Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Our current methods of contraception were largely developed in the 1950s and 1960s. Collectively these methods can limit population growth, although their acceptability at a personal level remains marginal. The number of abortions in the UK has risen progressively, from < 130,000 in 1980 to > 170,000 in 1990, and more people have sought sterilization. In global terms, population continues to increase on a scale unrecorded in human history. More than 800 million people, equal to the current population of North America, Europe and Japan, will be added to the world population of 5400 million by the year 2000, with 95% of the increase located in the economically and environmentally fragile regions of the South. Worldwide, in these 8 years, about 500 million abortions will be performed (> 40% by unsafe methods), about 80 million children under 1 year of age will die, and about 5 million women with be lost from pregnancy-related causes. Over 100 million people, most in Africa, Latin America, India and South-east Asia, will have become infected with human immunodeficiency virus. Religious, commercial and political pressures continue to constrain the development and distribution of contraceptive products, though some changes are in sight. Contraception is now being advanced in the broader context of neonatal and maternal health care. New scientific opportunities are also evident, with the potential to advance contraception in a quantal step. Third generation contraceptive steroids, anti-steroids, steroid-releasing vaginal rings, and injectable steroid preparations for men are all under clinical trial. Developments in the longer term, however, could hinge upon the greater specificity afforded by the manipulation of regulatory peptides. Agonists, antagonists and binding proteins for GnRH and the gonadotrophins are being investigated in an attempt to regulate the pituitary-gonadal axis more precisely. Inhibition of this axis may require the provision of low level steroid replacement, appropriately titrated to provide positive health care in the context of menstrual cyclicity, well-being, breast cancer and osteoporosis. Attempts are being made to identify and intercept the highly specific signals involved in fertilization and the maternal recognition of pregnancy, with the current clinical focus on the immunoneutralization of beta human chorionic gonadotrophin (beta hCG). More specific and more acceptable targets might include peptides involved in sperm-zona adhesion and sperm activation, sperm-oocyte fusion, and sperm-activated oocyte cleavage. The interception of these signals would prevent fertilization, implantation or both, and yet leave the hormonal profile of the menstrual cycle unchanged.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Human contraception: development of new scientific opportunities. 130 30

CD4, the cell-surface receptor for the human immunodeficiency virus (HIV), is a member of the immunoglobulin (Ig) gene superfamily. It contains 4 extracellular sequences homologous to Ig variable domains, the first of which (V1) is sufficient for binding to HIV. To develop CD4 as an anti-HIV therapeutic, we engineered a CD4 immunoadhesin (CD4-IgG)--a fusion protein containing the V1 and V2 domains of CD4 with the hinge and Fc regions of human Ig heavy chain. A chimeric protein of this type has several advantages compared to the soluble receptor, including a greatly extended in vivo half-life and greater avidity for HIV; moreover, like an antibody, it performs effector functions via its Fc domains, such as complement activation and antibody-dependent cell-mediated cytotoxicity. In vivo experiments show that CD4-IgG protects against HIV-I IIIB infection of chimpanzees when administered prior to viral challenge. In addition, CD4-IgG is transferred efficiently across the placenta from mother to fetus in rhesus monkeys. To evaluate its safety in humans, we conducted a phase-I clinical trial in adult patients with AIDS and AIDS-related complex. We found that, in a total of 16 patients, administration of CD4-IgG was well tolerated at doses up to 1000 micrograms/kg of body weight, with no important clinical or immunological toxicities noted. Given its unique properties, particularly the ability of CD4-IgG to cross the placenta, we plan to focus future clinical efforts on preventing infection of newborns via maternal-fetal transfer of HIV.
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PMID:CD4 immunoadhesins in anti-HIV therapy: new developments. 142 10

Enzymatically active retroviral proteinases are dimers of identical polypeptide chains with a fold similar to that of other aspartic proteinases. Each polypeptide chain, encoded on one of the viral polyproteins, is less than half the size of cellular aspartic proteinases and contains only one of the two active-site aspartate residues. A plasmid was constructed to generate a genetically linked dimer of the proteinase (PR) of human immunodeficiency virus (HIV) type 1, composed of two copies of the PR sequence linked by a structurally flexible hinge region. The expression product was stable and active against HIV polyprotein substrates. Mutational analysis revealed that the linked dimer, and not multimers thereof, contained the proteolytic activity. Expression of the linked dimer as a component of a HIV polyprotein by in vitro translation gave rapid autocatalytic processing, whereas the wild-type polyprotein was stable on prolonged incubation. Transfection of HIV subviral or proviral constructs, containing the linked dimer of HIV PR, gave premature processing of the viral polyproteins, thus preventing particle formation and infectivity. Premature processing also led to increased cell toxicity.
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PMID:Human immunodeficiency virus proteinase dimer as component of the viral polyprotein prevents particle assembly and viral infectivity. 201 42

Different chimeric antibody-like molecules consisting of the four human CD4 extracellular domains (amino acids 1-369) fused to different parts of human IgG1 and IgM heavy-chain constant regions have been created and expressed in mammalian cells. For both IgG1 and IgM fusion proteins, the best expression in COS cells was observed for molecules lacking the CH1 domain of the heavy-chain constant region. The chimeric molecules are potent inhibitors of human immunodeficiency virus (HIV) infection and HIV-mediated cytotoxicity. A CD4:IgG1 hinge fusion protein, which was analyzed in more detail, binds efficiently to HIV gp160 and human Fc receptors and shows complement-assisted inhibition of viral propagation in culture. Half-life studies after intravenous application of the latter human fusion protein into mice and monkeys showed significant prolongation of serum survival compared to soluble CD4. An IgG2b murine homolog of the human CD4:IgG1 hinge fusion protein was prepared and evaluated in mice, where it was found to be nontoxic and to have no detectable effect on the humoral response to soluble antigen.
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PMID:Expression and characterization of human CD4:immunoglobulin fusion proteins. 219 3

Monoclonal antibodies (MAb) directed against the immunoglobulin complementary determining region 3 (CDR3)-like region of the CD4 molecule inhibit human immunodeficiency virus type 1 (HIV-1) transcription. We report here data showing that the cytoplasmic tail of CD4 is required for such inhibition to be achieved. To this aim, we studied the effect of MAb 13B8-2 treatment on (i) HIV-1 production in A2.01 cells, which express different forms of the CD4 gene, (ii) Tat-induced HIV-1 promoter activation, and (iii) mitogen-activated protein kinase (MAPK) activation, which is induced in CD4-positive cells by HIV-1 cross-linking of CD4. Inhibition of HIV production by 13B8-2 MAb treatment was consistently observed in cells expressing wild-type CD4 and cells expressing a hybrid CD4-CD8 molecule (amino acids 1 to 177 of CD4 fused to the hinge, transmembrane, and cytoplasmic domains of CD8). However, no delay in HIV-1 production was observed in cells expressing a truncated CD4 which lacks the cytoplasmic domain (CD4.401). Chloramphenicol acetyltransferase assays demonstrated that Tat-dependent activation of the HIV-1 long terminal repeat promoter was inhibited by MAb 13B8-2 in A2.01/CD4 and A2.01/CD4-CD8 but not in A2.01/CD4.401 cells. Finally, we found that MAb 13B8-2 treatment inhibited the activation of MAPK induced in A2.01/CD4 and A2.01/CD4-CD8 following cross-linking of CD4 by HIV-1.
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PMID:The cytoplasmic tail of CD4 is required for inhibition of human immunodeficiency virus type 1 replication by antibodies that bind to the immunoglobulin CDR3-like region in domain 1 of CD4. 747 7

During replication of human immunodeficiency virus type 1 (HIV-1), proteolytic cleavage of Gag and Gag-Pol precursor proteins into different functional protein subunits is catalyzed by the viral proteinase, and this enzyme is the target of the antiviral proteinase inhibitor, Ro 31-8959. We investigated in vitro which HIV mutants with reduced sensitivity to Ro 31-8959 emerged during proteinase inhibition treatment; from three different HIV-1 strains, comparable progeny virus resistant to proteinase inhibitor were found, whereas the same experimental protocol detected no resistant HIV-2 mutants. Molecular analysis of the mutations underlying resistance revealed a multistep mechanism in which an amino acid exchange was common to all resistant isolates, and in all experiments preceded further exchanges at position 90 (leucine to methionine) and/or at position 54 (isoleucine to valine). For wild-type strains the 90% inhibitory concentrations of Ro 31-8959 were close to 20 nM, whereas HIV-1 mutants with all 3 amino acid exchanges had more than 50-fold increased 90% inhibitory concentrations (above 1000 nM). The primary event (Gly-48 to valine) occurs at the hinge of the flaps of the proteinase, thus hampering entry of the inhibitor to the active center and suggesting steric hindrance. Detailed knowledge of this stereotypic process could open inhibitor design, thus preventing conceivable escape of resistant virus on proteinase inhibitor action.
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PMID:Resistance of HIV type 1 to proteinase inhibitor Ro 31-8959. 757 26

Several domains of CD4 have been suggested to play a critical role in events that follow its binding to the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (gp120-gp41). It has been reported previously that cells expressing a chimeric molecule consisting of the first 177 residues of human CD4 attached to residues from the hinge, transmembrane, and cytoplasmic domains of human CD8 did not form syncytia with HIV-1-infected cells (L. Poulin, L.A. Evans, S. Tang, A. Barboza, H. Legg, D.R. Littman, and J.A. Levy, J. Virol. 65: 4893-4901, 1991). In contrast, we found that the hybrid CD4.CD8 molecule expressed in human cells did render them susceptible to fusion with cells expressing HIV-1IIIB or HIV-1RF envelope glycoproteins encoded by vaccinia virus recombinants, but only after long lag times. The lag time of membrane fusion mediated by the hybrid CD4.CD8 molecule was fivefold longer than that for the wild-type CD4 molecule. However, the rate of binding to and the affinity of soluble gp120 for membrane-associated CD4.CD8 were the same as for CD4. Both molecules were laterally mobile, as determined by patching experiments. Coexpression of the CD4.CD8 chimera with wild-type CD4 did not lead to interference in fusion but had an additive effect. Therefore, the proximal membrane domains of CD4 play an important role in determining the kinetics of postbinding events leading to membrane fusion. We hypothesize that the long lag time is due to the inability of the CD4.CD8-gp120-gp41 complex to undergo the rapid conformational changes which occur during the fusion mediated by wild-type CD4.
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PMID:Cell fusion mediated by interaction of a hybrid CD4.CD8 molecule with the human immunodeficiency virus type 1 envelope glycoprotein does occur after a long lag time. 841 50

The fourth conserved domain of the human immunodeficiency virus type 1 (HIV-1) envelope, the C4 region of glycoprotein 120 (gp120), is believed to be a major part of gp120 that is necessary for binding to CD4. Recently, we found that C4 in gp120 is probably an alpha-helix, because antibodies made against helical constructs of C4 react with native and recombinant gp120 but antibodies against linear C4 constructs do not. For the present study, we performed experiments to determine, first, if CD4 could bind to the helical C4 constructs and, second, if the binding was comparable with CD4 binding to gp120. Immobilized helical constructs derived from the C4s from HIV-1 and HIV-2 bound biotinylated recombinant CD4 with Kd values of 8.59 nM and 14.59 nM, respectively. Recombinant soluble CD4 inhibited the binding of biotinylated CD4 to the C4 construct from HIV-1 with a Kd of 9.88 nM, and recombinant gp120 blocked the binding of CD4 to the immobilized helical construct from C4 of HIV-1 with a Kd of 8.08 nM. The C4 peptide-(419-436) from HIV-1 (KIKQIINMWQEVGKAMYA-NH2) blocked CD4 binding to gp120 but only in a buffer containing 0.03% Brij 35 where the peptide displayed 17 +/- 1% alpha-helix; without the Brij 35, peptide-(419-436) displayed no helical content. The Kd for the peptide-(419-436) blocking CD4 binding to gp120 in Brij 35-containing buffer was found to be 42 microM. These results indicate that C4 constructs from HIV-1 and HIV-2 do bind CD4, but the constructs must display an alpha-helical conformation to do so. In addition, the results reported here will provide answers to key questions about structural requirements for HIV vaccines and therapeutics that hinge on understanding the molecular nature of the gp120-CD4 interaction as the first step in the HIV infection process.
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PMID:A synthetic conformational epitope from the C4 domain of HIV Gp120 that binds CD4. 866 8

Human CD4 is the receptor for human immunodeficiency virus (HIV). It is well established that the first domain of CD4 binds with high affinity to gp120, an envelope protein of HIV, but it has also been demonstrated that amino acids located in its second domain, within or close to residues 120-127 or 163-166 (lying 15 A away from the binding site), play a role in virus infectivity. We show here that these two stretches of amino acids happen to be important for the largest amplitude motion obtained with the normal-mode theory for the two N-terminal domains of human CD4: an overall rigid-body displacement of one domain with respect to the other. Such a 'hinge-bending' motion is unexpected since these two domains were found by crystallographers to be tightly abutting. On the other hand, since for several proteins the hinge-bending motion experimentally observed upon ligand binding was found to be similar to the largest amplitude motion obtained with the normal-mode theory for these proteins, our results suggest that CD4 may undergo such a kind of conformational change upon HIV binding.
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PMID:Normal-mode analysis suggests important flexibility between the two N-terminal domains of CD4 and supports the hypothesis of a conformational change in CD4 upon HIV binding. 887 44

CD4 is a co-receptor in the cellular immune response. It increases the avidity of association between a T cell and an antigen-presenting cell by interacting with non-polymorphic portions of the complex between class II major histocompatibility complex (MHC) and T-cell receptor (TCR) molecules, and it contributes directly to signal transduction through its cytoplasmic association with the lymphocyte kinase Lck. CD4 also serves as the high-affinity receptor for cellular attachment and entry of the human immunodeficiency virus (HIV). The extracellular portion of CD4 comprises four immunoglobulin-like domains (D1-D4). This part of human CD4 (residues 1-369) has been characterized as a recombinant soluble protein (sCD4), and crystal structures have been described for the human D1D2 fragment and for the rat D3D4 fragment. We have now determined the structures of intact sCD4 in three crystal lattices. These structures have a hinge-like variability at the D1D2 to D3D4 junction that might be important in immune recognition and HIV fusion, and a common dimeric association through D4 domains. Dynamic light scattering measurements and chemical crosslinking of sCD4 corroborate dimerization at high protein concentration. We suggest that such dimers mayhave relevance as mediators of signal transduction in T cells.
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PMID:Dimeric association and segmental variability in the structure of human CD4. 916 19


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