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1.
Involvement of a leukocyte adhesion receptor (LFA-1) in HIV-induced syncytium formation 总被引：46，自引：0，他引：46
Cell fusion (syncytium formation) is a major cytopathic effect of infection by human immunodeficiency virus (HIV) and may also represent an important mechanism of CD4+ T-cell depletion in individuals infected with HIV. Syncytium formation requires the interaction of CD4 on the surface of uninfected cells with HIV envelope glycoprotein gp120 expressed on HIV-infected cells. However, several observations suggest that molecules other than CD4 play a role in HIV-induced cell fusion. The leukocyte adhesion receptor LFA-1 is involved in a broad range of leukocyte interactions mediated by diverse receptor-ligand systems including CD4-class II major histocompatibility complex (MHC) molecules. Possible mimicry of class II MHC molecules by gp120 in its interaction with CD4 prompted an examination of the role of LFA-1 in HIV-induced cell fusion. A monoclonal antibody against LFA-1 completely inhibited HIV-induced syncytium formation. The antibody did not block binding of gp120 to CD4. This demonstrates that a molecule other than CD4 is also involved in cell fusion mediated by HIV. 相似文献
2.
Human CD4 binds immunoglobulins 总被引：5，自引：0，他引：5
P Lenert D Kroon H Spiegelberg E S Golub M Zanetti 《Science (New York, N.Y.)》1990,248(4963):1639-1643
T cell glycoprotein CD4 binds to class II major histocompatibility molecules and to the human immunodeficiency virus (HIV) envelope protein gp120. Recombinant CD4 (rCD4) bound to polyclonal immunoglobulin (Ig) and 39 of 50 (78%) human myeloma proteins. This binding depended on the Fab and not the Fc portion of Ig and was independent of the light chain. Soluble rCD4, HIV gp120, and sulfated dextrans inhibited the CD4-Ig interaction. With the use of a panel of synthetic peptides, the region critical for binding to Ig was localized to amino acids 21 to 38 of the first extracellular domain of CD4. CD4-bound antibody (Ab) complexed with antigen approximately 100 times better than Ab alone. This activity may contribute to the Ab-mediated enhancement of cellular HIV interaction that appears to depend on a trimolecular complex of HIV, antibodies to gp120, and CD4. 相似文献
3.
HIV-infected cells are killed by rCD4-ricin A chain 总被引：21，自引：0，他引：21
M A Till V Ghetie T Gregory E J Patzer J P Porter J W Uhr D J Capon E S Vitetta 《Science (New York, N.Y.)》1988,242(4882):1166-1168
The gp120 envelope glycoprotein of the human immunodeficiency virus (HIV), which is expressed on the surface of many HIV-infected cells, binds to the cell surface molecule CD4. Soluble derivatives of recombinant CD4 (rCD4) that bind gp120 with high affinity are attractive vehicles for targeting a cytotoxic reagent to HIV-infected cells. Soluble rCD4 was conjugated to the active subunit of the toxin ricin. This conjugate killed HIV-infected H9 cells but was 1/1000 as toxic to uninfected H9 cells (which do not express gp120) and was not toxic to Daudi cells (which express major histocompatibility class II antigens, the putative natural ligand for cell surface CD4). Specific killing of infected cells can be blocked by rgp120, rCD4, or a monoclonal antibody to the gp120 binding site on CD4. 相似文献
4.
Prevention of HIV-1 infection and preservation of CD4 function by the binding of CPFs to gp120 总被引：4，自引：0，他引：4
R W Finberg D C Diamond D B Mitchell Y Rosenstein G Soman T C Norman S L Schreiber S J Burakoff 《Science (New York, N.Y.)》1990,249(4966):287-291
Infection by human immunodeficiency virus type-1 (HIV-1) is initiated when its envelope protein, gp120, binds to its receptor, the cell surface glycoprotein CD4. Small molecules, termed N-carbomethoxycarbonyl-prolyl-phenylalanyl benzyl esters (CPFs), blocked this binding. CPFs interacted with gp120 and did not interfere with the binding of CD4 to class II major histocompatibility complex molecules. One CPF isomer, CPF(DD), preserved CD4-dependent T cell function while inhibiting HIV-1 infection of H9 tumor cells and human T cells. Although the production of viral proteins in infected T cells is unaltered by CPF(DD), this compound prevents the spread of infection in an in vitro model system. 相似文献
5.
Synergism between HIV gp120 and gp120-specific antibody in blocking human T cell activation 总被引：26，自引：0，他引：26
The human immunodeficiency virus (HIV) binds to CD4-positive cells through interaction of its envelope glycoprotein (gp120) with the CD4 molecule. CD4 is a prominent immunoregulatory molecule, and chronic exposure to antibody against CD4 (anti-CD4) has been shown to cause immunodeficiency in mice. T cell-dependent in vitro immune responses can also be inhibited by anti-CD4. Experimental findings reported here indicate that CD4-bound gp120 attracts gp120-specific antibodies derived from the blood of HIV-seropositive individuals to form a trimolecular complex with itself and CD4. Thus targeted to CD4, the gp120-specific antibody functions as an antibody to CD4; it cross-links and modulates the CD4 molecules and suppresses the activation of T cells as measured by mobilization of intracellular calcium (Ca2i+). The synergism between gp120 and anti-gp120 in blocking T cell activation occurs at low concentrations of both components. Neither gp120 nor anti-gp120 inhibits T cell activation by itself in the concentrations tested. 相似文献
6.
Self-nonself discrimination by T cells 总被引：28，自引：0，他引：28
The alpha beta T cell receptor (TCR) recognizes antigens that are presented by major histocompatibility complex (MHC)-encoded cell surface molecules by binding to both the antigen and the MHC molecules. Discrimination of self from nonself antigens and MHC molecules is achieved by negative and positive selection of T cells in the thymus: potentially harmful T cells with receptors that bind to self antigens plus self MHC molecules are deleted before they can mount immune responses. In contrast, the maturation of useful T cells with receptors that bind foreign antigens plus self MHC molecules requires the binding of their receptor to MHC molecules on thymic epithelium in the absence of foreign antigen. The binding of the TCR to either class I or class II MHC molecules directs differentiation of the selected cells into either CD4-8+ (killer) or CD4+8- (helper) T cells, respectively. 相似文献
7.
Second conserved domain of gp120 is important for HIV infectivity and antibody neutralization 总被引：43，自引：0，他引：43
Rabbit antisera were raised against three overlapping synthetic peptides with sequence homology to the second conserved domain of the external envelope glycoprotein (gp120) of the human immunodeficiency virus (HIV). All of the antisera immunoprecipitated the envelope glycoprotein. In particular, an antiserum directed against amino acids 254 to 274 of env was efficient in neutralizing three different isolates of HIV in vitro, without affecting the binding of the virus to CD4-positive cells. Therefore, this conserved region of gp120 appears to be critical in a postbinding event during virus penetration and may represent a target for antibody neutralization of HIV. These findings may be applicable in the design of a vaccine for the acquired immunodeficiency syndrome. 相似文献
8.
Inhibition of entry of HIV-1 in neural cell lines by antibodies against galactosyl ceramide. 总被引：54，自引：0，他引：54
J M Harouse S Bhat S L Spitalnik M Laughlin K Stefano D H Silberberg F Gonzalez-Scarano 《Science (New York, N.Y.)》1991,253(5017):320-323
Although the CD4 molecule is the principal cellular receptor for the human immunodeficiency virus (HIV), several CD4-negative cell lines are susceptible to infection with one or more HIV strains. These findings indicate that there are alternate modes of viral entry, perhaps involving one or more receptor molecules. Antibodies against galactosyl ceramide (galactocerebroside, or GalC) inhibited viral internalization and infection in two CD4-negative cell lines derived from the nervous system: U373-MG and SK-N-MC. Furthermore, recombinant HIV surface glycoprotein gp120 bound to GalC but not to other glycolipids. These results suggest a role for GalC or a highly related molecule in HIV entry into neural cells. 相似文献
9.
Induction of CD4+ human cytolytic T cells specific for HIV-infected cells by a gp160 subunit vaccine 总被引：25，自引：0，他引：25
R J Orentas J E Hildreth E Obah M Polydefkis G E Smith M L Clements R F Siliciano 《Science (New York, N.Y.)》1990,248(4960):1234-1237
Cytolytic T lymphocyte (CTL) responses were evaluated in humans immunized with recombinant human immunodeficiency virus type 1 (HIV) envelope glycoprotein gp160. Some vaccinees had gp160-specific CTLs that were shown by cloning to be CD4+. Although induced by exogenous antigen, most gp160-specific CTL clones also recognized gp160 synthesized endogenously in target cells. These clones lysed autologous CD4+ T lymphoblasts infected with HIV. Of particular interest were certain vaccine-induced clones that lysed HIV-infected cells, recognized gp160 from diverse HIV isolates, and did not participate in "innocent bystander" killing of noninfected CD4+ T cells that had bound gp120. 相似文献
10.
Huang CC Tang M Zhang MY Majeed S Montabana E Stanfield RL Dimitrov DS Korber B Sodroski J Wilson IA Wyatt R Kwong PD 《Science (New York, N.Y.)》2005,310(5750):1025-1028
The third variable region (V3) of the HIV-1 gp120 envelope glycoprotein is immunodominant and contains features essential for coreceptor binding. We determined the structure of V3 in the context of an HIV-1 gp120 core complexed to the CD4 receptor and to the X5 antibody at 3.5 angstrom resolution. Binding of gp120 to cell-surface CD4 would position V3 so that its coreceptor-binding tip protrudes 30 angstroms from the core toward the target cell membrane. The extended nature and antibody accessibility of V3 explain its immunodominance. Together, the results provide a structural rationale for the role of V3 in HIV entry and neutralization. 相似文献
11.
Dissociation of gp120 from HIV-1 virions induced by soluble CD4 总被引：108，自引：0，他引：108
The CD4 antigen is the high affinity cellular receptor for the human immunodeficiency virus type-1 (HIV-1). Binding of recombinant soluble CD4 (sCD4) or the purified V1 domain of sCD4 to the surface glycoprotein gp120 on virions resulted in rapid dissociation of gp120 from its complex with the transmembrane glycoprotein gp41. This may represent the initial stage in virus-cell and cell-cell fusion. Shedding of gp120 from virions induced by sCD4 may also contribute to the mechanism by which these soluble receptor molecules neutralize HIV-1. 相似文献
12.
Tomasec P Braud VM Rickards C Powell MB McSharry BP Gadola S Cerundolo V Borysiewicz LK McMichael AJ Wilkinson GW 《Science (New York, N.Y.)》2000,287(5455):1031
The nonclassical major histocompatibility complex (MHC) class I molecule HLA-E inhibits natural killer (NK) cell-mediated lysis by interacting with CD94/NKG2A receptors. Surface expression of HLA-E depends on binding of conserved peptides derived from MHC class I molecules. The same peptide is present in the leader sequence of the human cytomegalovirus (HCMV) glycoprotein UL40 (gpUL40). It is shown that, independently of the transporter associated with antigen processing, gpUL40 can up-regulate expression of HLA-E, which protects targets from NK cell lysis. While classical MHC class I molecules are down-regulated, HLA-E is up-regulated by HCMV. Induction of HLA-E surface expression by gpUL40 may represent an escape route for HCMV. 相似文献
13.
Depletion of CD4+ T cells in major histocompatibility complex class II-deficient mice 总被引：32，自引：0，他引：32
M J Grusby R S Johnson V E Papaioannou L H Glimcher 《Science (New York, N.Y.)》1991,253(5026):1417-1420
The maturation of T cells in the thymus is dependent on the expression of major histocompatibility complex (MHC) molecules. By disruption of the MHC class II Ab beta gene in embryonic stem cells, mice were generated that lack cell surface expression of class II molecules. These MHC class II-deficient mice were depleted of mature CD4+ T cells and were deficient in cell-mediated immune responses. These results provide genetic evidence that class II molecules are required for the maturation and function of mature CD4+ T cells. 相似文献
14.
D H Smith R A Byrn S A Marsters T Gregory J E Groopman D J Capon 《Science (New York, N.Y.)》1987,238(4834):1704-1707
The initial event in the infection of human T lymphocytes, macrophages, and other cells by human immunodeficiency virus (HIV-1) is the attachment of the HIV-1 envelope glycoprotein gp120 to its cellular receptor, CD4. As a step toward designing antagonists of this binding event, soluble, secreted forms of CD4 were produced by transfection of mammalian cells with vectors encoding versions of CD4 lacking its transmembrane and cytoplasmic domains. The soluble CD4 so produced binds gp120 with an affinity and specificity comparable to intact CD4 and is capable of neutralizing the infectivity of HIV-1. These studies reveal that the high-affinity CD4-gp120 interaction does not require other cell or viral components and may establish a novel basis for therapeutic intervention in the acquired immune deficiency syndrome (AIDS). 相似文献
15.
Huang CC Lam SN Acharya P Tang M Xiang SH Hussan SS Stanfield RL Robinson J Sodroski J Wilson IA Wyatt R Bewley CA Kwong PD 《Science (New York, N.Y.)》2007,317(5846):1930-1934
The CCR5 co-receptor binds to the HIV-1 gp120 envelope glycoprotein and facilitates HIV-1 entry into cells. Its N terminus is tyrosine-sulfated, as are many antibodies that react with the co-receptor binding site on gp120. We applied nuclear magnetic resonance and crystallographic techniques to analyze the structure of the CCR5 N terminus and that of the tyrosine-sulfated antibody 412d in complex with gp120 and CD4. The conformations of tyrosine-sulfated regions of CCR5 (alpha-helix) and 412d (extended loop) are surprisingly different. Nonetheless, a critical sulfotyrosine on CCR5 and on 412d induces similar structural rearrangements in gp120. These results now provide a framework for understanding HIV-1 interactions with the CCR5 N terminus during viral entry and define a conserved site on gp120, whose recognition of sulfotyrosine engenders posttranslational mimicry by the immune system. 相似文献
16.
Identification of the fusion peptide of primate immunodeficiency viruses 总被引：48，自引：0，他引：48
M L Bosch P L Earl K Fargnoli S Picciafuoco F Giombini F Wong-Staal G Franchini 《Science (New York, N.Y.)》1989,244(4905):694-697
Membrane fusion induced by the envelope glycoproteins of human and simian immunodeficiency viruses (HIV and SIVmac) is a necessary step for the infection of CD4 cells and for the formation of syncytia after infection. Identification of the region in these molecules that mediates the fusion events is important for understanding and possibly interfering with HIV/SIVmac infection and pathogenesis. Amino acid substitutions were made in the 15 NH2-terminal residues of the SIVmac gp32 transmembrane glycoprotein, and the mutants were expressed in recombinant vaccinia viruses, which were then used to infect CD4-expressing T cell lines. Mutations that increased the overall hydrophobicity of the gp32 NH2-terminus increased the ability of the viral envelope to induce syncytia formation, whereas introduction of polar or charged amino acids in the same region abolished the fusogenic function of the viral envelope. Hydrophobicity in the NH2-terminal region of gp32 may therefore be an important correlate of viral virulence in vivo and could perhaps be exploited to generate a more effective animal model for the study of acquired immunodeficiency syndrome. 相似文献
17.
Lang P Stolpa JC Freiberg BA Crawford F Kappler J Kupfer A Cambier JC 《Science (New York, N.Y.)》2001,291(5508):1537-1540
Previous findings suggest that during cognate T cell-B cell interactions, major histocompatability complex (MHC) class II molecules transduce signals, leading to Src-family kinase activation, Ca2+ mobilization, and proliferation. Here, we show that antigen stimulation of resting B cells induces MHC class II molecules to associate with Immunoglobulin (Ig)-alpha/Ig-beta (CD79a/CD79b) heterodimers, which function as signal transducers upon MHC class II aggregation by the T cell receptor (TCR). The B cell receptor (BCR) and MHC class II/Ig-alpha/Ig-beta are distinct complexes, yet class II-associated Ig-alpha/beta appears to be derived from BCR. Hence, Ig-alpha/beta are used in a sequential fashion for transduction of antigen and cognate T cell help signals. 相似文献
18.
Diskin R Scheid JF Marcovecchio PM West AP Klein F Gao H Gnanapragasam PN Abadir A Seaman MS Nussenzweig MC Bjorkman PJ 《Science (New York, N.Y.)》2011,334(6060):1289-1293
Antibodies against the CD4 binding site (CD4bs) on the HIV-1 spike protein gp120 can show exceptional potency and breadth. We determined structures of NIH45-46, a more potent clonal variant of VRC01, alone and bound to gp120. Comparisons with VRC01-gp120 revealed that a four-residue insertion in heavy chain complementarity-determining region 3 (CDRH3) contributed to increased interaction between NIH45-46 and the gp120 inner domain, which correlated with enhanced neutralization. We used structure-based design to create NIH45-46(G54W), a single substitution in CDRH2 that increases contact with the gp120 bridging sheet and improves breadth and potency, critical properties for potential clinical use, by an order of magnitude. Together with the NIH45-46-gp120 structure, these results indicate that gp120 inner domain and bridging sheet residues should be included in immunogens to elicit CD4bs antibodies. 相似文献
19.
Paludan C Schmid D Landthaler M Vockerodt M Kube D Tuschl T Münz C 《Science (New York, N.Y.)》2005,307(5709):593-596
CD4+ T cells classically recognize antigens that are endocytosed and processed in lysosomes for presentation on major histocompatibility complex (MHC) class II molecules. Here, endogenous Epstein-Barr virus nuclear antigen 1 (EBNA1) was found to gain access to this pathway by autophagy. On inhibition of lysosomal acidification, EBNA1, the dominant CD4+ T cell antigen of latent Epstein-Barr virus infection, slowly accumulated in cytosolic autophagosomes. In addition, inhibition of autophagy decreased recognition by EBNA1-specific CD4+ T cell clones. Thus, lysosomal processing after autophagy may contribute to MHC class II-restricted surveillance of long-lived endogenous antigens including nuclear proteins relevant to disease. 相似文献
20.
马传染性贫血病毒(EIAV)gp45基因编码跨膜蛋白TM,该蛋白在介导病毒与靶细胞之间的融膜过程中起关键作用。gpl20蛋白是人类免疫缺陷病毒(HIV)的外膜糖蛋白,是病毒的主要抗原。通过大肠杆菌原核表达系统和果蝇细胞真核表达系统分别表达gp45及gp120,并对其表达效果进行对比,结果表明: 在大肠杆菌表达系统中,gp45可成功表达,而gp120却不能表达。在真核表达系统中,gp120成功表达,而gp45却未能表达。通过对这两种系统表达情况效果的比较,发现gp45在原核系统中表达有利,而gp120在真核系统中表达有优势,表明这些基因的表达具有特异性,本研究指导我们根据特定的基因选用适当的表达系统,以便纯化所需的目的蛋白,同时也为深入研究HIV的包膜蛋白的生物学结构特性及推动相关疫苗的研究奠定基础。 相似文献