recognition of this versatile peptide by CD4+ Th cells with class II MHC molecules and by CD8+ cytotoxic T cells with class I MHC molecules is remarkably similar in both the core peptide used and the role of different residues in the ternary complex.
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PMID:Molecular analysis of the same HIV peptide functionally binding to both a class I and a class II MHC molecule. 753 Jul 49

Activated T-cells expressing MHC class II surface antigens are able to present antigen and thus function as peptide-presenting cells (T-APCs). In this study we investigated whether antigen presentation by T-cells induced programmed cell death. As a model we used tetanus p30 peptide (aa 947-967)-specific, noncytotoxic CD4+ T-cell clones (C11 and C31). For experimental purposes these T-cell clones were stimulated (a) with p30 peptide-pulsed and fixed EBV-transformed antigen-presenting cells (B-APCs), (b) with p30-pulsed and fixed activated T-cells as APCs (as T-APCs we used either the T-cell clones themselves or an autologous T-cell clone (CT3) with p30 unrelated specificity), or (c) with soluble p30 peptide. The efficiency of antigen presentation was monitored by measuring proliferation as [3H]thymidine uptake. Apoptosis was measured by quantifying fragmented, cytoplasm DNA with the fluorescent dye 4,6-diamidino-2-phenylindole or by visualizing fragmented DNA by gel electrophoresis. Stimulation with p30-pulsed and fixed B-APCs or T-APCs induced proliferation but no apoptosis of the responding T-cells. However, stimulation of cloned T-cells with soluble peptide induced up-regulation of the FAS surface molecules and apoptosis, which was dependent on the peptide doses. Because cloned T-cells express HLA class II molecules, they can theoretically exert both functions at once: antigen presentation and antigen response when they are stimulated with soluble peptide. Because death by apoptosis is only seen under such circumstances, we suggest that T-cells simultaneously presenting and responding to an antigen die of apoptosis and thus contribute to the down-regulation of the immune response. Such phenomena might occur in HIV infection when activated CD4+ T-cells take up gp120 via their CD4 molecules, present it on their HLA class II surface antigens, and are simultaneously stimulated via their TCR.
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PMID:Noncytotoxic human CD4+ T-cell clones presenting and simultaneously responding to an antigen die of apoptosis. 753 49

One mechanism of the immune suppression in HIV infection has been postulated as being caused by the interaction of HIV envelope glycoprotein gp120 with CD4 molecules. Thus, pretreatment of purified peripheral blood T cells or CD4+ T cell clones with gp120 (or an anti-CD4 mAb) results in inhibition of anti-CD3 mAb-induced proliferative responses. In this study, we have analyzed the role of the interacting pairs of costimulatory molecules, CD28-B71 (CD80) and CD40 ligand (CD40L)-CD40, to elucidate further the mechanism of HIV gp120-induced inhibitory effects on T cell functions. Interactions between CD28-B71 and CD40L-CD40 were found to be essential for the anti-CD3 mAb-induced T cell proliferation, as demonstrated by up-regulation of B71 and CD40L and the ability of anti-B71 and anti-CD40L mAbs to inhibit this response. Pretreatment of CD4+ T cells with gp120 before CD3 ligation with anti-CD3 mAb resulted in failure of up-regulation of CD40L on T cells and B71 on APC. Exogenous addition of anti-CD28 mAb overcame the inhibitory effect of gp120 on anti-CD3 mAb-induced T cell proliferation. We conclude that binding of gp120 to CD4 molecules on T cells may interrupt the sequential cascade of intercellular interaction involving 1) Ag/MHC class II-TCR/CD4, 2) CD40L-CD40, and 3) B71-CD28. These studies indicate that the CD4-gp120 interaction results in dysregulation of expression of costimulatory molecules, CD40L, and B71 expression on T cells and APC, respectively, thereby contributing to the T cell hyporesponsiveness in HIV infection.
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PMID:HIV gp120 inhibits T cell activation by interfering with expression of costimulatory molecules CD40 ligand and CD80 (B71). 754 27

In this study we analyzed the behavior of a CD3+ T cell subpopulation lacking CD5 antigen expression in PBMC from HIV-1-infected patients. CD3+CD5- lymphocytes were greatly increased in peripheral blood of HIV-1+ patients, accounting for 20.6 +/- 9.9% of the total CD3+ cells, compared to seronegative individuals (5.5 +/- 3.2%). In both seropositive patients and controls, CD3+CD5- cells belonged to the CD8+ compartment; they were nonactivated, TCR alpha/beta+, naive lymphocytes, and in seronegative individuals preferentially expressed NK cell-associated markers, such as CD11b, CD16, CD56, and CD57. The phenotypic profile of this subset was slightly different in seropositive patients; while TCR expression and CD45RA/RO profile were comparable, CD11b and CD16 expression was lower compared to control figures, while CD56 expression was not changed, and CD57 expression was enhanced. Functional analysis of enriched CD3+CD8+CD5- cells showed an impaired ability to proliferate in response to mitogenic and antigenic stimuli; despite their NK-like phenotype, CD3+CD8+CD5- cells did not exert any NK cytotoxic activity, and only a lectin-dependent cytotoxic potential could be evidenced in this population. These results describe a novel alteration in the lymphocytes phenotypic profile during HIV-1 infection, involving a "transitional" population, which shares some properties of the T and of the NK cell lineage.
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PMID:A CD3+CD8+ T cell population lacking CD5 antigen expression is expanded in peripheral blood of human immunodeficiency virus-infected patients. 758 35

Chimeric receptors in which a signaling component of the TCR complex such as zeta is fused directly to the ligand binding domain of a heterologous receptor or Ab have been shown to redirect the specific effector activity of T lymphocytes. We previously described the ability of two classes of such chimeric zeta-receptors bearing extracellular domains derived from either the HIV receptor CD4 (CD4 zeta) or an HIV-specific single chain Ab to redirect primary human CD8+ T cells to kill HIV-infected T cells. In this report we demonstrate that human NK cells can be genetically modified to express high levels of CD4 zeta using retroviral transduction. The CD4 zeta chimeric receptor is biochemically active, as cross-linking of CD4 zeta on NK cells results in tyrosine phosphorylation of CD4 zeta and multiple cellular proteins. More importantly, the CD4 zeta chimeric receptor is functionally active and can direct NK cells to specifically and efficiently lyse either NK-resistant tumor cells expressing the relevant ligand, gp120, or CD4+ T cells infected with HIV. These results show that human NK cells can be readily activated via zeta-based chimeric receptors to target both tumor and virally infected cells, and suggest a novel approach to the treatment of disease.
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PMID:Chimeric zeta-receptors direct human natural killer (NK) effector function to permit killing of NK-resistant tumor cells and HIV-infected T lymphocytes. 760 31

Lymphoid enhancer-binding factor 1 (LEF-1) is a regulatory high mobility group (HMG) protein that activates the T cell receptor alpha (TCR alpha) enhancer in a context-restricted manner in T cells. In this paper we demonstrate that the distal region of the human immunodeficiency virus-1 (HIV-1) enhancer, which contains DNA-binding sites for LEF-1 and Ets-1, also provides a functional context for activation by LEF-1. First, we show that mutations in the LEF-1-binding site inhibit the activity of multimerized copies of the HIV-1 enhancer in Jurkat T cells, and that LEF-1/GAL4 can activate a GAL4-substituted HIV-1 enhancer 80- to 100-fold in vivo. Second, recombinant LEF-1 is shown to activate HIV-1 transcription on chromatin-assembled DNA in vitro. By using a nucleosome-assembly system derived from Drosophila embryos, we find that the packaging of DNA into chromatin in vitro strongly represses HIV-1 transcription and that repression can be counteracted efficiently by preincubation of the DNA with LEF-1 (or LEF-1 and Ets-1) supplemented with fractions containing the promoter-binding protein, Sp1. Addition of TFE-3, which binds to an E-box motif upstream of the LEF-1 and Ets-1 sites, further augments transcription in this system. Individually or collectively, none of the three enhancer-binding proteins (LEF-1, Ets-1, and TFE-3) could activate transcription in the absence of Sp1. A truncation mutant of LEF-1 (HMG-88), which contains the HMG box but lacks the trans-activation domain, did not activate transcription from nucleosomal DNA, indicating that bending of DNA by the HMG domain is not sufficient to activate transcription in vitro. We conclude that transcription activation by LEF-1 in vitro is a chromatin-dependent process that requires a functional trans-activation domain in addition to the HMG domain.
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PMID:Activation of the HIV-1 enhancer by the LEF-1 HMG protein on nucleosome-assembled DNA in vitro. 765 62

The T cell response to HIV-1 gp160 is among the most thoroughly studied immune responses to HIV-1 products. In our previous work, the MHC class I molecule Dd as well as H-2u, p, and q, were found to present P18 and HP53, two determinants of HIV-1 gp160, to CD8+ CTL in mice. We have studied the TCR V beta chain expression in CTL lines, either cross-reactive for these two peptides or specific for P18 alone, in these four different MHC haplotypes. The usage of V beta in T cells showing cross-reaction between these two peptides was remarkably conserved (primarily V beta 8 family, with some use of V beta 14) despite the extensive TCR V beta diversity of the non-cross-reactive CTL, which did not use V beta 8 or 14. This correlation of V beta usage with fine specificity was consistent in H-2d, u, and p (p < 0.01), but not in H-2q. The correlation of V beta use with peptide fine specificity independent of MHC restriction was unexpected. The strong predominance of V beta 8 family TCR was all the more surprising in view of the finding that mice bearing a genomic deletion of V beta 8 can still produce T cells with the cross-reactive phenotype, implying that other V beta chains can produce this specificity. We therefore asked whether the complexes of P18 with H-2d, p, and u are recognized as identical, and observed the surprising result that H-2d, p, and u cells mutually cross-present the peptides P18 and HP53 to allogeneic CTL lines and individual clones of each of the other haplotypes, whereas none of these cross-present to H-2q CTL, nor do H-2q targets present to CTL of the other haplotypes. This degeneracy of MHC restriction is novel for class I molecules. Moreover, the observed restriction in V beta usage occurs only in the unique set of CTL that exhibit both peptide-cross-reactive fine specificity and MHC allogeneic cross-presentation. The observation that a strain of mice in which the V beta 8 family is genomically deleted can still make CTL of this phenotype using another V beta demonstrates the plasticity of the class I MHC-restricted repertoire when the dominating receptor is not available.
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PMID:Preferential V beta usage by cytotoxic T cells cross-reactive between two epitopes of HIV-1 gp160 and degenerate in class I MHC restriction. 768 97

Complexes of five peptides (from HIV-1, influenza A virus, HTLV-1, and hepatitis B virus proteins) bound to the human class I MHC molecule HLA-A2 have been studied by X-ray crystallography. While the peptide termini and their second and C-terminal anchor side chains are bound similarly in all five cases, the main chain and side chain conformations of each peptide are strikingly different in the center of the binding site, and these differences are accessible to direct TCR recognition. Each of the central peptide residues is seen to point up for some bound peptides, but down or sideways for others. Thus, although fixed at its ends, the structure of an MHC-bound peptide appears to be a highly complex function of its entire sequence, potentially sensitive to even small sequence differences. In contrast, MHC structural variation is relatively limited. These results offer a structural framework for understanding the role of nonanchor peptide side chains in both peptide-MHC binding affinity and TCR recognition.
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PMID:The antigenic identity of peptide-MHC complexes: a comparison of the conformations of five viral peptides presented by HLA-A2. 769 6

Studies by several groups have suggested that HIV infection in vivo results in a V beta-specific alteration of the TCR repertoire and that this might play a role in the pathogenesis of AIDS. However, there is very little agreement as to which V beta segments are affected. In order to circumvent the confounding factors present in vivo we have examined the abilities of both a crude protein extract of HIV and purified gp160 to alter the V beta repertoire of normal T cells in vitro. We find that both a crude extract of HIV as well as gp160 specifically activate T cells expressing a common set of V beta segments (V beta 3, 12, 14, 15, and sometimes V beta 17 and 20) in individuals of disparate HLA type. This set of V beta segments is remarkably similar to those recognized by staphlococcal enterotoxin B and supports the hypothesis that bacterial superantigens produced by opportunistically acquired micro-organisms could have an exacerbating effect in AIDS.
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PMID:V beta-specific activation of T cells by the HIV glycoprotein gp 160. 772 68

Autoimmunity during HIV-1 infection may contribute to the immunopathogenesis of AIDS. Titers of autoantibodies to HLA molecules and other surface markers of CD4+ T cells appear to increase with the progression of disease and may correlate with lymphopenia. Other autoantibodies are directed at a number of regulatory molecules of the immune system. Genesis of autoreactivity may be related to structural homologies of HIV-1 env-products to such functional molecules involved in the control of self-tolerance. The most impressive similarities include the HLA-DR4 and DR2, the variable regions of TCR alpha-, beta-, and gamma-chain, the Fas protein, and several functional domains of IgG and IgA. Thus, HIV-1 infection may induce dysregulation leading to autoimmune response, through a number of molecular mimicry mechanisms. Pathogenicity of antibodies to T cells could also include the activation of membrane-to-nucleus signal transducers resulting in increased apoptosis. The evolution of autoimmune mechanisms during HIV-1 infection cannot exclude, however, progression to immunoproliferative malignancy, since aspects of oligoclonal immune response to HIV-1 components may occur in several autoimmune diseases which in some instances evolve to lymphoma.
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PMID:Autoreactivity in HIV-1 infection: the role of molecular mimicry. 776 37


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