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)

Several human immunodeficiency virus type 2 (HIV-2) strains have been shown to infect some CD4-negative cell lines (P. R. Clapham, A. McKnight, and R. A. Weiss, J. Virol. 66:3531-3537, 1992). Using molecular clones of HIV-2 with a CD4-independent tropism, we have identified critical amino acid residues in the envelope protein which are required for CD4-independent infection. Mutations located immediately upstream of a proposed coiled coil domain in the transmembrane protein (A526T or I528M) and flanking the base of the V4 loop (L378F and K403R) are crucial for the CD4-independent phenotype. Of several mutations conferring a positive charge in V1, V2, and V3, only the change in V3 (Q310K) helped to enhance the CD4-independent phenotype but could not mediate it on its own. These mutations reduce the amount of soluble CD4 required to trigger CD4-independent cell-cell fusion, suggesting that they lower the activation threshold for the fusion process. After binding to cell surface-anchored CD4, a CD4-independent recombinant envelope protein showed an increased binding of anti-envelope protein antibodies, suggesting either an enhanced binding to cell surfaces or more extensive conformational changes in CD4-independent compared to CD4-dependent envelope proteins. The reduced activation threshold of CD4-independent envelope proteins may thus enable them to utilize a membrane molecule for entry which is not as efficient as CD4 in triggering the conformational changes required for the membrane fusion process. CD4-independent HIV-2 variants may be conceptually similar to influenza virus variants capable of fusing at a higher than normal pH (R. S. Daniels, J. C. Downie, J. A. Hay, M. Knossow, J. J. Skehel, M. L. Wang, and D. C. Wiley, Cell 40:431-439, 1985).
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PMID:The CD4-independent tropism of human immunodeficiency virus type 2 involves several regions of the envelope protein and correlates with a reduced activation threshold for envelope-mediated fusion. 899 71

To characterize the mechanisms of complement activation by human immunodeficiency virus type 1 (HIV-1)-infected cells, Cl-4 cells stably expressing the envelope glycoproteins of HIV-1 and the parent African green monkey cell line CV-1 were tested for C1q binding and complement activation. While the parent cell line CV-1 only showed a weak spontaneous activation of the alternative pathway, Cl-4 cells additionally triggered the classical pathway of complement activation independent of anti-HIV antibodies by direct C1q binding. Earlier studies had shown different complement activating potential of cells infected with various HIV isolates. Recombinant soluble CD4-induced shedding of gp120 from the surface of HIV-1-infected cells converted a weak activator isolate (MVP-899) into a strong complement activator. The increase in complement activation was paralleled by the concomitant unmasking of a previously hidden gp41 epitope comprising the major complement-activating domain of gp41 (aa. 601-613). Our results strongly suggest that the transmembrane protein gp41 induces the activation of complement on the surface of infected cells as has been described previously for purified HIV-1 virions. Furthermore, we present evidence that the different potential of HIV isolates to activate the complement system on the cell surface is caused by different degrees of spontaneous gp120 shedding by various HIV isolates.
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PMID:Complement activation by HIV-1-infected cells: the role of transmembrane glycoprotein gp41. 905 18

HIV-1 Nef protein shares a significant homology with the immunosuppressive and highly conserved retroviral transmembrane protein p15E. In the present study, extracellular Nef protein is shown to induce interleukin (IL)-10 mRNA expression in human peripheral blood mononuclear cells as well as in cells of H9 T and U937 promonocytic human cell lines. Release of IL-10 protein into supernatants of peripheral blood mononuclear cells stimulated with Nef is dose-dependent. Expression of cytokines IL-2, IL-4, IL-5, IL-12 p40, IL-13, and interferon gamma is not affected by Nef stimulation. IL-10 protein production induced by Nef is inhibited by the calcium/calmodulin phosphodiesterase inhibitor W-7 but not by the protein kinase A inhibitor H-89 nor the protein kinase C inhibitors staurosporine and calphostin C. The calcium chelating agent EGTA also inhibits the IL-10 production induced by Nef, and this inhibition is reversed by the addition of calcium along with Nef. These findings indicate that extracellular Nef may contribute to the immunopathogenesis of HIV infection by inducing IL-10.
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PMID:Interleukin 10 is induced by recombinant HIV-1 Nef protein involving the calcium/calmodulin-dependent phosphodiesterase signal transduction pathway. 909 66

Five peptides derived from human immuno deficiency virus (HIV-1) gp41 transmembrane protein have been synthesized: M9 (610-618), M12 (598-609), M15 (600-614), M21 (584-604) and M23 (587-609). These sequences partially overlap in the region vicinal to the immunodominant epitope CSGKLIC, between two cysteine residues 603-609 and three of them (M12, M15 and M23) include this complete heptapeptide. M23, the longer peptide, includes an hydrophilic chain in addition to the heptapeptide loop. The purpose of this work was to determine the influence of contiguous chains to the heptapeptide loop on antibody recognition in fluid and solid phases, and dissociation constants (KD) of each sequence with human anti-HIV-1 antibodies. Two peptides, M13 and M23, overlapped on this loop, were found to be more reactive. Antigen-antibody dissociation constants were determined for both peptides by competition enzyme-linked immunosorbent assay, using each peptide alternatively as the solid phase-immobilized antigen. In addition to the influence of solid-phase antigen on calculated dissociation constants (a phenomenon described by Seligman, 1994), the inhibitory effect of M15 in liquid phase on antibody binding to solid phase M23 was higher than exerted by M23 in solution over antibody binding to M15 on solid phase. On the basis of peptide sequence and predicted antigenicity, this behavior appeared to be contradictory. It is assured that the possible origin of this phenomenon is due to unfavorable conformation of the longer peptide. Even though synthetic peptides mimic mainly sequential epitopes, conformational preferences in fluid or solid phase play an important role in epitope functionality. In particular, addition of residues to known immunodominant sequences may not always amplify antibody recognition if conformation provokes steric hindrance in the native epitope.
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PMID:Epitope contiguous chains and antibody recognition in HIV-1 synthetic peptide antigens. 917 49

Hetero-oligomerization between human immunodeficiency virus type 2 (HIV-2) envelope glycoprotein (Env) truncation mutants and epitope-tagged gp160 is dependent on the presence of gp41 transmembrane protein (TM) amino acids 552 to 589, a putative amphipathic alpha-helical sequence. HIV-2 Env truncation mutants containing this sequence were also able to form cross-type hetero-oligomers with HIV-1 Env. HIV-2/HIV-1 hetero-oligomerization was, however, more sensitive to disruption by mutagenesis or increased temperature. The conservation of the Env oligomerization function of the HIV-1 and HIV-2 alpha-helical sequences suggests that retroviral TM alpha-helical motifs may have a universal role in oligomerization.
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PMID:Human immunodeficiency virus type 1 and 2 envelope glycoproteins oligomerize through conserved sequences. 918 54

A 100-kDa astrocyte antigen previously shown to cross-react with a monoclonal antibody (MAb) generated against amino acids (aa) 598 to 609 of the transmembrane protein gp41 of human immunodeficiency virus type 1 [HIV-1] has now been molecularly characterized and found to be an alpha-actinin (alpha-actinin) related protein. Western blot analyses of human astrocytoma cells fractionated by differential centrifugation and detergent phase separation showed that the antigen was membrane associated. The astrocyte protein was purified to apparent homogeneity by immunoaffinity chromatography. Amino acid analysis of three peptide fragments obtained by cleavage of the purified 100-kDa protein revealed sequence identities of 77, 83 and 100% to a non-muscle isoform of human alpha-actinin. In addition, the aa 598-609 sequence of gp41 recognized by MAb 781.4, and the aa 581-597 sequence recognized by another cross-reactive MAb 781.3, were 73% and 53% similar to regions of alpha-actinin. This molecular mimicry between gp41 and alpha-actinin was supported by antibody cross-reactivity in Western immunoblot and ELISA analyses. Both anti-gp41 and anti-alpha-actinin MAbs bind to the surface of the human astrocytoma cells as detected by a cell surface binding assay and immunofluorescence. Antibodies made against this immunodominant region of gp41 in the serum and CSF of HIV-infected individuals have access to astrocytes within the CNS. The identification of the astrocyte antigen as an alpha-actinin related protein will allow further work to determine how this immunological cross-reactivity could perturb astrocyte function and contribute to HIV neuropathology.
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PMID:Molecular mimicry between HIV-1 gp41 and an astrocyte isoform of alpha-actinin. 922 81

CD4-expressing T cells in lymphoid organs are infected by the primary strains of HIV and represent one of the main sources of virus replication. Gene therapy strategies are being developed that allow the transfer of exogenous genes into CD4(+) T lymphocytes whose expression might prevent viral infection or replication. Insights into the mechanisms that govern virus entry into the target cells can be exploited for this purpose. Major determinants of the tropism of infection are the CD4 molecules on the surface of the target cells and the viral envelope glycoproteins at the viral surface. The best characterized and most widely used gene transfer vectors are derived from Moloney murine leukemia virus (MuLV). To generate MuLV-based retroviral gene transfer vector particles with specificity of infection for CD4-expressing cells, we attempted to produce viral pseudotypes, consisting of MuLV capsid particles and the surface (SU) and transmembrane (TM) envelope glycoproteins gp120-SU and gp41-TM of HIV type 1 (HIV-1). Full-length HIV-1 envelope glycoproteins were expressed in the MuLV env-negative packaging cell line TELCeB6. Formation of infectious pseudotype particles was not observed. However, using a truncated variant of the transmembrane protein, lacking sequences of the carboxyl-terminal cytoplasmic domain, pseudotyped retroviruses were generated. Removal of the carboxyl-terminal domain of the transmembrane envelope protein of HIV-1 was therefore absolutely required for the generation of the viral pseudotypes. The virus was shown to infect CD4-expressing cell lines, and infection was prevented by antisera specific for gp120-SU. This retroviral vector should prove useful for the study of HIV infection events mediated by HIV-1 envelope glycoproteins, and for the targeting of CD4(+) cells during gene therapy of AIDS.
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PMID:Pseudotyping of murine leukemia virus with the envelope glycoproteins of HIV generates a retroviral vector with specificity of infection for CD4-expressing cells. 923 30

Noninfectious Pr55gag virus-like particles containing high quantities of oligomeric human immunodeficiency virus type 1 (HIV-1) envelope (Env) proteins represent potential candidate immunogens for a vaccine against HIV-1 infection. Thus, chimeric env genes were constructed encoding the HIV-1 exterior glycoprotein gp120 which was covalently linked at different C-terminal positions to a transmembrane domain (TM) from the Epstein-Barr virus (EBV) major Env glycoprotein gp220/ 350. All chimeric Env-TM polypeptides as well as the wild-type HIV Env proteins were equally produced and incorporated at the outer surface of insect cells using the baculovirus expression system. In the presence of coexpressed HIV Pr55gag polyproteins significantly decreased amounts of wild-type Env proteins were presented at the cell surface, whereas the membrane incorporation of the Env-TM chimeras was not affected. Biochemical and immunoelectron microscopical analysis of particles that were efficiently released from these cells displayed the incorporation of both wild-type Env and chimeric Env-TM proteins on the surface of VLPs. However, the quantities of particle-associated chimeric Env-TM proteins exceeded those of incorporated wild-type Env proteins by a factor of 5-10. Chemical cross-linking and subsequent polyacrylamide gel electrophoresis of VLP-entrapped Env proteins revealed that the chimeric Env-TM proteins form homodimers and a higher-order oligomer, similar to that observed for wild-type Env proteins. Thus, the results of this study clearly demonstrate that the replacement of the gp41 transmembrane protein of gp160 by a heterologous, EBV gp220/350-derived membrane anchor provides an effective strategy to incorporate high quantities of oligomeric HIV gp120 proteins on the surface of Pr55gag virus-like particles.
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PMID:Increased incorporation of chimeric human immunodeficiency virus type 1 gp120 proteins into Pr55gag virus-like particles by an Epstein-Barr virus gp220/350-derived transmembrane domain. 930 33

Very recently, we demonstrated that the replacement of the human immunodeficiency virus type-1 (HIV-1) gp41 transmembrane protein by an Epstein-Barr virus gp220/350-derived membrane anchor resulted in the incorporation of chimeric envelope (Env) oligomers into Pr55gag virus-like particles (VLPs), exceeding that of wild-type gp160 by a factor of 10. In this study, we examined the immunostimulatory properties of Pr55gag VLPs to both (i) chimeric HIV-1 gp120 external envelope proteins and (ii) full-length gp160 presented on the outer surface of the particles. Immunization studies carried out with VLPs presenting different derivatives of the chimeric and wild-type Env proteins elicited a consistent anti-Pr55gag as well as anti-Env antibody response in complete absence of additional adjuvants. In both cases, the immune sera exhibited an in vitro neutralizing activity against homologous HIV-1 infection in MT4 cells. Noteworthy, these VLPs were also capable of inducing a strong CD8+ cytotoxic T-cell (CTL) response in immunized BALB/c mice that was directed toward a known CTL epitope in the third variable domain V3 of the gp120 external glycoprotein. However, the induction of V3-loop-specific CTLs critically depended on the amounts of Env proteins that were presented by the Pr55gag VLPs. Moreover, the CD8+ CTL response was not significantly altered by adsorbing the VLPs to alum or by repeated booster immunizations. These results illustrate that Pr55gag VLPs provide a safe and effective means of enhancing neutralizing humoral responses to particle-entrapped gp120 proteins and are also capable of delivering these proteins to the MHC class I antigen processing and presentation pathway. Therefore, antigenically expanded Pr55gag VLPs represent an attractive approach in the design of vaccines for which specific stimulation of neutralizing antibodies and cytotoxic effector functions to complex glycoproteins is desired.
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PMID:Recombinant human immunodeficiency Pr55gag virus-like particles presenting chimeric envelope glycoproteins induce cytotoxic T-cells and neutralizing antibodies. 930 34

Adhesion molecules are known to contribute to infectivity of HIV-1. Here we tested whether the complement receptor type 3 (CR3, CD11b), an alpha(m)beta2 integrin, plays an accessory role in the infection process of HIV-1, because ICAM-1, a ligand of CR3, is present on the envelope of HIV-1. In addition, the viral transmembrane protein gp41 shares four regions of homology with the complement component C3, a further CR3 ligand. Infection of PBMCs with HIV-IIIB and primary isolates was partially inhibited by anti-CR3 antibodies. A peptide derived from the complement component C3, covering the CR3-binding site of C3 and sharing strong similarity to the immunosuppressive region of gp41, significantly reduced the HIV-1 titer in infection assays. Recombinant soluble gp41 (rsgp41) and the peptide covering the immunosuppressive domain of gp41 inhibited the rosetting of iC3b-coated sheep erythrocytes with U937 via complement receptors (CRs) with an efficiency comparable to monoclonal anti-CR antibodies. In addition, sub-populations of CD4 + and CD8 + T-cells isolated from HIV-infected individuals were found to upregulate CR3 as determined by FACS analysis and on the mRNA level. Since gp41 has been implicated in viral fusion, an interaction of its C3-homology region in gp41 or an interaction of ICAM on the surface of free virus with CRs might contribute to facilitate viral entry.
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PMID:Inhibition of HIV-1 infection in vitro by monoclonal antibodies to the complement receptor type 3 (CR3): an accessory role for CR3 during virus entry? 946 21

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