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

A fast growing family of ATPases has recently been highlighted. It was named the AAA family, for ATPases Associated to a variety of cellular Activities. The key feature of the family is a highly conserved module of 230 amino acids present in one or two copies in each protein. Despite extensive sequence conservation, the members of the family fulfil a large diversity of cellular functions: cell cycle regulation, gene expression in yeast and HIV, vesicle-mediated transport, peroxisome assembly, 26S protease function etc. In addition, several members of this family can be found in the same organism (up to 17 in S. cerevisiae). The contrast between functional diversity and structural conservation of the module, from archaebacteria to mammals, suggests that it plays an essential, but as yet unknown, role at key points of the cellular machinery. Two (non-exclusive) such possibilities are: (1) ATP-dependent proteasome function and (2) ATP-dependent anchorage of proteins. Finally, the basic biochemical activity of the AAA module is still a matter of speculation, and we propose that it acts as an ATP-dependent protein clamp.
 ...
PMID:A 200-amino acid ATPase module in search of a basic function. 764 86

The ability of minigene-encoded viral peptide epitopes to be presented by class I molecules in the absence of MHC-encoded transporters has been evaluated in mutant T2 cells. These cells have a large deletion in the class II MHC region that includes the known transporter protein for antigenic peptides and proteasome genes and they are defective in presenting viral epitopes to CTL. T2 cells that express minigenes encoding the influenza virus matrix peptide 58-66 (GILGFVFTL) and two HTLV 1 Tax peptides 11-19 (LLFGYPVYV) and 12-19 were lysed by HLA-A2-restricted peptide-specific CTL. Minigene expression of a HLA-A2-restricted HIV reverse transcriptase peptide 476-484 (ILKEPVHGV) with three charged residues sensitized T2 cells poorly for lysis by HIV-specific CTL unless the peptide was preceded by an endoplasmic reticulum translocation signal sequence. Expression of an influenza virus nucleoprotein peptide 383-391 (SRYWAIRTR) with three charged arginine residues did sensitize HLA-B27+ T2 cells for lysis by peptide-specific CTL. These and other results with endogenously expressed peptide analogs in which hydrophobic and charged amino acids were interchanged demonstrate that antigenic peptides can be translocated from the cytoplasm into the class I Ag presentation pathway independent of MHC-encoded transporters; and that peptide hydrophobicity appears not to be a major determinant in selecting peptides for this alternate pathway.
 ...
PMID:Presentation of endogenous peptides to MHC class I-restricted cytotoxic T lymphocytes in transport deletion mutant T2 cells. 767 94

CD8+ cytolytic T lymphocytes (CTL) identify virally infected cells by recognizing processed viral antigen in association with class I major histocompatibility complex (MHC) molecules on infected cells. Processing begins in the cytosol with the generation of peptides, possibly by a protease complex with MHC-encoded subunits, known as the proteasome. Transport of the resulting cytosolic peptides into the endoplasmic reticulum for association with class I molecules is essential and probably involves a heterodimer of the MHC-encoded proteins, Tap-1 and Tap-2. The site of processing of viral envelope proteins is uncertain. These proteins are not present in the cytosol because of cotranslational translocation into the endoplasmic reticulum. We show here that the HIV-1 envelope (env) protein is processed in infected cells by a novel Tap-1/Tap-2-independent pathway that seems to be localized to the endoplasmic reticulum.
 ...
PMID:Transporter-independent processing of HIV-1 envelope protein for recognition by CD8+ T cells. 832 Dec 86

HIV-1 Nef protein is important for pathogenicity, but its biochemical function remains obscure. To clarify its role, a yeast two-hybrid system (ths) screening was utilized to identify Nef cellular partners. Of 79 yeast clones harboring cDNAs for putative Nef binding proteins, 27 (34%) contained the coding region for HsN3 proteasomal subunit. HsN3 behaved as bona fide Nef partner in ths control crosses. Nef-HsN3 interaction was confirmed by in vitro binding experiments. In particular, recombinant Nef was able to capture the HsN3 subunit from a natural proteasome preparation. In Nef, the interacting region was mapped within aa 34-143, which span the structured portion of the protein, including the SH3-binding domain. In HsN3, Nef-binding portion was restricted to aa 73-249, and the tract 219-249-reminiscent of SH3 domain N-terminal 3/5ths-was shown to be essential, though not sufficient. Attempts to purify a Nef-HsN3 complex from transfected COS7 cells were unsuccessful. However, Nef was found to markedly downregulate intracellular levels of both a coexpressed HsN3 and the endogenous simian homologue. These results suggest that Nef, by binding to a subunit, might alter proteasome function in infected cells.
 ...
PMID:HsN3 proteasomal subunit as a target for human immunodeficiency virus type 1 Nef protein. 934 5

Cellular localization of Tat-binding protein-1 (TBP-1) mRNA is studied in the rat central nervous system (CNS) by in situ hybridization histochemistry. TBP-1 is one of the molecules which interact with HIV Tat and influence HIV amplification. Also, TBP-1 is recognized as a component of a 19S regulatory subunit of the 26S proteasome which degrades ubiquitinated proteins and is essential for a remarkably wide range of cellular processes, including vesicle fusion, proteolysis, peroxisomal and mitochondrial biogenesis and transcription. A detectable amount of TBP-1 mRNA exists widely in neurons but with high heterogeneity in the CNS. Many motor neurons, e.g. those in the oculomotor nucleus, trochlear nucleus, motor trigeminal nucleus, facial nucleus and hypoglossal nucleus, are TBP-1 mRNA positive. In addition, neurons in the sensory nuclei, such as the mesencephalic trigeminal nucleus and the nucleus ambiguus, and many cortical neurons are TBP-1 mRNA positive. These results suggest that TBP-1 is one of the basic molecules in the brain and that the expression of TBP-1 mRNA is differentially regulated at the cellular level, probably reflecting the rate of protein turnover as a whole.
 ...
PMID:Distribution of mRNA encoding Tat-binding protein-1 (TBP-1), a component of 26S proteasome, in the rat brain. 947 11

Following cell surface receptor binding and membrane fusion, human immunodeficiency virus (HIV) virion cores are released in the cytoplasm. Incoming viral proteins represent potential targets for cytosolic proteases. We show that treatment of target cells with the proteasome inhibitors MG132 and lactacystin increased the efficiency of HIV infection. Proteasome inhibitors were active at the early steps of the viral cycle. Incoming p24Gag proteins accumulated in the cytosol, and larger amounts of proviral DNA were synthesized. In vitro, purified 20S proteasome degraded HIV virion components. Thus, degradation of incoming viral proteins by the proteasome represents an early intracellular defense against infection.
 ...
PMID:Antiviral activity of the proteasome on incoming human immunodeficiency virus type 1. 955 68

Tat binding protein-1 (TBP-1) is one of the molecules that interact with HIV Tat protein and have influence on Tat-mediated transactivation of HIV. In addition, TBP-1 has been recognized as a component of the 19S regulatory subunit of the multiprotein complex, the 26S proteasome, that is essential for many basic events in cells, e.g. cell cycle regulation, by degrading the ubiquitinized proteins. Here we have cloned a mouse TBP-1, confirmed its inhibitory action on Tat activity and revealed its in vivo heterogeneous expression pattern in the mouse. The cloned mouse TBP-1 cDNA is 1569 bp in size, longer than reported human TBP-1 cDNA, and another possible initiation site has been identified. Robust expression of TBP-1 mRNA can be observed in the testis, especially in the spermatogonia and spermatocytes. Our immunohistochemical study has revealed that TBP-1 is mainly localized in the nuclei of these testicular cells. Expression of TBP-1 mRNA in CD4+ lymphocytes is confirmed by RT-PCR. Localization of TBP-1 transcripts in vivo is similar to the reported distribution of constitutive components of the 20S proteasome. The heterogeneous and restricted expression of TBP-1 in vivo suggests that there may be a diverse reaction of tissues against the HIV proliferation and a diverse capability of tissues in degrading ubiquitinized proteins in vivo.
 ...
PMID:Cloning and heterogeneous in vivo expression of Tat binding protein-1 (TBP-1) in the mouse. 971 59

Inhibitors of the protease of HIV-1 have been used successfully for the treatment of HIV-1-infected patients and AIDS disease. We tested whether these protease inhibitory drugs exerted effects in addition to their antiviral activity. Here, we show in mice infected with lymphocytic choriomeningitis virus and treated with the HIV-1 protease inhibitor ritonavir a marked inhibition of antiviral cytotoxic T lymphocyte (CTL) activity and impaired major histocompatibility complex class I-restricted epitope presentation in the absence of direct effects on lymphocytic choriomeningitis virus replication. A potential molecular target was found: ritonavir selectively inhibited the chymotrypsin-like activity of the 20S proteasome. In view of the possible role of T cell-mediated immunopathology in AIDS pathogenesis, the two mechanisms of action (i.e., reduction of HIV replication and impairment of CTL responses) may complement each other beneficially. Thus, the surprising ability of ritonavir to block the presentation of antigen to CTLs may possibly contribute to therapy of HIV infections but potentially also to the therapy of virally induced immunopathology, autoimmune diseases, and transplantation reactions.
 ...
PMID:An inhibitor of HIV-1 protease modulates proteasome activity, antigen presentation, and T cell responses. 978 51

HIV-1 infection of the central nervous system can cause severe neurologic disease although only microglial cells and brain macrophages are susceptible to productive viral infection. Substances secreted by infected cells are thought to cause disease indirectly. Tumor necrosis factor alpha (TNF-alpha) is one candidate neurotoxin and is upregulated during HIV-1 infection of the brain, likely via activation of the transcription factor NF-kappaB. We used the proteasome inhibitors, MG132 and ALLN (N-acetyl-Leu-Leu-Norleucinal), to inhibit NF-kappaB activation in primary human fetal microglia (PHFM) and primary monocyte derived-macrophages, and showed that they could block TNF-alpha release stimulated by lipopolysaccharide (LPS) or TNF-alpha. In addition, we performed electrophoretic mobility shift analysis and determined that in microglia, the p50/p65 heterodimer of NF-kappaB is activated by LPS stimulation, and is inhibited by MG132. Thus, blockade of NF-kappaB activation in microglia in vitro can decrease production of TNF-alpha and may prove to be a novel strategy for treating HIV-1 dementia.
 ...
PMID:Proteasome blockers inhibit TNF-alpha release by lipopolysaccharide stimulated macrophages and microglia: implications for HIV-1 dementia. 1022 15

The proteasome, an essential component of the ATP-dependent proteolytic pathway in eukaryotic cells, is responsible for the degradation of most cellular proteins and is believed to be the main source of MHC class I-restricted antigenic peptides for presentation to CTL. Inhibition of the proteasome by lactacystin or various peptide aldehydes can result in defective Ag presentation, and the pivotal role of the proteasome in Ag processing has become generally accepted. However, recent reports have challenged this observation. Here we examine the processing requirements of two HLA A*0201-restricted epitopes from HIV-1 reverse transcriptase and find that they are produced by different degradation pathways. Presentation of the C-terminal ILKEPVHGV epitope is impaired in ME275 melanoma cells by treatment with lactacystin, and is independent of expression of the IFN-gamma-inducible proteasome beta subunits LMP2 and LMP7. In contrast, both lactacystin treatment and expression of LMP7 induce the presentation of the N-terminal VIYQYMDDL epitope. Consistent with these observations we show that up-regulation of LMP7 by IFN-gamma enhances presentation of the VIYQYMDDL epitope. Hence interplay between constitutive and IFN-gamma-inducible beta-subunits of the proteasome can qualitatively influence Ag presentation. These observations may have relevance to the patterns of immunodominance during the natural course of viral infection.
 ...
PMID:IFN-gamma exposes a cryptic cytotoxic T lymphocyte epitope in HIV-1 reverse transcriptase. 1035 50


1 2 3 4 5 6 7 8 9 10 Next >>