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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A combination of saturation and site-directed mutagenesis was utilized to disrupt the alpha 2 domain disulfide bridge of HLA-A*0201. Mutation of cysteine 101 to a serine (C101S) or of cysteine 164 to alanine (C164A) decreased the rate of maturation of the heavy chain, the total amount of mature heavy chain within the cell, and the level of surface expression. Cells expressing these genes and loaded with a synthetic peptide derived from the influenza A matrix protein (58-66) were recognized poorly by HLA-A*0201-restricted, peptide-specific CTLs. Cells expressing mutant HLA-A*0201 loaded with a synthetic peptide derived from the HIV-1 pol protein (476-484) were not recognized by pol IV-9-specific CTLs. Mutant C164A cells infected with influenza virus were partially recognized by influenza matrix peptide-specific CTLs, while C101S cells were not lysed. Surprisingly, endogenous peptide loading of cells expressing mutant HLA-A*0201 using a minigene coding for either the influenza A matrix peptide 58-66, or HIV-1 pol peptide 476-484, resulted in efficient CTL recognition. This suggests different structural constraints for peptide binding in the endoplasmic reticulum during biosynthesis and for binding to exported molecules on the cells surface.
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PMID:Mutation of the alpha 2 domain disulfide bridge of the class I molecule HLA-A*0201. Effect on maturation and peptide presentation. 807 Nov 1

We have used the molecular dynamics (MD) simulation package AMBER4 to search the conformation of a peptide predicted as a leucine zipper motif for the human immunodeficiency virus type 1 integrase protein (HIV IN-LZM). The peptide is composed of 22 amino acid residues and its location is from Val 151 to Leu 172. The searching procedure also includes two known alpha-helices that served as positive controls--namely, a 22-residue GCN4-p1 (LZM) and a 20-residue poly (L-alanine) (PLA). A 21-residue peptide extracted from a cytochrome C crystal (CCC-t) with determined conformation as a beta-turn is also included as a negative control. At the beginning of the search, two starting conformations--namely, the standard right-handed alpha-helix and the fully stretched conformations--are generated for each peptide. Structures generated as standard alpha-helix are equilibrated at room temperature for 90 ps while structures generated as a fully stretched one are equilibrated at 600 K for 120 ps. The CCC-t and PLA helices are nearly destroyed from the beginning of equilibration. However, for both the HIV IN-LZM and the GCN4-p1 LZM structures, there is substantial helicity being retained throughout the entire course of equilibration. Although helix propagation profiles calculated indicate that both peptides possess about the same propensity to form an alpha-helix, the HIV IN-LZM helix appears to be more stable than the GCN4-p1 one as judged by a variety of analyses on both structures generated during the equilibration course. The fact that predicted HIV IN-LZM can exist as an alpha-helix is also supported by the results of high temperature equilibration run on the fully stretched structures generated. In this run, the RMS deviations between the backbone atoms of the structures with the lowest potential energy (PE) identified within every 2 ps and the structure with the lowest PE searched in the same course of simulation are calculated. For both the HIV IN-LZM and the GCN4-p1 LZM, these rms values decrease with the decrease of PE, which indicates that both structures are closer in conformations as their PEs are moved deeper into the PE well.
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PMID:Molecular dynamics simulation of a leucine zipper motif predicted for the integrase of human immunodeficiency virus type 1. 807 85

Previous studies on the role of specific residues of the peptide or MHC molecule in Ag presentation have revealed the sensitivity of this complex system to even small changes in structure. In our study, we have analyzed the effect of amino acid substitution in a major CD4+ T cell determinant (T1) of HIV-1 gp160 on binding and recognition in the context of various E alpha E beta MHC class II molecules. Individual alanine substitutions at all but three positions had little or no negative effect on either MHC binding or recognition by a specific T hybridoma, whereas substitutions with larger side chains often diminished reactivity. A poly-alanine peptide containing only four of the original residues was an effective MHC class II binder and in vivo immunogen, although lacking the ability to stimulate the hybridoma. Replacement of a glutamic acid in T1 with alanine or a size-conservative, uncharged glutamine, but not a negatively charged aspartic acid produced a peptide at least 100-fold more potent than the parent peptide, indicating an inhibitory effect of the negative charge. Conversely, substitution of a glutamic acid for valine at position 29 in the floor of the peptide binding site of the E alpha E beta molecule decreased functional presentation of this peptide by more than 2 logs. However, these two effects of glutamic acid were not complementary and were mediated by distinct mechanisms, as the change in the peptide altered the extent of binding to class II, but the change in the MHC molecule decreased recognition without inhibiting peptide binding. Taken together, the data all suggest the conclusion that changes in side-chains of peptides and MHC molecules affect Ag presentation and T cell stimulation most often by introducing dominant negative or interfering groups that prevent or alter the pattern of binding events primarily mediated by a very limited number of other residues in the Ag or presenting molecule. These results have important implications for understanding the biochemistry of peptide-MHC-TCR interactions and for the possible design of vaccines both more potent and less subject to allele-specific limitations on immunogenicity.
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PMID:The importance of dominant negative effects of amino acid side chain substitution in peptide-MHC molecule interactions and T cell recognition. 809 57

Sequential overlapping Gag protein-derived oligopeptides of human immunodeficiency virus type 1 (HIV-1) 22 to 24 amino acids long, were synthesized and tested in vitro for antiviral activity. Two synthetic peptides, one derived from the matrix protein p17 (NPGLLETSEGCRQ, amino acids 47 to 59) and one located in the capsid protein p24 (PAATLEEMMTA, amino acids 339 to 349) inhibited the production of infectious virus when added to HIV-1-infected cultures when used in the range of 20 to 200 micrograms/ml. As shown by thin section electron microscopy, peptide treatment resulted in the release of immature, deformed virus particles suggesting that the two peptides interfered with assembly and maturation. Other Gag protein-derived oligopeptides had little or no influence on virus production. To characterize further the functionally active regions we synthesized peptide derivatives with three consecutive amino acids substituted by alanine; they did not cause inhibition. Therefore the regions responsible for inhibition were located between amino acids 50 to 61 in p17, and 342 to 350 in p24. These observations might lead to the development of a new antiviral strategy affecting the late stage of virus replication.
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PMID:Inhibition of infectious human immunodeficiency virus type 1 particle formation by Gag protein-derived peptides. 820 12

Antinociceptive activity of seven pentapeptide fragments of human adenovirus type 2 (Ad2) virion proteins: Thr-Val-Pro-Pro-Arg (1), Thr-Arg-Pro-Pro-Arg (2), Thr-Gly-Pro-Pro-Thr (3), Pro-Arg-Pro-Pro-Thr (4), Phe-Val-Pro-Pro-Arg (5), Ala-Arg-Pro-Pro-Ala (6), Tyr-Gly-Pro-Pro-Lys (7)--analogs of known tuftsin inhibitor Thr-Lys-Pro-Pro-Arg, was measured by hot-plate procedure. Also two tuftsin-like fragments of epitopes of HIV-1 and HIV-2: Thr-Lys-Ala-Lys (8), Thr-Lys-Glu-Lys (9), and tuftsin analog Thr-Lys-Asp-Lys (10) were tested. In the control experiments the effects of tuftsin and pentapeptide tuftsin inhibitor were also studied. The peptides 2, 4 and 5 were found to produce very strong analgesia after the icv injection. It was observed that pretreatment with peptide 8 remarkably diminished the antinociceptive effect induced by tuftsin.
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PMID:The analgesic activity of some tuftsin- and tuftsin inhibitor-like fragments of the viral coat proteins. 822 Jun 60

Using the process of "antibody antigenization," we engineered two antibody molecules carrying in the third complementarity-determining region of the heavy chain variable domain a 7-mer or a 15-mer peptide epitope of the first extracellular domain (D1) of human CD4 receptor--namely, Ser-Phe-Leu-Thr-Lys-Gly-Pro-Ser (SFLTKGPS; positions 42 through 49) and Gly-Ser-Phe-Leu-Thr-Lys-Gly-Pro-Ser-Lys-Leu-Asn-Asp-Arg-Ala (GSFLTKGPSKLNDRA; positions 41 through 55). These amino acid sequences are contained in the consensus binding site for the human immunodeficiency virus (HIV) on CD4 receptor. Both antigenized antibodies (AgAbs) bound recombinant gp120 and were recognized by a prototype monoclonal antibody to CD4 whose binding site is within amino acid residues 41-55. AgAbs were then used as immunogens in rabbits and mice to elicit a humoral response against CD4. Only the AgAb carrying the sequence 41GSFLTKGPSKLN-DRA55 induced a response against CD4. The induced antibodies showed specificity for the amino acid sequence of CD4 engineered in the AgAb molecule, were able to inhibit the formation of syncytia between human CD4+ T cells MOLT-3 and 8E5 (T cells that are constitutively infected with HIV), and stained human CD4+ CEM T cells. Four murine monoclonal antibodies were used to analyze the relationship between syncytia inhibition and CD4 binding at the single antibody level, and indicated that recognition of native CD4 is not an absolute requirement for inhibition of syncytia. This study demonstrates that antigenized antibodies can be used as immunogens to elicit site-specific and biologically active immunity to CD4. The importance of this approach as a general way to induce anti-receptor immunity and as a possible new measure to immunointervention in HIV infection is discussed.
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PMID:Active immunity against the CD4 receptor by using an antibody antigenized with residues 41-55 of the first extracellular domain. 826 9

In Brazil, clinicians followed 32 transfusion-dependent beta-thalassemia patients, 1-49 years old, at the Regional Blood Center and the Department of Hematology of University Hospital of the School of Medicine of Ribeirao Preto to determine the prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV), HIV-1, and HTLV-1. They also measured serum levels of ferritin and alanine aspartate transaminase (ALAT) to examine liver iron content and liver damage, respectively. 46.8% tested positive for antibodies to HCV, which was much higher than that of voluntary blood donors of the Regional Blood Center (1.4%) or of other countries. Yet it was about the same as that of multitransfused patients in the UK (23.2%), Italy (92.9%), and Saudi Arabia (33.3%). 3 of these 15 patients also tested positive for HBV markers. 15.5% tested positive only for HBV markers. 37.5% had no hepatitis markers. Hepatitis-positive people were older than those who tested negative for hepatitis (15.2 years vs. 8.5 years; p .05). The number of units of blood transfused and the levels of ferritin and ALAT were not statistically different between the 2 groups (192.1-336 vs. 135.2 and 36.6-52.3 U/l vs. 36.7 U/l, respectively). 75% of the HCV positive patients received more than 100 units of packed red blood cells while only 42% did in the HCV negative group. 2 people tested positive for HIV-1 1 of whom also tested positive for anti-HBs-Ag and the other for HCV antibodies. The HIV-1 cases had become infected before the blood bank began screening for HIV-1 in 1987. None of the patients receiving blood from the center became infected with HIV-1, yet 60% of hemophiliacs treated at the hospital were HIV-1 infected. No one tested positive for HTLV-1, even though all 32 patients had received more than 6250 units of blood not screened for HTLV-1. This reflected the low incidence of HTLV-1 in the general population (0.05%). No one was positive for HBs-Ag or HBe-Ag.
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PMID:The frequency of blood-born viral infections in a population of multitransfused Brazilian patients. 827 57

Structural and functional studies were made to assess interactions between human serum albumin (HSA) and the amino-terminal peptide (FP-I; 23-residue peptide 519-541) of glycoprotein 41,000 (gp41) of human immunodeficiency virus type-1 (HIV-1). Circular dichroism (CD) spectroscopy indicated that the peptide binds to albumin with dominant alpha-helical character. Peptide binding to albumin was also examined using FP-I spin labeled at either the amino-terminal alanine (FP-II; residue 519) or methionine (FP-III; position 537). Electron spin resonance (ESR) spectra of FP-II bound to HSA at 38 degrees C indicated that the spin label at the amino-terminal residue (Ala-519) was motionally restricted. The ESR spectrum of 12-nitroxide stearate (12-NS)-labeled HSA was identical to that obtained with FP-II, indicating that the reporter groups for the 12-NS and FP-II probes are similarly bound to albumin. Contrarily, ESR spectra of HSA labeled with FP-III indicated high mobility for the reporter group (Met-537) at the aqueous-protein interface. This suggests that the N-terminal gp41 peptide binds as an alpha helix (residues 519-536) to fatty acid sites on HSA, such that Ala-519 of the peptide residues in the interior of the protein while Met-537 lies outside the protein in aqueous solution. It is also of interest that addition of HSA to human red blood cells dramatically reduced the ability of FP-I to induce hemolysis, presumably through peptide-albumin binding that inhibited FP-I interactions with red cell membranes. The significance of these results focuses on the following three points. The first is that high serum levels of albumin may limit the efficacy of anti-HIV therapies using peptides based on the N-terminal gp41 domain. The second is that the elucidation of FP-I and HSA interactions with physical techniques may provide clues on the molecular features underlying viral FP-I combination with receptors on the target cell surface. Last, the affinity of albumin for the N-terminal gp41 peptide may play a subordinate role in the blocking of HIV infectivity in vitro that has been reported for chemically modified albumins.
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PMID:The amino-terminal peptide of HIV-1 gp41 interacts with human serum albumin. 831 56

Aurothioglucose and aurothiomalate have anti-HIV-1 activity in vitro. Antiviral activity requires the formation of a reactive intermediate with a molar equivalent amount of a thiol ligand. This activates gold(I) ligand exchange between the reactive species bis(thiolato)gold(I) and acidic thiol groups exposed on the surface of proteins. Bis(thioglucose)gold(I) (bisAuTG) which is formed by the reaction of molar equivalent amounts of aurothioglucose and 1-thio-beta-D-glucose completely protected MT-4 and CEM cells against HIV-1NL4-3-induced cytopathogenicity. Although bisAuTG is an inhibitor of human immunodeficiency virus-1 (HIV-1) reverse transcriptase in a cell-free assay, its antiviral effect is due to modification of a surface component of the virion. The HIV-1 strain NL4-3 is 200-fold more sensitive to inhibition of infectivity by bisAuTG than are the strains MN, RF, and SF-2. HIV-1NL4-3 has a unique cysteine residue close to the amino terminus of its gp41 envelope glycoprotein (residue 532 of gp160) which we hypothesize is the target of bisAuTG binding. Mutation of that residue alters HIV-1NL4-3 infectivity and dominantly suppresses virus assembly when coexpressed with the wild-type NL4-3 genome. We show that bisAuTG treatment releases gp120 from the surface of cells expressing wild-type HIV-1NL4-3 envelope glycoprotein, but it does not release gp120 if Cys532 is mutationally altered to Ala. Thus, the antiviral effect of bisAuTG on HIV-1NL4-3 is due to an effect on the association of gp120 with gp41.
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PMID:Aurothiolates inhibit HIV-1 infectivity by gold(I) ligand exchange with a component of the virion surface. 842 3

Amplified polymerase chain reaction (PCR) products, corresponding to the V3 loop and gp41 of the env, and p7 of the gag region, from proviral DNA of several Ethiopian and Swedish HIV-1 strains were sequenced. Of the six amino acids (GPGRAF) that constitute the principal neutralizing determinant (PND) within the V3 loop, the Ethiopian isolates all showed two amino acid changes (GPGQTF). Four to five other substitutions were found in the amino acids flanking the PND. Substitution of alanine (A) for threonine (T) should result in a change in the predicted secondary structure, i.e., disappearance of a coil structure. Percentage similarity data on a stretch of 22 amino acids within the V3 loop showed a concordance of the Ethiopian HIV-1 isolates with the sequences of published macrophage-T-cell tropic HIV isolates. Additionally derived protein sequences in two other regions showed two common substitutions in p7 and one to two substitutions in gp41 compared to a recent consensus sequence. These changes are hitherto unique for the Ethiopian strains, and suggest the presence of a clustering of a divergent HIV-1 strain in Addis Ababa, Ethiopia.
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PMID:Sequence analysis of selected regions of the env (V3 loop and gp41) and gag (p7) reading frames of Ethiopian human immunodeficiency virus type 1 strains. 843 43


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