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

A trypsin-like proteinase which is inhibited by recombinant gp120 and by synthetic peptides of various lengths spanning the conserved sequence of the V3 loop has been purified and partially characterized from a U-937 cell membrane extract. V3 loop peptides behave as competitive inhibitors of the enzyme, while gp120 exerts a tight-binding inhibition, reacting in stoichiometric amounts with the proteinase to provide significant inhibition. Though the properties of the U-937 membrane proteinase towards gp120 and synthetic peptides of the V3 loop resemble those of the Molt-4 T-cell tryptase TL2, these two proteinases differ by their physicochemical properties and their susceptibility to other inhibitors of serine proteinases. These results give support to the concept of a membrane-associated proteinase as a complementary or alternative receptor to the CD4, for allowing virus to enter host cells and thus spreading HIV infection.
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PMID:Interaction between a membrane-associated serine proteinase of U-937 monocytes and peptides from the V3 loop of the human immunodeficiency virus type 1 (HIV-1) gp120 envelope glycoprotein. 842 26

Although multiple forms of the HIV-1 Tat protein are synthesized during infection from alternatively spliced mRNAs, only 72 amino acid residues encoded in the first Tat exon are necessary for full transactivation activity. We used limited proteolytic digestions of proteins expressed in vitro to study the structures of three Tat proteins from isolate HXB2: 72R Tat (first Tat exon); 86R Tat (first and second Tat exons), Tev or TNV (first Tat exon plus Env and Rev exons). For the 86R and Tev proteins, either trypsin or chymotrypsin cleaved the majority of carboxyl residues from the first exon. Moreover, when released from carboxyl residues, the first exon of 86R and Tev was relatively resistant to subsequent proteolysis. The entire 72R Tat protein was relatively resistant to proteolysis. The protease-resistant first exon in all Tat proteins was abolished by EDTA treatment, suggesting that divalent cations are required for its conformation. Our results suggest that the first exon in the 86R, 72R, and Tev proteins is folded into a similar structure which, as defined by partial proteolysis, acts as a single biochemical domain.
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PMID:Limited proteolytic digestions identify common structural features of HIV-1 Tat proteins expressed during infection from alternatively spliced mRNAs. 845 40

It has been suggested that the third variable domain (V3) loop of human immunodeficiency virus type 1 (HIV-1) gp120 has to interact with a cell-surface-associated protease(s) that acts as a cofactor after binding of gp120 to the CD4 receptor during entry of HIV-1 into susceptible cells. We isolated the membrane-associated serine protease, tryptase TL2, from human CD4-positive lymphocytes. This enzyme specifically binds gp120 through interaction with its V3 domain. To investigate the role of tryptase TL2 in HIV infection, we examined the affinity of the interaction and the proteolytic susceptibility of various recombinant gp120 expressed in mammalian cells to the enzyme, and we determined the cleavage sites. Tryptase TL2 bound gp120 with an apparent dissociation constant of 38 nM. The affinity was lower than that of gp120 for CD4 which suggests that gp120 initially binds to CD4, followed by interaction with tryptase TL2 which is localized close to CD4 on the cell surface. After binding, tryptase TL2 cleaved recombinant gp120 expressed in mammalian cells into two protein species of 70 kDa and 50 kDa but did not cleave gp120 expressed in insect cells, which indicates that the structure of the oligosaccharides linked to the polypeptide backbone of gp120 affects the proteolytic susceptibility. Cleavage was specifically inhibited by a neutralizing antibody against the V3 loop. Cleavage-site determination revealed that tryptase TL2 cleaved gp120 at various sites in the V3 in a strain-dependent manner. The amino acid variability at the cleavage site(s) in almost all HIV-1 isolates was restricted to amino acids which are susceptible to the chymotryptic and/or tryptic activities of tryptase TL2.
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PMID:T-cell membrane-associated serine protease, tryptase TL2, binds human immunodeficiency virus type 1 gp120 and cleaves the third-variable-domain loop of gp120. Neutralizing antibodies of human immunodeficiency virus type 1 inhibit cleavage of gp120. 862 Aug 95

Human secretory leukocyte protease inhibitor (SLPI), a serine protease inhibitor found concentrated in secretory fluids, has been postulated to participate in the body's natural defense against infection by the human immunodeficiency virus type-1 (HIV-1) by affecting trypsin-like enzymes on the surface of target cells. SLPI was evaluated for potential antiviral activity against laboratory, clinical and monocytotropic strains of HIV-1 in human T-cell lines, peripheral blood lymphocytes and monocyte/macrophage cultures. SLPI was tested in a single cycle of infection assay and under conditions in which SLPI was preincubated both with target cells and with virus and then maintained during the virus-to-cell adsorption phase and throughout the entire culture period. However, SLPI did not exert anti-HIV activity under any experimental conditions, and mechanistic studies showed SLPI to have no inhibitory activity on HIV-1 binding, reverse transcriptase or protease. Thus, SLPI exhibited no suggestive anti-HIV-1 activity.
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PMID:Human immunodeficiency virus type-1 (HIV-1) replication is unaffected by human secretory leukocyte protease inhibitor. 873 5

Water-protein interactions drive protein folding, stabilize the folded structure, and influence molecular recognition and catalysis. We analyzed the closest protein contacts of 10,837 water molecules in crystallographic structures to define a specific hydrophilicity scale reflecting specific rather than bulk solvent interactions. The tendencies of different atom and residue types to be the nearest protein neighbors of bound water molecules correlated with other hydrophobicity scales, verified the relevance of crystallographically determined water positions, and provided a direct experimental measure of water affinity in the context of the folded protein. This specific hydrophilicity was highly correlated with hydrogen-bonding capacity, and correlated better with experimental than computationally derived measures of partitioning between aqueous and organic phases. Atoms with related chemistry clustered with respect to the number of bound water molecules. Neutral and negatively charged oxygen atoms were the most hydrophilic, followed by positively-charged then neutral nitrogen atoms, followed by carbon and sulfur atoms. Agreement between observed side-chain specific hydrophilicity values and values derived from the atomic hydrophilicity scale showed that hydrophilicity values can be synthesized for different functional groups, such as unusual side or main chains, discontinuous epitopes, and drug molecules. Two methods of atomic hydrophilicity analysis provided a measure of complementarity in the interfaces of trypsin:pancreatic trypsin inhibitor and HIV protease:U-75875 inhibitor complexes.
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PMID:Atomic and residue hydrophilicity in the context of folded protein structures. 874 49

We demonstrated that a synthetic peptide (EWDREINNYTSLIHSLIEESQNQQEKNEQEGGC), designated SJ-2176, corresponding to the HIV-1 IIIB gp41 sequence (637-666), inhibited HIV-1 replication, virus-induced cell-cell fusion and cytopathic effects in both CD4+ T and monocytic cell lines. In this study, we show that lengthening the peptide at either the N- or C-terminus enhanced its activity, while shortening the peptide from either end decreased the antiviral activity. Substitution of conserved residues in SJ-2176 by alanines resulted in a decrease or elimination of antiviral activity. Replacement of arginine and lysine in the peptide by glutamines did not diminish antiviral activity and rendered the peptide resistant to trypsin.
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PMID:Effect of amino acid replacements, additions and deletions on the antiviral activity of a peptide derived from the HIV-1 GP41 sequence. 883 18

In enveloped viruses, post-translational proteolytic activation is a critical step for the fusion activity and thus for the infectivity of the virus. In addition to the membrane receptors for the viruses, proteolytic activation is indispensable for effective virus spread in the infected host and it is a prime determinant for pathogenicity. Here we described the host cellular processing proteases, tryptase Clara and tryptase TL2, which proteolytically activate the infectivity of influenza A and Sendai viruses in the respiratory tract and HIV-1 in human CD4+ T cells, respectively. A novel trypsin-like protease, designated tryptase Clara, was purified from rat lung. The enzyme is localized in Clara cells of the bronchial epithelium and is secreted into the airway lumen. The enzyme specifically recognizes the consensus cleavage motif Gln(Glu)-X-Arg of influenza A and Sendai viruses and proteolytically activates the envelope fusion glycoproteins of the progeny viruses extracellularly in the airway lumen. Human mucus protease inhibitor and pulmonary surfactant in airway fluid inhibited the proteolytic activation of these viruses and also suppressed multiple cycles of viral replication in vitro. These results suggest that an imbalance between the amount of tryptase Clara and that of endogenous inhibitors in airway fluid is a prime determinant for pneumopathogenicity of the viruses. Therefore supplementing an endogenous inhibitor at therapeutic doses may protect against virus infection. In HIV-1 infection, binding of the gp120 envelope glycoprotein to the CD4 receptor is not sufficient in itself to allow virus entry, and an additional component(s) in the membrane is required for cell infection as a cofactor. We isolated a serine protease named tryptase TL2, in the membrane of CD4+ lymphocytes, which specifically binds to the V3 loop of HIV-1 gp120 as a cofactor. After binding, tryptase TL2 proteolytically processed gp120 into two protein species of 70 and 50 kDa and the cleavage was suppressed by a neutralizing antibody against the V3 loop. The amino acids that constitute the cleavage sites in the V3 loop of almost all HIV isolates are variable, but they are restricted to those which are susceptible to chymotryptic and/or tryptic enzyme. The multi-substrate specificity of tryptase TL2, which has tryptic and chymotryptic specificities, may correspond tot he variability of the V3 loop. The selective cleavage of the V3 loop by tryptase TL2 may lead to a conformational change of gp120, resulting in the dissociation of gp120 from gp41, exposing the fusogenic domain of the transmembrane protein gp41 following virus-host cell fusion.
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PMID:Cellular proteases involved in the pathogenicity of enveloped animal viruses, human immunodeficiency virus, influenza virus A and Sendai virus. 886 54

HIV-1 actively replicates in dendritic cell (DC)-T cell cocultures, but it has been difficult to demonstrate substantial infection of purified mature DCs. We now find that HIV-1 begins reverse transcription much more efficiently in DCs than T cells, even though T cells have higher levels of CD4 and gp120 binding. DCs isolated from skin or from blood precursors behave similarly. Several M-tropic strains and the T-tropic strain IIIB enter DCs efficiently, as assessed by the progressive formation of the early products of reverse transcription after a 90-min virus pulse at 37 degrees C. However, few late gag-containing sequences are detected, so that active viral replication does not occur. The formation of these early transcripts seems to follow entry of HIV-1, rather than binding of virions that contain viral DNA. Early transcripts are scarce if DCs are exposed to virus on ice for 4 h, or for 90 min at 37 degrees C, conditions which allow virus binding. Also the early transcripts once formed are insensitive to trypsin. The entry of a M-tropic isolates is blocked by the chemokine RANTES, and the entry of IIIB by SDF-1. RANTES interacts with CCR5 and SDF-1 with CXCR4 receptors. Entry of M-tropic but not T-tropic virus is ablated in DCs from individuals who lack a functional CCR5 receptor. DCs express more CCR5 and CXCR4 mRNA than T cells. Therefore, while HIV-1 does not replicate efficiently in mature DCs, viral entry can be active and can be blocked by chemokines that act on known receptors for M- and T-tropic virus.
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PMID:Efficient interaction of HIV-1 with purified dendritic cells via multiple chemokine coreceptors. 897

The platelet-activating factor PAF (1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine) is a potent lipid first messenger active in general cell activation, fertilization, inflammatory and allergic reactions, asthma, HIV pathogenesis, carcinogenesis, and apoptosis. There is substantial evidence that PAF is involved in intracellular signalling, but the pathways are poorly understood. Inactivation of PAF is carried out by specific intra- and extracellular acetylhydrolases (PAF-AHs), a subfamily of phospholipases A2 that remove the sn-2 acetyl group. Mammalian brain contains at least three intracellular isoforms, of which PAF-AH(Ib) is the best characterized. This isoform contains a heterodimer of two homologous catalytic subunits alpha1 and alpha2, each of relative molecular mass 26K, and a non-catalytic 45K beta-subunit, a homologue of the beta-subunit of trimeric G proteins. We now report the crystal structure of the bovine alpha1 subunit of PAF-AH(Ib) at 1.7 A resolution in complex with a reaction product, acetate. The tertiary fold of this protein is closely reminiscent of that found in p21(ras) and other GTPases. The active site is made up of a trypsin-like triad of Ser 47, His 195 and Asp 192. Thus, the intact PAF-AH(Ib) molecule is an unusual G-protein-like (alpha1/alpha2)beta trimer.
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PMID:Brain acetylhydrolase that inactivates platelet-activating factor is a G-protein-like trimer. 898 54

Controversy exists concerning the preferential infection and replication of human immunodeficiency virus-1 (HIV-1) within naive (CD45RA+) and memory (CD45RO+) subsets of CD4+ lymphocytes. To explore the susceptibility of these subsets to HIV-1 infection, we purified CD45RA+/CD4+ (RA) and CD45RO+/CD4+ (RO) cells from normal donors and subjected them to a novel monokine activation culture scheme. Following HIV-1 infection and interleukin-2 (IL-2) induction, viral production measured on day 13 was 19-fold greater in RO cultures compared with RA cultures. IL-2-stimulated proliferation in uninfected control cultures was equivalent. To explore the mechanisms by which RA cells were reduced in viral production capacity, RA and RO cells were exposed to HIV-1 followed by treatment with trypsin, and then phytohemagglutinin antigen (PHA)-stimulated at days 4, 7, and 10 postinfection. HIV-1 production in day 4 postinfection RA and RO cultures was analogous, indicating that viral fusion and entry had occurred in both cell types. However, whereas similarly treated day 7 and 10 postinfection RO cultures produced virus, HIV-1 was markedly reduced or lost in the corresponding RA cultures. These results suggest that a temporally labile postfusion HIV-1 complex exists in unstimulated RA cells that requires cellular activation signals beyond that provided by IL-2 alone for productive infection.
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PMID:Loss of inducible virus in CD45RA naive cells after human immunodeficiency virus-1 entry accounts for preferential viral replication in CD45RO memory cells. 905 46


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