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

Initial studies suggested that major histocompatibility complex class I-restricted viral epitopes could be predicted by the presence of particular residues termed anchors. However, recent studies showed that nonanchor positions of the epitopes are also significant for class I binding and recognition by cytotoxic T lymphocytes (CTLs). We investigated if changing nonanchor amino acids could increase class I affinity, complex stability, and T-cell recognition of a natural viral epitope. This concept was tested by using the HLA-A 0201-restricted human immunodeficiency virus type 1 epitope from reverse transcriptase (pol). Position 1 (P1) amino acid substitutions were emphasized because P1 alterations may not alter the T-cell receptor interaction. The peptide with the P1 substitution of tyrosine for isoleucine (I1Y) showed a binding affinity for HLA-A 0201 similar to that of the wild-type pol peptide in a cell lysate assembly assay. Surprisingly, I1Y significantly increased the HLA-A 0201-peptide complex stability at the cell surface. I1Y sensitized HLA-A 0201-expressing target cells for wild-type pol-specific CTL lysis as well as wild-type pol. Peripheral blood lymphocytes from three HLA-A2 HIV-seropositive individuals were stimulated in vitro with I1Y and wild-type pol. I1Y stimulated a higher wild-type pol-specific CTL response than wild-type pol in all three donors. Thus, I1Y may be an "improved" epitope for use as a CTL-based human immunodeficiency virus vaccine component. The design of improved epitopes has important ramifications for prophylaxis and therapeutic vaccine development.
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PMID:Amino-terminal alteration of the HLA-A*0201-restricted human immunodeficiency virus pol peptide increases complex stability and in vitro immunogenicity. 754 95

The karyophilic properties of the viral matrix (MA) protein govern HIV nuclear import in nondividing cells such as macrophages. A critical regulator of this process is the C-terminal tyrosine phosphorylation of MA during virus maturation. Here, we reveal the mechanism of this phenomenon, by demonstrating that tyrosine phosphorylation induces the binding of MA to integrase (IN). This leads to the incorporation of MA molecules into virus cores, and subsequently into uncoated viral nucleoprotein complexes. A direct interaction between tyrosine-phosphorylated MA and the central domain of IN can be demonstrated in vitro. It is blocked by phosphotyrosine, indicating that IN recognizes the phosphorylated C-terminal residue of MA. These results explain how the karyophilic potential of MA is conferred to the HIV nucleoprotein complex.
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PMID:HIV nuclear import is governed by the phosphotyrosine-mediated binding of matrix to the core domain of integrase. 758 60

CD4+ T cell clones specific for the HIV-1 envelope (env) protein are able to recognize not only uninfected APC that have taken up and processed exogenous env protein, but also virally infected cells expressing the env protein. We have evaluated the hypothesis that endocytosis of endogenously synthesized env protein from the plasma membrane of infected cells permits entry of the protein into the MHC class II-restricted Ag processing pathway. We show here that the env protein of HIV-1 is internalized at a surprisingly high rate through a mechanism that is dependent upon a tyrosine-containing motif located in the cytoplasmic domain of the gp41 subunit. Mutation of a critical cytoplasmic tyrosine residue or truncation of the C-terminal portion of the cytoplasmic domain resulted in forms of the env protein that did not undergo rapid internalization. However, by a variety of assays, these poorly internalized forms of the env protein were processed for class II-restricted Ag presentation as efficiently as wild-type env protein, indicating that internalization by this pathway is not essential for class II-restricted presentation. In addition, a secreted form of the env protein was presented efficiently by class II MHC under conditions that prevented re-uptake by endocytosis. Taken together, these results suggest that although rapid endocytosis from the cell surface is likely to be a major mechanism by which endogenously synthesized env protein is processed for association with class II MHC, an internal pathway may also be used.
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PMID:Endocytosis of endogenously synthesized HIV-1 envelope protein. Mechanism and role in processing for association with class II MHC. 760 19

Chimeric receptors in which a signaling component of the TCR complex such as zeta is fused directly to the ligand binding domain of a heterologous receptor or Ab have been shown to redirect the specific effector activity of T lymphocytes. We previously described the ability of two classes of such chimeric zeta-receptors bearing extracellular domains derived from either the HIV receptor CD4 (CD4 zeta) or an HIV-specific single chain Ab to redirect primary human CD8+ T cells to kill HIV-infected T cells. In this report we demonstrate that human NK cells can be genetically modified to express high levels of CD4 zeta using retroviral transduction. The CD4 zeta chimeric receptor is biochemically active, as cross-linking of CD4 zeta on NK cells results in tyrosine phosphorylation of CD4 zeta and multiple cellular proteins. More importantly, the CD4 zeta chimeric receptor is functionally active and can direct NK cells to specifically and efficiently lyse either NK-resistant tumor cells expressing the relevant ligand, gp120, or CD4+ T cells infected with HIV. These results show that human NK cells can be readily activated via zeta-based chimeric receptors to target both tumor and virally infected cells, and suggest a novel approach to the treatment of disease.
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PMID:Chimeric zeta-receptors direct human natural killer (NK) effector function to permit killing of NK-resistant tumor cells and HIV-infected T lymphocytes. 760 31

The 96-amino acid Vpr protein is the only virion-associated regulatory protein encoded by the human immunodeficiency virus type 1 (HIV-1). Vpr incorporation into the viral particle is most likely due to an interaction with a viral structural protein. Recent data have shown that DNA encoding for the p55 Gag precursor protein (Pr55gag) is the minimal viral genetic information necessary for Vpr incorporation. Other studies have suggested that the p6 portion of Pr55gag, which is unique to lentiviruses, is involved in Vpr incorporation. To investigate the mechanism of incorporation of Vpr into HIV-1 virions, COS-7 cells were cotransfected with ptrENV, an expression vector that encodes all of the HIV-1 regulatory proteins including Rev and Vpr, and different constructs of pIIIgagCAR, a rev-dependent Gag expression plasmid that encodes Pr55gag and the viral protease. Virions produced from gag constructs containing a premature p6 termination codon at positions Leu-1, Ser-17, Tyr-36, or Leu-44 lacked detectable Vpr. In contrast, gag constructs with double Pro-10-Pro-11 substitutions for Leu-10-Leu-11 or a premature termination codon at position Pro-49 of p6 were still able to incorporate Vpr, however, with lower efficiency than wild type. The mutations described in this study affected directly two short regions within the p6 domain, which are highly conserved among primate immunodeficiency viruses. Our results suggest that the conserved (P-T/S-A-P-P) and (L-X-S-L-F-G) motifs located near the N-terminus and C-terminus, respectively, of the p6 domain of Gag are critical for Vpr incorporation into HIV-1 virions.
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PMID:Incorporation of Vpr into human immunodeficiency virus type 1: role of conserved regions within the P6 domain of Pr55gag. 764 78

The intrinsic fluorescence of tyrosine increases by a factor of approximately two when the carboxy group is liberated from a peptide bond by hydrolysis. The increase in fluorescence provides a novel way to monitor the hydrolysis of native tyrosine peptides that contain only proteinogenic amino acids. Thus, for example, the hydrolysis by HIV-1 proteinase of a heptapeptide viral protein fragment gag129-135, Ser-Gln-Asn-Tyr-Pro-Ile-Val, was followed continuously at excitation and emission wavelengths 275 and 305 nm. The fluorescence increase is magnified by at least a factor of a thousand when a resonance energy quencher, such as paranitrophenylalanine, is in the vicinity. For example, the peptide Lys-Ala-Arg-Val-Tyr-Phe(p-NO2)-Glu-Ala-Nle-NH2 [Richards et al. (1990) J. Biol. Chem. 265, 7733], widely used for spectrophotometric assays of the HIV-1 proteinase, yields a substrate:product fluorescence ratio greater than 1:1000. Tyrosine-containing substrates of pepsin and trypsin showed similar behavior. The detection limit of the present method is at least one order of magnitude lower than absorbance assays of p-nitrophenylalanine peptides.
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PMID:Increase in fluorescence upon the hydrolysis of tyrosine peptides: application to proteinase assays. 766 86

Human immunodeficiency virus binds to CD4 T lymphocytes by interaction between its envelope glycoprotein gp120 and the CD4 molecule. The latter is non-covalently associated with a src-related tyrosine kinase, p56lck. CD4 cross-linking increases the activity of p56lck, leading to phosphorylation of several cellular substrates. We report here that gp160/120 increases both the autophosphorylation of p56lck and its enzymatic activity (reflected by phosphorylation of an exogenous substrate) in normal T cells and the HUT78 CD4+ T cell line. This effect was detectable 5 min after activation and persisted for 40 min in normal T cells. It did not require gp120 cross-linking and was associated with phosphorylation of tyrosine residue on several proteins, as shown by phosphotyrosine Western blot analysis. The pattern of proteins phosphorylated on tyrosine residues in response to gp120 activation was distinct from that induced by anti-CD4 antibodies. p56lck activation required its association with CD4, since p56lck activity was not modified in HUT78 T cell lines expressing a truncated or mutated form of CD4 unable to associate with p56lck. Peptides mimicking residues 418 to 434 and 449 to 464 of HIV-1 Bru gp120, regions known to participate in gp120 binding to CD4, also increased p56lck activity and triggered phosphorylation of similar substrates. Taken together, these results show that gp160/120 and derived peptides can transiently increase p56lck activity without the need for CD4 cross-linking. This activation led to a specific pattern of tyrosine phosphorylation on cellular proteins that may be of significance in the biological effects of the gp120/CD4 interaction, e.g. syncytium formation and inhibition of T cell activation.
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PMID:Human immunodeficiency virus gp120 and derived peptides activate protein tyrosine kinase p56lck in human CD4 T lymphocytes. 768 Jun 10

The TIBO, HEPT, nevirapine, pyridinone, BHAP, TSAO, and alpha-APA derivatives, although belonging to structurally diverging classes of molecules, share remarkable common features. They are specifically active against the reverse transcriptase of HIV-1 (TIBO and HEPT also, to a certain extent, against the reverse transcriptase of SIVagm strains), but not against the reverse transcriptases of HIV-2 or any other retroviruses. Nor are they active against any of the cellular DNA polymerases. These HIV-1-specific RT inhibitors seem to interact with a specific target site (YQYMDDLY) at positions 181-188, which is distinct from, but functionally and spatially related to, the substrate (dNTP) binding site. The tyrosine residues Y181 and Y188 play a crucial role in the interaction of TIBO and its congeners with their target site. The HIV-1-specific RT inhibitors have proven to inhibit the replication of various HIV-1 strains, including AZT-resistant HIV-1 strains, in different cell culture systems, including peripheral blood lymphocytes and monocyte/macrophages. In vitro they exhibit selectivity indexes of up to 5 orders of magnitude, which means that they are inhibitory to virus replication in cell culture at concentrations that are up to 100,000 times lower than the concentrations at which they are toxic to the host cells. As a rule, the HIV-1-specific RT inhibitors are orally bioavailable, as has been demonstrated with the TIBO and HEPT derivatives, nevirapine, pyridinones, and the alpha-APA derivatives in rats, dogs, monkeys, and humans. They sustain plasma drug levels that are well above the concentration required to inhibit virus replication in cell culture. Clinical studies have been undertaken with TIBO R82913, nevirapine, and pyridinones, and others (i.e., alpha-APA R89439) will soon follow. The problem of virus-drug resistance, which seems to readily emerge in vitro, will have to be addressed in the in vivo studies.
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PMID:HIV-1-specific RT inhibitors: highly selective inhibitors of human immunodeficiency virus type 1 that are specifically targeted at the viral reverse transcriptase. 768 60

HIV-1 strains were isolated from three patients treated with AZT and from three patients not treated with AZT. Progenomes of HIV-1 RT gene were amplified by PCR and cloned to M13mp18 vecter. Four amino acid mutations in RT gene (Asp67, Lys70, Thr215, Lys219) associated with resistance to AZT were analysed. All of the 14 clones obtained from the three patients with AZT therapy had mutations at codon 215 (Thr-->Tyr or Phe). Some of the 14 clones also had other mutations at codon 67 (Asp-->Asn or Ser), codon 70 (Lys-->Arg) and codon 219 (Lys-->Glu). All of 18 clones obtained from the patients not treated with AZT have no mutation at any codon mentioned above.
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PMID:[Mutations of HIV-1 RT gene isolated from patients treated with AZT]. 768 6

Pentosan polysulfate, a polyanionic mucopolysaccharide, which has been shown to exert inhibitory effects on human immunodeficiency virus (HIV-I) replication, inhibited the activities of protein tyrosine kinases from lymphocytes (Jurkat cells) and rat lung in a concentration dependent manner. In addition, the autophosphorylation of p56lck, a lymphocyte associated protein tyrosine kinase from Jurkat cells was also inhibited by pentosan polysulfate (100 micrograms/ml). Furthermore, the activities of protein serine/threonine kinases such as Ca2+, phospholipid-dependent protein kinase (protein kinase C) from human platelets and the catalytic subunit of cAMP-dependent protein kinase from skeletal muscle were also inhibited by this mucopolysaccharide. However, the activity of phosphorylase kinase was not altered. The inhibition of rat lung protein tyrosine kinase was rapid and competitive with respect to ATP with an apparent Ki value of 5-20 micrograms/ml. These results suggest that the ability of pentosan polysulfate to inhibit various protein serine/threonine and tyrosine kinases may be one of the mechanisms by which this compound exerts its inhibitory effect of HIV-I replication.
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PMID:Pentosan polysulfate, a potent anti HIV and anti tumor agent, inhibits protein serine/threonine and tyrosine kinases. 768 45


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