UMLS:C0019693 - FACTA Search

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

Monoclonal antibodies (MAbs) that bind linear or conformational epitopes on monomeric or oligomeric human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins were screened for their recognition of maturational intermediates. On the basis of reactivities with gp160 at different times after pulse-labeling, the MAbs were sorted into groups that exhibited binding which was immediate and constant, immediate but transient, delayed, late, or very late. This grouping was consistent with the selectivity of the MAbs for structural features of gp160. Thus, a MAb to the V3 loop reacted with envelope proteins at all times, in accord with the relative conformational independence and accessibility of the epitope. Several MAbs that preferentially react with monomeric gp160 exhibited diminished binding after the pulse. A 10-min tag occurred before gp160 reacted with conformational MAbs that inhibited CD4 binding. The availability of epitopes for other conformational MAbs, including some that react equally with monomeric and oligomeric gp160 and some that react better with oligomeric forms, was half-maximal in 30 min and closely followed the kinetics of gp160 oligomerization. Remarkably, there was a 1- to 2-h delay before gp160 reacted with stringent oligomer-specific MAbs. After 4 h, approximately 20% of the gp160 was recognized by these MAbs. Epitopes recognized by monomerspecific or CD4-blocking MAbs but not by oligomer-dependent MAbs were present on gp160 molecules associated with the molecular chaperone BiP/GRP78. MAbs with a preference for monomers reacted with recombinant or HIV-1 envelope proteins in the endoplasmic reticulum, whereas the oligomer-specific MAbs recognized them in the Golgi complex. Additional information regarding gp160 maturation and intracellular trafficking was obtained by using brefeldin A, dithiothreitol, and a low temperature.
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PMID:Folding, assembly, and intracellular trafficking of the human immunodeficiency virus type 1 envelope glycoprotein analyzed with monoclonal antibodies recognizing maturational intermediates. 864 72

The HIV-1 Vpu protein induces the proteolysis of CD4 in the endoplasmic reticulum (ER) and enhances the release of virus particles from the plasma membrane. The two biological activities of HIV-1 Vpu appear to be reconstituted in distinct membrane compartments of the mammalian cell. We carried out experiments to understand the role of Vpu sequences in membrane trafficking of the Vpu protein and to gain insights into Vpu-mediated proteolytic reactions. To this end, we generated CD4/Vpu hybrid proteins and analyzed their biochemical and biological properties in HeLa cells. We show here that all hybrid proteins are delivered to the plasma membrane undergoing endo-H-resistant modifications in the Golgi complex. Importantly, a hybrid protein bearing the CD4 extracellular domain and full-length Vpu induced the degradation of HIV envelope glycoproteins bearing the transmembrane and cytoplasmic domains of CD4 (Vpu-responsive elements, VRE). Glycoproteins lacking the VRE are stable under these conditions. In addition, a hybrid protein having the extracellular-transmembrane domains of CD4 and the Vpu cytoplasmic domain was only partially active in inducing the degradation of Vpu-sensitive proteins. These results suggest that the Vpu transmembrane domain is capable of regulating Vpu activity in the cell. Mutational studies have further demonstrated that casein kinase-2 phosphorylation is critically important in the degradation reaction, but does not regulate membrane trafficking of the CD4/Vpu hybrid proteins. We also show that the CD4 extracellular domain appended to the Vpu protein is protected from degradation while existing in a complex with Vpu-sensitive ectodomains. Taken together, these studies have revealed that the Vpu protein does not possess sequences that have the ability to sequester CD4 in the intracellular compartments of mammalian cells and that the Vpu protein tethered to the CD4 extracellular domain was biologically active in inducing the degradation of VRE-bearing glycoproteins in the ER.
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PMID:The human immunodeficiency virus type 1 Vpu protein tethered to the CD4 extracellular domain is localized to the plasma membrane and is biologically active in the secretory pathway of mammalian cells: implications for the mechanisms of Vpu function. 865 6

Formation of CD4-gp160 intracellular complexes represents an important mechanism leading to the induction of receptor interference. Previous studies have demonstrated that cells coexpressing gp160 and CD4 formed complexes of CD4 and gp160 which became blocked within the endoplasmic reticulum (ER), preventing CD4 from reaching the cell surface. In this report we have investigated the domains and residues of CD4 and gp160 involved in intracellular interaction. Accordingly, we have introduced mutations in both CD4 and gp160 at sites previously shown to disrupt CD4-gp120 interactions at the cell surface. Using a T7-vaccinia virus transient expression system, we expressed these gp160 and CD4 mutants in HeLa cells and analyzed their effects on intracellular complex formation and CD4 surface modulation. We observed that a number of gp160 mutants which failed to interact with CD4 at the cell surface also failed to bind and trap CD4 within the ER as expected. However, mutations at a critical residue, W427, did not abrogate intracellular CD4 binding. These gp160 mutants continued to interact with intracellular CD4 and inhibit CD4 transport to the cell surface, although gp120 produced from these mutants did not bind CD4 at the cell surface as expected. A number CD4 mutants also continued to form intracellular complexes with gp160, resulting in the loss of CD4 surface expression. Again, these CD4 mutants did not bind to gp120 at the cell surface, consistent with earlier reports. These results demonstrate that intracellular interactions between gp160 and CD4 in the ER may utilize different contact sites compared to those used during CD4 and gp120 binding at the cell surface. The data provide further evidence that the environment in which CD4 and the HIV-1 envelope glycoprotein interact can have a significant effect on their interaction.
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PMID:Mutational analysis of HIV-1 gp160-mediated receptor interference: intracellular complex formation. 866 96

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 HIV-1-specific Vpu protein is an 81 amino acid class I integral membrane phosphoprotein that induces degradation of the virus receptor CD4 in the endoplasmic reticulum and enhances the release of virus particles from infected cells. Vpu is of amphipathic nature and consists of a hydrophobic N-terminal membrane anchor proximal to a polar C-terminal cytoplasmic domain. In our recent work, focussed on the structural analysis of the cytoplasmic tail, we established an alpha-helix-flexible-alpha-helix-turn model. Now we present the experimental solution structure of the Vpu cytoplasmic domain which has been elucidated in aqueous 50% trifluoroethanol solution by 2D 1H NMR spectroscopy, and restrained molecular dynamics and energy minimization calculations. Under these conditions the peptide, Vpu32-81, is predominantly monomeric and adopts a well defined helix-interconnection-helix-turn conformation, in which the four regions are bounded by residues 37-51, 52-56, 57-72 and 73-78. The presence of the cis isomer of Pro-75 manifests itself as a doubling of cross peaks of neighbouring residues in the 2D spectra. A related variant peptide, Vpum32-81, in which the Vpu-phosphoacceptor sites Ser52 and Ser56 were exchanged for Asn, adopts a very similar structure and, taken together, provides evidence that the second helix and the turn form a comparatively rigid region. Both helices are amphipathic in character, but show different charge distributions. In general the cytoplasmic region is N-terminally positively charged, passes through a region of alternating charges in helix 1 and then becomes negatively charged. The flexibility of the interconnection permits orientational freedom of the two helices. The motif found here is the first experimentally refined solution structure of the cytoplasmic domain of Vpu, and it is conceivable that these alpha-helices are important for a previously defined physical interaction with an alpha-helical Vpu-responsive element located within the cytoplasmic tail of CD4.
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PMID:Solution structure of the cytoplasmic domain of the human immunodeficiency virus type 1 encoded virus protein U (Vpu). 873 56

Delivery of genetic expression constructs into living animals can effectively induce both humoral and cellular immunity to the expressed proteins. Here we test the effectiveness of genetic immunization with a minigene coding for single epitopes derived from mutant p53 or from HIV gp120. We show that when these constructs are delivered by particle bombardment-mediated DNA transfer into the skin of mice, it results in efficient induction of tumor protective CTL. The immunogenicity of the epitope derived from mutant p53 is significantly enhanced if the epitope sequence is fused in frame with the adenovirus E3 leader sequence to target the epitope to the endoplasmic reticulum, thus acting like a "genetic adjuvant." We conclude that genetic T cell epitope immunization is an alternative to peptide-based techniques for eliciting an effective immune response targeted against a single defined epitope. in some cases, the fusion of the gene product of the DNA vaccine vector with an endoplasmic reticulum targeting sequence may enhance immune induction.
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PMID:Induction of cytotoxic T lymphocytes and antitumor immunity with DNA vaccines expressing single T cell epitopes. 878 93

The HIV-1 envelope glycoprotein gp120 displays inefficient intracellular transport, which is caused by its retention in the endoplasmic reticulum. Coexpression in insect cells (Sf9) of HIV-1 gp120 with calnexin has shown that their interaction was modulated by the signal sequence of HIV-1 gp120. gp120, with its natural signal sequence, showed a prolonged association with calnexin with a t1/2 of greater than 20 min. Replacement of the natural signal sequence with the signal sequence from mellitin led to a decreased time of association of gp120 with calnexin (t1/2 < 10 min). These different times of calnexin association coincided both with the folding of gp120 as measured by the ability of bind CD4 and with endoplasmic reticulum to Golgi transport as analyzed by the acquisition of partial endoglycosidase H resistance. Using a monospecific antibody to the HIV-1 gp120 natural signal peptide, we showed that calnexin associated with N-glycosylated but uncleaved gp120. Only after dissociation from calnexin was gp120 cleaved, but very inefficiently. Only the small proportion of signal-cleaved gp120 molecules acquired transport competence and were secreted. This is the first report demonstrating the effect of the signal sequence on calnexin association.
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PMID:Effects of inefficient cleavage of the signal sequence of HIV-1 gp 120 on its association with calnexin, folding, and intracellular transport. 879 Mar 77

The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) plays a major role in the down-regulation of its receptor, CD4. This down-regulation, at least in part, is caused by the formation of gp160-CD4 intracellular complexes which fail to transport out of the endoplasmic reticulum (ER). In this report, we have evaluated the ability of envelope glycoproteins from various isolates to block CD4 transport within the endoplasmic reticulum. Using a recombinant vaccinia virus expression system in HeLa cells, we expressed different HIV-1 and HIV-2 envelope glycoproteins with CD4. Pulse-chase labeling followed by immunoprecipitation demonstrated that envelope glycoproteins from primary and lab-adapted isolates were capable of forming intracellular complexes with CD4, resulting in the partial inhibition of CD4 transport to the Golgi. Although the efficiency of CD4 modulation was variable, these differences did not correlate with the type of isolate from which the HIV-1 glycoprotein was derived. However, we did find that the HIV-2 ST envelope glycoprotein (gp150) was not as efficient at blocking CD4 as the glycoprotein (gp140) derived from HIV-2 ROD. The decreased ability of ST gp150 to block CD4 within the ER was associated with an increased efficiency of ST gp150 transport and cleavage. Thus, differences in the ability of HIV envelope glycoproteins to block CD4 transport do exist, and these differences may be determined by envelope glycoprotein transport kinetics.
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PMID:Receptor interference mediated by the envelope glycoproteins of various HIV-1 and HIV-2 isolates. 889 48

Perbutylated-N-butyl-1-deoxynojiromycin (p-N-butyl-DNJ, SC-49483), an alpha-glucosidase-1 inhibitor, is a candidate anti-HIV agent targeted against viral glycoprotein processing in host cell endoplasmic reticulum. The potential toxicity of this compound was evaluated in Sprague-Dawley rats after 4, 13, or 26 wk of oral administration at doses ranging from 300 to 3,670 mg/kg/day. In these studies, the target organs of p-N-butyl-DNJ effects were thyroid gland, salivary gland, stomach, and pancreas. The most prominent histologic change in these organs was the presence of clear or lightly eosinophilic vacuoles in the cytoplasm of thyroid follicular cells, gastric chief cells, salivary gland acinar cells, and exocrine pancreatic acinar cells. Ultrastructurally, these vacuoles were consistent with dilated rough endoplasmic reticulum, which sometimes contained homogeneously stained, moderately electron-dense material. The vacuoles in thyroid follicular cells contained pale eosinophilic colloidlike material consistent with accumulated thyroglobulin, as shown by immunohistochemical staining methods. The biological functions of these organs were not adversely affected as evidenced by the absence of clinical signs and the results of selected hormonal analyses. The morphologic changes were completely reversed after a 4-wk recovery period. The incidence and severity of histologic changes were decreased after 13 and 26 wk of treatment compared to 4 wk of treatment, indicating an attenuation of the host response or adaptation to the prolonged p-N-butyl-DNJ administration. We believe that morphologic changes in thyroid follicular cells, salivary gland acinar cells, pancreatic acinar cells, and gastric chief cells were the result of nonspecific inhibition of host alpha-glucosidase(s) by p-N-butyl-DNJ, causing clinically silent perturbation in host cell glycoprotein processing and/or glycoprotein transport.
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PMID:Pathology of perbutylated-N-butyl-1-deoxynojiromycin (an alpha-glucosidase-1 inhibitor) in Sprague-Dawley rats. 892 73

HIV-1 Vpu catalyzes two independent functions, degradation of the virus receptor CD4 in the endoplasmic reticulum and enhancement of virus release from the cell surface. These activities are confined to distinct structural domains of Vpu, the cytoplasmic tail and the transmembrane (TM) anchor, respectively. It was recently reported that Vpu forms cation-selective ion channels in lipid bilayers. Here we report that this property of Vpu is a characteristic of its TM anchor. Expression of full-length Vpu in Xenopus oocytes increases membrane conductance. The Vpu-induced conductance is selective to monovalent cations over anions, does not discriminate Na+ over K+ and shows marginal permeability to divalent cations. Notably, introduction of the scrambled TM sequence into full-length Vpu abrogates its capacity to increase membrane conductance in oocytes and to promote virus release from infected cells. Reconstitution of synthetic Vpu fragments in lipid bilayers identified an ion channel activity for a sequence corresponding to the TM domain of Vpu. In contrast, a peptide with the same amino acid composition but with a scrambled sequence does not form ion channels. Our findings therefore suggest that the ability of Vpu to increase virus release from infected cells may be correlated with an ion channel activity of the TM domain, thereby providing a potential target for drug intervention based on the development of Vpu-specific channel blockers.
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PMID:Identification of an ion channel activity of the Vpu transmembrane domain and its involvement in the regulation of virus release from HIV-1-infected cells. 894 45

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