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)

Human immunodeficiency virus-1 Tat protein and human Cyclin T1 mediate transcriptional activation by enhancing the elongation efficiency of RNA polymerase II. Activation of transcription of the related equine infectious anemia virus (EIAV) requires a similar protein known as eTat, which does not function in human cells. Expression of equine Cyclin T1 in human cells rescues eTat function, suggesting a general mechanism of transcription activation among lentiviruses. Here we present the cloning of Cyclin T1 from canine D17 osteosarcoma cells, which support EIAV transactivation, and show that canine Cyclin T1 confers eTat transactivation to human cells. A two-amino-acid change, from 79-proline-glycine-80 to 79-histidine-arginine-80, confers on the human Cyclin T1 the ability to cooperate with eTat in transcriptional activation. These findings suggested that the regions of Cyclin T1 that interact with lentiviral Tat proteins and TAR RNA elements form an extended domain, which very likely has a conserved fold.
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PMID:Canine cyclin T1 rescues equine infectious anemia virus tat trans-activation in human cells. 1068 21

In a systematic search for developing a virucidal spermicide with potent anti-human immunodeficiency virus (HIV) and spermicidal activities, we synthesized and evaluated 14 phosphoramidate derivatives of 5-bromo-6-methoxy-zidovudine (PP-BMZ) with differing amino acid ester side chains and para substitutions on the phenyl moiety. Anti-HIV activity was tested by measuring viral p24 antigen production as a marker of viral replication in HIV-1-infected human peripheral blood mononuclear cells. The effect of various PP-BMZ compounds on human sperm motion kinematics was analysed by computer-assisted sperm analysis. Varying the Ala side chain of the phosphoramidate group to other non-polar amino acids, including the cyclic amino acids proline and tryptophan, led to significant alterations in both anti-HIV and spermicidal activities. Our findings highlight the necessity of the Ala side chain and the presence of an electron-withdrawing para-bromo substituent on the phenyl moiety in addition to the bromo-methoxy functional groups on the thymine ring for the PP-BMZ compounds to be effective virucidal spermicides. These membrane permeable dual-function nucleoside analogues may provide the basis for a new strategy aimed at prevention of the sexual transmission of HIV while providing fertility control for women.
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PMID:Importance of the alanine methyl ester side chain for the biological activity profile of dual-function phenyl phosphate derivatives of bromo-methoxy-zidovudine. 1069 52

Acquired immune deficiency syndrome (AIDS) is an incurable disease at present and so many efforts to conquer this disease are being made around the world. In studies of human immunodeficiency virus (HIV) infection and the disease progression, it has been reported that T cells expressing CD26 are preferentially infected and depleted in HIV-infected individuals. CD26 is a widely distributed 110 kDa cell-surface glycoprotein with known dipeptidyl peptidase IV (DPPIV) activity in its extracellular domain. This ectoenzyme is capable of cleaving N-terminal dipeptides from polypeptides with either proline or alanine residues in the penultimate position. On human T cells, CD26 exhibits the co-stimulatory function and plays an important role in immune response via its ability to bind adenosine deaminase (ADA) and association with CD45. Recent studies have been stripping the veil from over the relationship between CD26 and HIV infection. Susceptibility of cells to HIV infection is correlated with CD26 expression, and HIV transactivator Tat and envelope protein gp120 are reported to interact with CD26. These observations indicate that CD26 is closely involved in HIV cell entry and that CD26-mediated T cell immune response is suppressed. In addition, it has been demonstrated that the anti-HIV and chemotactic activities of RANTES (regulated on activation, normal T cell expressed and secreted) and stromal cell-derived factor-1 (SDF-1) are controlled with the DPPIV activity of CD26. Thus, the regulation of the function of chemokines by CD26/DPPIV appears to be essential for lymphocyte trafficking and infectivity of HIV strains.
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PMID:Good or evil: CD26 and HIV infection. 1069 52

SIVmac Nef contains two N-terminal tyrosines that were proposed to be part of an SH2-ligand domain and/or a tyrosine-based endocytosis signal and a putative SH3-ligand domain (P(104)xxP(107)). In the present study, we investigated the effects of combined mutations in these tyrosine and proline residues on simian immunodeficiency virus (SIV) Nef interactions with the cellular signal transduction and endocytic machinery. We found that mutation of Y(28)F, Y(39)F, P(104)A, and P(107)A (FFAA-Nef) had little effect on Nef functions such as the association with the cellular tyrosine kinase Src, downregulation of cell surface expression of CD4 and class I major histocompatibility complex, and enhancement of virion infectivity. However, mutations in the PxxP sequence reduced the ability of Nef to stimulate viral replication in primary lymphocytes. Three macaques infected with the SIVmac239 FFAA-Nef variant showed high viral loads during the acute phase of infection. Reversions in the mutated prolines were observed between 12 and 20 weeks postinfection. Importantly, reversion of A(107)-->P, which restored the ability of Nef to coprecipitate a 62-kDa phosphoprotein in in vitro kinase assays, did not precede the development of a high viral load. The Y(28)/Y(39)-->F(28)/F(39) substitutions did not revert. In conclusion, mutations in both the tyrosine residues and the putative SH3 ligand domain apparently do not disrupt major aspects of SIV Nef function in vivo.
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PMID:Simian immunodeficiency virus containing mutations in N-terminal tyrosine residues and in the PxxP motif in Nef replicates efficiently in rhesus macaques. 1075 28

The envelope protein is a primary pathogenic determinant for T-cell-tropic feline leukemia virus (FeLV) variants, the best studied of which is the immunodeficiency-inducing virus, 61C. We have previously demonstrated that T-cell-tropic, cytopathic, and syncytium-inducing viruses evolve in cats infected with a relatively avirulent, transmissible form of FeLV, 61E. The envelope gene of an 81T variant, which encoded scattered single-amino-acid changes throughout the envelope as well as a 4-amino-acid insertion in the C-terminal half of the surface unit (SU) of envelope, was sufficient to confer the T-cell-tropic, cytopathic phenotype (J. L. Rohn, M. S. Moser, S. R. Gwynn, D. N. Baldwin, and J. Overbaugh, J. Virol. 72:2686-2696, 1998). In the present study, we examined the role of the 4-amino-acid insertion in determining viral replication and tropism of FeLV-81T. The 4-amino-acid insertion was found to be functionally equivalent to a 6-amino-acid insertion at an identical location in the 61C variant. However, viruses expressing a chimeric 61E/81T SU, containing the insertion together with the N terminus of 61E SU, were found to be replication defective and were impaired in the processing of the envelope precursor into the functional SU and transmembrane (TM) proteins. In approximately 10% of cultured feline T cells (3201) transfected with the 61E/81T envelope chimeras and maintained over time, replication-competent tissue culture-adapted variants were isolated. Compensatory mutations in the SU of the tissue culture-adapted viruses were identified at positions 7 and 375, and each was shown to restore envelope protein processing when combined with the C-terminal 81T insertion. Unexpectedly, these viruses displayed different phenotypes in feline T cells: the virus with a change from glutamine to proline at position 7 acquired a T-cell-tropic, cytopathic phenotype, whereas the virus with a change from valine to leucine at position 375 had slower replication kinetics and caused no cytopathic effects. Given the differences in the replication properties of these viruses, it is noteworthy that the insertion as well as the two single-amino-acid changes all occur outside of predicted FeLV receptor-binding domains.
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PMID:Feline leukemia virus envelope sequences that affect T-cell tropism and syncytium formation are not part of known receptor-binding domains. 1084 53

PRO 542 (CD4-IgG2) is a recombinant antibody-like fusion protein wherein the Fv portions of both the heavy and light chains of human IgG2 have been replaced with the D1D2 domains of human CD4. Unlike monovalent and divalent CD4-based proteins, tetravalent PRO 542 potently neutralizes diverse primary human immunodeficiency virus (HIV) type 1 isolates. In this phase 1 study, the first evaluation of this compound in humans, HIV-infected adults were treated with a single intravenous infusion of PRO 542 at doses of 0.2-10 mg/kg. PRO 542 was well tolerated, and no dose-limiting toxicities were identified. Area under the concentration-time curve, and peak serum concentrations increased linearly with dose, and a terminal serum half-life of 3-4 days was observed. No patient developed antibodies to PRO 542. Preliminary evidence of antiviral activity was observed as reductions in both plasma HIV RNA and plasma viremia. Sustained antiviral effects may be achieved with repeat dosing with PRO 542.
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PMID:Single-dose safety, pharmacology, and antiviral activity of the human immunodeficiency virus (HIV) type 1 entry inhibitor PRO 542 in HIV-infected adults. 1088 17

The Vif (virion infectivity factor protein of human immunodeficiency virus type I (HIV-1) is essential for viral replication in vivo and productive infection of peripheral blood mononuclear cells, macrophages, and H9 T-cells. However, the molecular mechanism(s) of Vif remains unknown and needs to be further determined. In this report, we show that, like many other proteins encoded by HIV-1, Vif proteins possess a strong tendency toward self-association. In relatively native conditions, Vif proteins formed multimers in vitro, including dimers, trimers, or tetramers. Through in vivo binding assays such as coimmunoprecipitation and the mammalian two-hybrid system, we also demonstrated that Vif proteins could interact with each other within a cell, indicating that the multimerization of Vif proteins is not simply due to fortuitous aggregation. Further studies indicated that the domain affecting Vif self-association is located at the C terminus of this protein, especially the proline-enriched 151-164 region. Moreover, we found that a Vif mutant with deletion at amino acid 151-164 was unable to rescue the infectivity of vif-defective viruses generated from H9 T-cells, suggesting that the multimerization of Vif proteins could be important for Vif function in the viral life cycle. Our studies identified a new feature of Vif and should accelerate our understanding of its role in HIV-1 pathogenesis.
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PMID:The multimerization of human immunodeficiency virus type I Vif protein: a requirement for Vif function in the viral life cycle. 1107 84

CCR5 serves as a requisite fusion coreceptor for clinically relevant strains of human immunodeficiency virus type 1 (HIV-1) and provides a promising target for antiviral therapy. However, no study to date has examined whether monoclonal antibodies, small molecules, or other nonchemokine agents possess broad-spectrum activity against the major genetic subtypes of HIV-1. PRO 140 (PA14) is an anti-CCR5 monoclonal antibody that potently inhibits HIV-1 entry at concentrations that do not affect CCR5's chemokine receptor activity. In this study, PRO 140 was tested against a panel of primary HIV-1 isolates selected for their genotypic and geographic diversity. In quantitative assays of viral infectivity, PRO 140 was compared with RANTES, a natural CCR5 ligand that can inhibit HIV-1 entry by receptor downregulation as well as receptor blockade. Despite their divergent mechanisms of action and binding epitopes on CCR5, low nanomolar concentrations of both PRO 140 and RANTES inhibited infection of primary peripheral blood mononuclear cells (PBMC) by all CCR5-using (R5) viruses tested. This is consistent with there being a highly restricted pattern of CCR5 usage by R5 viruses. In addition, a panel of 25 subtype C South African R5 viruses were broadly inhibited by PRO 140, RANTES, and TAK-779, although approximately 30-fold-higher concentrations of the last compound were required. Interestingly, significant inhibition of a dualtropic subtype C virus was also observed. Whereas PRO 140 potently inhibited HIV-1 replication in both PBMC and primary macrophages, RANTES exhibited limited antiviral activity in macrophage cultures. Thus CCR5-targeting agents such as PRO 140 can demonstrate potent and genetic-subtype-independent anti-HIV-1 activity.
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PMID:Potent, broad-spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140. 1113 70

Progenics's rCD4-IgG2 (PRO-542) is a recombinant fusion protein, which has been developed using the company's Universal Antiviral Binding (UnAB) technology, and is in phase I/II clinical trials for the treatment of human immunodeficiency virus type I (HIV-1) infection [273391]. At the beginning of 1997, Progenics received a Phase II Small Business Innovation Research Program (SBIR) grant from the National Institute of Allergy and Infectious diseases (NIAID) to fund the development of PRO-542 [236048]. A further grant of $2.7 million was awarded in August 1998 for the clinical evaluation of PRO-542 and other anti-HIV therapies [294200]. Progenics is collaborating with the Aaron Diamond AIDS Research Center (ADARC) in New York and the Center for Disease Control and Prevention in Atlanta [178410]. In February 2000, Progenics and Genzyme Transgenics Corp signed an agreement to continue the development of a transgenic source of PRO-542. Genzyme will develop transgenic goats that produce PRO-542 in their milk in exchange for undisclosed fees and milestone payments. Genzyme will supply PRO-542 to Progenics for clinical trials with a possibility for eventual commercial supply [357291]. Following on from this, in October 2000, Progenics received an SBIR grant to fund a two-year project with Genzyme Transgenics into the development of cost-effective methods for the manufacture of PRO-542, by optimization of the production of the drug in the milk of transgenic dairy animals [385982]. In August 2000, Punk, Ziegel & Company predicted that Progenics Pharmaceuticals will become sustainably profitable in 2003 following the launch of PRO-542 and GMK (Progenics Pharmaceuticals) in 2002 [390063].
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PMID:Technology evaluation: PRO-542, Progenics Pharmaceuticals inc. 1124 48

CCR5 is a G-protein-coupled receptor activated by the chemokines RANTES (regulated on activation normal T cell expressed and secreted), macrophage inflammatory protein 1alpha and 1beta, and monocyte chemotactic protein 2 and is the main co-receptor for the macrophage-tropic human immunodeficiency virus strains. We have identified a sequence motif (TXP) in the second transmembrane helix of chemokine receptors and investigated its role by theoretical and experimental approaches. Molecular dynamics simulations of model alpha-helices in a nonpolar environment were used to show that a TXP motif strongly bends these helices, due to the coordinated action of the proline, which kinks the helix, and of the threonine, which further accentuates this structural deformation. Site-directed mutagenesis of the corresponding Pro and Thr residues in CCR5 allowed us to probe the consequences of these structural findings in the context of the whole receptor. The P84A mutation leads to a decreased binding affinity for chemokines and nearly abolishes the functional response of the receptor. In contrast, mutation of Thr-82(2.56) into Val, Ala, Cys, or Ser does not affect chemokine binding. However, the functional response was found to depend strongly on the nature of the substituted side chain. The rank order of impairment of receptor activation is P84A > T82V > T82A > T82C > T82S. This ranking of impairment parallels the bending of the alpha-helix observed in the molecular simulation study.
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PMID:The TXP motif in the second transmembrane helix of CCR5. A structural determinant of chemokine-induced activation. 1127 62


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