Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Tat mutants (tat22, tat37 and tat22/37) were constructed in the transactivation domain, where cysteines at positions 22 or/and 37 were substituted with glycine and serine, respectively. These mutants were expressed either in a BK virus episomal vector or in the retroviral vector LXSN. Constitutive production of tat22 by Jurkat T cells in the context of both vectors blocked HIV-1 replication during lytic infection. Conversely, the tat37 mutant did not show any inhibitory activity and tat22/37 displayed a mild effect on HIV-1 infection only when expressed by the recombinant retrovirus. However, constitutive production of tat22/37 by the BK virus vector in Jurkat T cells chronically infected by HIV-1 was effective in blocking reactivation of viral replication induced by tumor necrosis factor-alpha or human herpesvirus-6. These results suggest that mutants in the transactivation domain of tat may be considered in designing alternative strategies to control HIV-1 replication and reactivation from latency during different phases of infection.
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PMID:Inhibition of HIV-1 replication and reactivation from latency by tat transdominant negative mutants in the cysteine rich region. 864 55

Zidovudine (AZT) inhibits HIV replication. Many studies have demonstrated its toxic myopathic effect in both HIV-positive patients treated with the drug and experimental animal models. So far hepatic lesions induced by AZT have not been reported. In our study, an experimental rat model was used in which the rats were administered AZT (1 mg/ml) in drinking water; histological and ultrastructural alterations were observed in the liver of treated animals and compared with the findings in control animals. The histological alterations detected were turbid swelling, vacuolar degeneration and microvacuolar fatty degeneration of panlobular distribution; these lesions were progressively greater as the duration of treatment increased. The ultrastructural alterations detected involved the mitochondria (similar to those described in cardiac muscle), smooth and rough endoplasmic reticulum (SER and RER), and the accumulation of fat and glycogen in the hepatocytes of treated animals. The histopathological and ultrastructural findings in our experimental model suggest hepatotoxicity induced by AZT or its catabolites in treated, as compared to control animals.
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PMID:Hepatic Morphological alterations induced by zidovudine (ZDV) in an experimental model. 869 20

The human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) contains two binding sites for the NF-kappa B/Rel family of transcription factors which are required for the transcriptional activation of viral genes by inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin-1. In the present study, we examined the effect of transdominant mutants of I kappa B alpha on the synergistic activation of the HIV-1 LTR by TNF-alpha and the HIV-1 transactivator, Tat, in Jurkat T cells. The synergistic induction of HIV-1 LTR-driven gene expression represented a 50- to 70-fold stimulation and required both an intact HIV-1 enhancer and Tat-TAR element interaction, since mutations in Tat protein (R52Q, R53Q) or in the bulge region of the TAR element that eliminated Tat binding to TAR were unable to stimulate LTR expression. Coexpression of I kappa B alpha inhibited Tat-TNF-alpha activation of HIV LTR in a dose-dependent manner. Transdominant forms of I kappa B alpha, mutated in critical serine or threonine residues required for inducer-mediated (S32A, S36A) and/or constitutive (S283A, T291A, T299A) phosphorylation of I kappa B alpha were tested for their capacity to block HIV-1 LTR transactivation. I kappa B alpha molecules mutated in the N-terminal sites were not degraded following inducer-mediated stimulation (t1/2, > 4 h) and were able to efficiently block HIV-1 LTR transactivation. Strikingly, the I kappa B alpha (S32A, S36A) transdominant mutant was at least five times as effective as wild-type I kappa B alpha in inhibiting synergistic induction of the HIV-1 LTR. This mutant also effectively inhibited HIV-1 multiplication in a single-cycle infection model in Cos-1 cells, as measured by Northern (RNA) blot analysis of viral mRNA species and viral protein production. These experiments suggest a strategy that may contribute to inhibition of HIV-1 gene expression by interfering with the NF-kappa B/Rel signaling pathway.
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PMID:Transdominant mutants of I kappa B alpha block Tat-tumor necrosis factor synergistic activation of human immunodeficiency virus type 1 gene expression and virus multiplication. 870 93

To clarify the physiological function of two zinc finger motifs in the nucleocapsid (NC) domain of the Gag protein of human immunodeficiency virus type 1 (HIV-1), we changed cysteine to serine in either of the two motifs or both by site-directed mutagenesis. Viral infectivity was lost by any of the mutations, but their effects appeared differently in the respective mutants. Northern blot analysis showed that the first finger mutant was far less efficient (approximately 10% of the wild type) in genomic RNA encapsidation and that the dual mutant of both fingers completely failed to encapsidate the RNA. In contrast, the second finger mutant retained its ability for RNA encapsidation with an efficiency similar to that of the wild type. Immunoblot analysis of the lysates of CD4-positive M8166 cells transfected with the mutant proviral DNAs showed that the processing of Gag precursors was delayed in two mutant viruses having alterations in the first finger sequence, whereas the processing of the second finger mutant appeared to be normal. On the other hand, immunoblot analysis of the virus particles showed that the second finger mutant particles contained some proteins that were thought to be degradation products of p24CA. Electron microscopic observation showed that all particles of these mutant viruses were morphologically alike except that they had a slightly larger diameter than that of the wild type. These results indicate that these finger motifs of HIV-1 NC protein do not function equivalently. Namely, the first finger is primarily responsible for RNA encapsidation and the second is required for stabilization of virus particles.
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PMID:Mutational analysis of two zinc finger motifs in HIV type 1 nucleocapsid proteins: effects on proteolytic processing of Gag precursors and particle formation. 873 31

Activated protein C (APC) is a highly specific serine proteinase which functions as an important naturally occurring antithrombotic enzyme. APC also has anti-inflammatory properties. We have developed a large-scale process for the production of APC for therapeutic use starting with cryoprecipitate-poor human plasma. This report describes the process, its performance at the pilot plant scale, and the characteristics of immunoaffinity-purified human APC concentrate referred to as APC (human). The process consists of three chromatographic steps, an enzymatic conversion step, and incorporates a solvent/detergent treatment step for the inactivation of lipid-enveloped viruses. Solvent/detergent was shown to rapidly inactivate spiked HIV-1, as well as three marker viruses to nondetectable levels under process conditions. The immunoaffinity-purified protein C (PC) intermediate was enriched 13,600-fold over plasma and had a specific activity of 231 U/mg. The overall yield of the process following enzymatic conversion of the PC intermediate to APC and its processing by anion exchange chromatography was 36%. APC (human) was shown to be highly purified, functional and stable.
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PMID:Large-scale production and properties of immunoaffinity-purified human activated protein C concentrate. 875

We have examined structural interactions of Gag proteins in human immunodeficiency virus type 1 (HIV-1) particles by utilizing cysteine mutagenesis and cysteine-specific modifying reagents. In immature protease-minus but otherwise wild-type (wt) particles, precursor Pr55Gag proteins did not form intermolecular cystines naturally but could be cross-linked at cysteines, and cross-linking appeared to occur across nucleocapsid (NC) domains. Capsid (CA) proteins in wt mature viruses possess cysteines near their carboxy termini at gag codons 330 and 350, but these residues are not involved in natural covalent intermolecular bonds, nor can they be intermolecularly cross-linked by using the membrane-permeable cross-linker bis-maleimido hexane. The cysteine at gag codon 350 (C-350) is highly reactive to thiol-specific modifying reagents, while the one at codon 330 (C-330) appears considerably less reactive, even in the presence of ionic detergent. These results suggest that the HIV-1 CA C terminus forms an unusually stable conformation. Mutagenesis of C-350 to a serine residue in the mutant C350S (C-350 changed to serine) virtually eliminated particle assembly, attesting to the importance of this region. We also examined a C330S mutant, as well as mutants in which cysteines were created midway through the capsid domain or in the C-terminal section of the major homology region. All such mutants appeared wt on the basis of biochemical assays but showed greatly reduced infectivities, indicative of a postassembly, postprocessing replicative block. Interestingly, capsid proteins of mature major homology region mutant particles could be cysteine cross-linked, implying either that these mutations permit cross-linking of the native C-terminal CA cysteines or that major homology regions on neighbor capsid proteins are in close proximity in mature virions.
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PMID:Structural analysis of human immunodeficiency virus type 1 Gag protein interactions, using cysteine-specific reagents. 876 18

A majority of human immunodeficiency virus type 1 (HIV-1) infected individuals display a rapid loss of CD4+ lymphocytes with fast progression towards overt acquired immunodeficiency syndrome (AIDS). However, a small proportion of individuals infected by HIV-1 remain immunologically intact for many years. In order to identify factors that might influence the pathogenesis of HIV-1 infection, 21 Italian mothers and 11 Swedish homosexual men were studied for the presence of autologous neutralizing antibodies in serum, biological phenotype of virus isolates and envelope variable region 3 (V3) sequences. The results were compared to the risk of mother-to-child transmission and progression of the disease. The presence of a neutralizing antibody response to the autologous virus as well as a virus with slow replicative capacity were linked both to low risk of mother-to-child transmission and non-progression of the disease. Patients whose peripheral blood mononuclear cells contained a mutation in the tip of the V3 loop (Arg318 to serine, lysine or leucine) significantly more often had neutralizing antibodies to autologous virus isolates containing arginine at this position. Thus, it appears that the interplay and balance between neutralizing antibody response of the host and the biological phenotype of HIV-1 strongly influence pathogenesis.
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PMID:Interplay of HIV-1 phenotype and neutralizing antibody response in pathogenesis of AIDS. 881 40

The CD4 molecule acts as a receptor for class II MHC molecules to stabilize Ag recognition by the TCR and as a high affinity receptor for HIV-1. In this study, we investigated the effect of oxidative stress on the level of CD4 expression on cultured peripheral blood T lymphocytes (PBL blasts). As previously reported, we observed that the surface CD4 was down-regulated by PMA. Unexpectedly, treatment of PBL blasts with hydrogen peroxide (H2O2) or a sulfhydryl oxidative reagent, diamide, almost completely inhibited PMA-induced CD4 down-regulation, although these oxidants per se did not affect the level of CD4 expression. We next assessed the serine phosphorylation of CD4, which is reported to be an indispensable process for PMA-induced CD4 endocytosis. PMA could induce the serine phosphorylation even in the presence of oxidants. We also found that these oxidants had an additive effect on PMA-induced dissociation between CD4 and p56(lck), which is known to be another necessary step for CD4 endocytosis. These results indicate that in T cells, oxidants inhibit protein kinase C-mediated CD4 down-regulation due to perturbing a signaling process other than the above two steps, implying that oxidative stress may tune the functions of CD4+ T cells and their susceptibility to HIV-1 through the control of CD4 expression.
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PMID:Inhibition of protein kinase C-mediated CD4 down-regulation by oxidative stress in T lymphocytes. 895 81

Production of the structural and enzymatic proteins of type 1 human immunodeficiency virus (HIV-1) is controlled by the rev regulatory gene product. The 116-amino acid Rev protein acts by binding to the Rev response element (RRE), a complex RNA stem-loop structure located within the env gene of HIV. Rev exerts a series of posttranscriptional effects, including the inhibition of viral RNA splicing, the activation of nuclear export of incompletely spliced viral RNAs, and the enhancement of translation of RRE-containing RNAs. Our studies now demonstrate that at least one member of the SR family of splicing factors, SF2/ASF, specifically binds to a subregion of the RRE in vitro in a Rev-dependent manner. Furthermore, expression of high levels of SF2/ASF inhibits Rev function and impairs HIV replication in vivo. Both the in vitro binding of SF2/ASF to the Rev/RRE complex and the in vivo inhibition of Rev action by SF2/ASF are abrogated by mutation of the N-terminal RNA recognition motif but are not affected by mutation of the C-terminal arginine-serine-rich domain. These findings suggest that Rev inhibition of HIV splicing likely involves recruitment of the essential splicing factor SF2/ASF to the Rev/RRE complex. However, these inhibitory effects of Rev on viral RNA splicing are apparently overcome by augmenting the intracellular levels of SF2/ASF expression.
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PMID:HIV Rev-dependent binding of SF2/ASF to the Rev response element: possible role in Rev-mediated inhibition of HIV RNA splicing. 902 67

Inflammatory cytokines including TNF-alpha, IL-1beta, and IFN-gamma are increased in sera and lesions of Kaposi's sarcoma (KS) patients. Previous data have indicated that the combination of these cytokines as found in conditioned media from activated T cells induces normal endothelial cells to acquire the features of KS spindle cells (KS cells) including spindle morphology, marker expression, and the responsiveness to the effects of HIV-1 Tat protein. Conditioned media from activated T cells or the single cytokines also induce AIDS-KS cells to produce and release basic fibroblast growth factor (bFGF). bFGF is highly expressed also by in situ KS cells and mediates KS-like lesion formation after inoculation of the cells in nude mice. Here we show that both large and small vessel endothelial cells chronically exposed to inflammatory cytokines produce and release bioactive bFGF in the absence of cell death. In addition, after this treatment, endothelial cells acquire angiogenic capability and induce KS-like lesions after inoculation in nude mice. Production and release of bFGF is induced in a synergistic fashion by TNF-alpha, IL-1beta, and IFN-gamma, and its release is further promoted by low cell density and by the serine proteases plasmin and thrombin. These results indicate that inflammatory cytokines induce endothelial cells to export bFGF and to acquire angiogenic properties, a key feature of the KS cell phenotype, and suggest a mechanism by which these cytokines can cooperate in the induction of KS.
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PMID:Inflammatory cytokines induce endothelial cells to produce and release basic fibroblast growth factor and to promote Kaposi's sarcoma-like lesions in nude mice. 902 30


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