Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

HCN-1A is a human cerebral cortical neuronal cell line having properties consistent with cells of immature neuronal origin. This article details evidence for productive low-level infection of HCN-1A cells with human immunodeficiency virus type 1 (HIV-1). In vitro exposure to HCN-1A monolayers to a high titer of either LAV/HTLV-IIIB or HTLV-IIIMN resulted in HIV-1 p24 antigen production and a moderate increase in reverse transcriptase activity in cell-free supernatants. The cells in both LAV/HTLV-IIIB- and HTLV-IIIMN-infected cultures were passaged and proliferated as long as 5 weeks while continuing to express low levels of viral antigen. Virus-positive cells were detected by indirect immunofluorescence, using serum from an individual with acquired immune deficiency syndrome (AIDS) as well as with a gp120 monoclonal antibody. Confirmation of HCN-1A infection was provided by polymerase chain reaction analyses of both nuclear and cytoplasmic DNA and by de novo synthesis of viral proteins as shown by metabolic labeling and immunoprecipitation. Virus in cell-free supernatants from infected HCN-1A cultures was passaged to a permissive human T cell line (A3.01). HCN-1A cells had no detectable surface CD4 protein or CD4 message. However, the cells expressed the membrane glycolipids, galactocerebroside and sulfatide, possible receptors for gp120 on cells of neuronal origin. Undifferentiated HCN-1A cells provide an in vitro model for investigating potential interactions of HIV-1 with a homogeneous population of immature cortical neurons.
 ...
PMID:Human cortical neuronal cell line: a model for HIV-1 infection in an immature neuronal system. 831 71

Considerable effort is being made to design anti-viral drugs for the human immunodeficiency virus type 1 (HIV-1) infection process. Some of this work has focused on CD4 protein, the HIV-1 receptor on T helper lymphocytes. One drug that binds to CD4 protein and inhibits both viral infection and growth is DIDS (4,4'-diisothiocyanato-2,2'-stilbenedisulfonate). DIDS is best known for its ability to inhibit erythrocyte band 3 anion exchange. Although the antiviral potency of DIDS is evident in vitro (IC50 approximately 30 microM), intravenous administration of DIDS should not be effective owing to the large number of band 3 molecules present on the red blood cell membrane (approximately 10(6)/cell), and to the very small Kd for DIDS binding to band 3 (approximately 30 nM). Therefore, we sought to identify other anion transport inhibitors that would bind weakly to band 3, but tightly to CD4 protein, and that could be administered to humans without significant toxic side effects. On the basis of our previous work with band 3 (Salhany, J. M., Rauenbuehler, P. B., and Sloan, R. L. (1987) J. Biol. Chem. 262, 15965-15973), we elected to study the binding of pyridoxal 5'-phosphate (PLP) to soluble CD4 protein. We have discovered that PLP binds surprisingly tightly to soluble CD4 protein (Kd = 45 microM), with a stoichiometry of about 1 mol of PLP/mol of protein. Furthermore, PLP binding was found to be competitive with DIDS for its binding site on soluble CD4 protein. These results suggest that PLP may be an effective anti-viral agent for the HIV-1 infection process.
 ...
PMID:Pyridoxal 5'-phosphate binds specifically to soluble CD4 protein, the HIV-1 receptor. Implications for AIDS therapy. 846 94

A retroviral vector was constructed in which a gene encoding a mutated soluble CD4 protein that is retained in the endoplasmic reticulum (sCD4-KDEL) is expressed under control of human immunodeficiency virus type 1 (HIV-1) regulatory elements. HIV-1 infection of a human T-cell line transduced with this vector led to induction of sCD4-KDEL synthesis and a block in transport of the HIV envelope protein to the cell surface. There was a complete block to maturation of infectious HIV-1 in the transduced cells, no viral spread, and little or no syncytium formation. Infected cells gradually disappeared from the culture over a period of 2 months. This intracellular trap for HIV has potential application in gene therapy for AIDS.
 ...
PMID:Blockade of human immunodeficiency virus type 1 production in CD4+ T cells by an intracellular CD4 expressed under control of the viral long terminal repeat. 846 77

The gastrointestinal tract plays a major role in the pathogenesis and pathophysiology of infection by the type 1 human immunodeficiency virus (HIV-1). It is a potential route for viral entry and it is the site of a number of complications, including both opportunistic infections and a primary HIV-induced enteropathy. Correspondingly, both in vivo and in vitro studies have demonstrated HIV infection of gastrointestinal cells of lymphoid and epithelial origin. HT-29, a human colonic epithelial cell line that is infectable with many HIV-1 strains, does not express CD4 protein or mRNA. Recent studies showed that antibodies recognizing a neutral glycolipid related to galactosylceramide (GalCer) in HT-29 cells inhibited HIV-1 infection of this cell line, extending previous findings in neural cells. In the current studies, we further analyzed the neutral glycolipids of HT-29 cells and showed that they contained authentic GalCer and that recombinant gp120 bound to this glycolipid. Moreover, by analyzing GalCer expression in clones derived from HT-29 and Caco-2 (another human colonic cell line), we observed that the level of expression of this glycolipid was associated with the sensitivity to HIV-1 infection. Subclones of Caco-2 did not express GalCer and were not infectable with any of three HIV-1 strains. These results strengthen the possibility that GalCer is an alternative receptor in CD4- cell lines. Furthermore, since GalCer is a major glycolipid in epithelial cells of the small intestine and colon, these results provide a structural basis for the binding of HIV-1 by gastrointestinal epithelial cells and the entry of the virus into those cells.
 ...
PMID:Infection of colonic epithelial cell lines by type 1 human immunodeficiency virus is associated with cell surface expression of galactosylceramide, a potential alternative gp120 receptor. 846 78

A new model system is delineated that will enable study of CD4 cofactors and gp120 binding proteins other than CD4. We have previously described a nontransformed rat fibroblast cell line that can efficiently produce HIV-1 upon transfection with an HIV-1 infectious clone, in contrast to other nonhuman mammalian cell lines tested. In the present study we analyzed the susceptibility to HIV-1 infection of Rat2 cells expressing the human CD4 protein. We have used the mammalian expression vector pKS286, in which HIV-1 LTR drives the expression of the CD4 gene. We show that the Rat2 cell line, expressing the human CD4 (Rat2/CD4), is susceptible to fusion with and infection by HIV-1. The virus produced by the Rat2/CD4 cells was infectious. CD4 expression in the Rat2/CD4 was down-regulated over time, similarly to HIV-1 expression in HIV-1-transfected Rat2 cells. Transfection of the Rat2/CD4 cells with a tat expression vector reestablished the CD4 expression on the surface of those cells, as expected. We conclude that the expression of a gp120 binding protein on the Rat2 cells' surface suffices to render the Rat2 cells susceptible to HIV-1 infection.
 ...
PMID:CD4 confers susceptibility to human immunodeficiency virus type 1 infection in a rat fibroblast cell line. 889 Nov 10

Although the Nef proteins encoded by human immunodeficiency virus type 1 (HIV-1) and simian immuno-deficiency virus (SIV) are known to induce the efficient internalization and degradation of cell surface CD4, it remains unclear whether this process involves a direct interaction between Nef and CD4. Here, we report that CD4 downregulation by HIV-1 and SIV Nef requires distinct but overlapping target sites within the CD4 intracytoplasmic domain. In particular, mutation of a glutamic acid residue located at CD4 residue 405 or of arginine and methionine residues located, respectively, at residue 406 and 407 results in a mutant CD4 protein that is efficiently downregulated by HIV-1 Nef but refractory to downregulation by SIV Nef. However, both HIV-1 and SIV Nef require an isoleucine located at residue 410 and the dileucine motif found at CD4 residues 413 and 414. CD4 downregulation induced by the Nef protein encoded by HIV-2 is shown to require a CD4 target sequence that is similar to, but distinct from, that observed with SIV Nef. These data explain the previous finding that the murine CD4 protein, which has an alanine at residue 405, is refractory to downregulation by SIV, but not HIV-1, Nef (J. L. Foster, S.J. Anderson, A. L. B. Frazier, and J. V. Garcia, Virology 201:373-379, 1994). In addition, these observations provide strong genetic support for the hypothesis that the Nef-mediated downregulation of cell surface CD4 requires a direct Nef-CD4 interaction.
 ...
PMID:Human immunodeficiency virus types 1 and 2 and simian immunodeficiency virus Nef use distinct but overlapping target sites for downregulation of cell surface CD4. 926 98

Entry of the type 1 human immunodeficiency virus into most cells requires the presence of the CD4 protein in combination with one of several recently described co-receptors. CXCR-4 (fusin) was the first identified, and it serves as co-receptor for T-cell-line tropic (T-tropic) HIV-1 isolates. To determine the expression of CXCR-4 in the brain, a major target of HIV pathology, we used immunohistochemistry and reverse transcriptase polymerase chain reaction with CXCR-4-specific antibodies and probes. We found that CXCR-4 was expressed in several cell types in brain, but notably in neurons and microglia, a finding that was replicated in tissue culture. The study of the expression of CXCR-4 in the brain, which may be one of many chemokine receptors in the central nervous system, may provide further insight into the interactions between brain cells, pathogens, and the immune system, and help understand the pathogenesis of HIV dementia.
 ...
PMID:CXCR-4 (Fusin), a co-receptor for the type 1 human immunodeficiency virus (HIV-1), is expressed in the human brain in a variety of cell types, including microglia and neurons. 932 37

The human immunodeficiency virus type 1 (HIV-1) employs a number of complex strategies to interfere with the synthesis, stability, and subcellular localization of its specific cellular receptor CD4. To define better the mechanisms of inhibition of CD4 expression, we used a rabbit reticulocyte lysate in vitro system, in which cDNAs derived from HIV-1-infected cells were used to generate mRNA for the Tat, Vpu, and gp160 envelope proteins that were translated together with CD4-encoding mRNA. In the presence of microsomal membranes, we observed that cotranslation of Env mRNA resulted in a dose-dependent inhibition of CD4 translation. This effect was enhanced further when an mRNA-encoding Vpu in addition to Env mRNA was utilized. However, the activity of Vpu was mostly post-translational, since translation of Vpu alone, but not Env, was able to destabilize CD4 molecules presynthesized into microsomes. The Env-mediated inhibitory effect was specifically targeted at CD4 and did not affect the synthesis or stability of the CD8 molecule. Interestingly, mutated CD4 species, with a 20-fold lower affinity for HIV-1 Env than wild-type, were less sensitive to cotranslational inhibition. Our report identifies the envelope as the HIV-1 protein responsible for down-regulation of CD4 translation. We further propose a mechanism whereby direct interactions between gp160 and nascent CD4 molecules can cause interference with and premature termination of CD4 protein elongation.
 ...
PMID:Inhibition of CD4 translation mediated by human immunodeficiency virus type 1 envelope protein in a cell-free system. 936 Sep 74

An apparent species-specific relatedness of SIVagm suggests a coevolution with their natural hosts. However, the exact species or subspecies classification of African green monkeys, AGM, is uncertain because current classification schemes rely on phenotype markers, while more definitive genetic data are lacking. In this study, the CD4 protein involved in tissue type recognition was genetically cloned and sequenced from PBMC RNA from all AGM species, including Barbados green monkeys (BGM). Phylogenetic trees were constructed that also included genomic CD4 nucleotide sequences from patas, sooty mangabeys, rhesus and pig-tail macaques, chimpanzees, and humans. Chimpanzees and humans consistently clustered together. Monkeys within the Cercopithecus genus formed a separate cluster which included pata monkeys, supporting its grouping as a member of Cercopithecus. Surprisingly, sooty mangabeys were genetically more closely related to Asian macaques than to other African species, which might explain why macaques are more susceptible to infection by the SIVsm group than to infection by SIVagm or HIV-1 and why patas, on the other hand, are highly susceptible to SIVagm infection. Based on CD4 genetic data, tantalus, vervets, grivets, and sabaeus formed separate subgroups with BGM grouping closely with vervets. The branching order of the AGM species was related to that of their respective SIVagm env sequences. The study suggests a strong correlation between CD4 phylogeny and the susceptibility of the host species to infection by a specific lentivirus and supports the assumption of a coevolution of SIVagm and AGM. CD4 sequencing is suggested as a relevant method for genetic determination of primate species.
 ...
PMID:Relation between phylogeny of African green monkey CD4 genes and their respective simian immunodeficiency virus genes. 937 78

The crystal structure of CD4 suggested that the C/G38 and C/L44 replacements with the consequent cystine bridge formation are compatible with the native structure of that molecular moiety. As the NQGSF sequence, corresponding to the 39-43 fragment of human CD4 protein, was found to be involved in the HIV gp120 interaction, it has been synthesized in a cyclic form by adding two cysteine residues at the amino and carboxy termini. 1H-NMR studies show that the predominant solution conformation of cyclo-[CNQGSFC] is a type II beta-turn centred on the NQGS segment. Structural and dynamic properties of the peptide are also analysed in relation to the in vitro activity.
 ...
PMID:The design of a specific ligand of HIV gp120. 939 13


<< Previous 1 2 3 4 5 6 7 8 Next >>