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)

The tumor suppressor protein p53 plays a critical role in the maintenance of genetic integrity. p53 possesses 3'-->5' exonuclease activity, however, the significance of this function in DNA replication process remains elusive. It was suggested that 3'-->5' exonuclease activity of p53 may provide a proofreading function for DNA polymerases. In order to better understand the significance of this activity, the purified wild-type recombinant p53 was further evaluated for substrate specificity and for contribution to the accuracy of DNA synthesis. p53-associated 3'-->5' exonuclease displays 3' terminal nucleotide excision from RNA/DNA template-primer using ribosomal RNA as a template. The data demonstrate that p53 is highly efficient in removing a terminal mispair. Analysis of mispair excision opposite the template adenine residue shows that p53 catalyzes 3' terminal mismatch excision with a specificity of A : G>A : A>A : C. Hence, the observed specificity of mismatch excision indicates that p53 exonucleolytic proofreading preferentially repairs transversion mutations. The influence of the p53 on the accuracy of DNA synthesis was determined with exonuclease-deficient human immunodeficiency virus-1 (HIV-1) reverse transcriptase (RT), a key enzyme in the life cycle of the virus, that contributes significantly to the low accuracy of proviral DNA synthesis. Using an in vitro biochemical assay with recombinant purified HIV-1 RT, p53 and defined RNA/DNA or DNA/DNA template-primers, two basic features related to fidelity of DNA synthesis were studied: the misinsertion and mispair extension. The misincorporation of non-complementary deoxynucleotides into nascent DNA and subsequent mispair extension by HIV-1 RT were substantially decreased in the presence of p53 with both RNA/DNA and DNA/DNA template-primers. In addition, the productive interaction between polymerization (by HIV-1 RT) and exonuclease (by p53) activities was observed; p53 preferentially hydrolyzes mispaired 3'-termini, permitting subsequent extension of the correctly paired 3'-terminus by HIV-1 RT. Taken together the data demonstrate that preferential excision of mismatched nucleotides by 3'-->5' exonuclease activity of wild-type p53 enhances the fidelity of DNA synthesis by HIV-1 RT in vitro, thus providing a biochemical mechanism to reduce mutations caused by incorporation of mismatched nucleotides. The fact that p53 is reactive with both RNA/DNA and DNA/DNA template-primers raises an interesting possibility of the existence of functional cooperation between p53 and HIV-1 RT in cytoplasm during the reverse transcription process, which may be important for maintaining HIV genomic integrity.
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PMID:p53 enhances the fidelity of DNA synthesis by human immunodeficiency virus type 1 reverse transcriptase. 1175 41

Pigtailed macaques infected with a virulent human immunodeficiency virus-2 (HIV-2) strain develop renal thrombotic microangiopathy (TMA), which morphologically resembles aspects of human HIV-associated TMA. Apoptotic cell death of microvascular endothelial cells might be a pathogenetic clue to this disease. For defining further the pattern of cellular injury in this model, serial kidney sections of 58 macaques infected with HIV-2 and 7 uninfected controls were studied by routine microscopy, terminal deoxynucleotidyl-transferase-mediated dUTP nick-end labeling (TUNEL), 4',6-diamidino-2-phenylindole staining, and immunohistochemistry for single-stranded DNA, p53, the Wilms' tumor suppressor gene-1 peptide product, caspase-3, and the proliferation marker Ki67. Selected cases were further evaluated by in situ end labeling and transmission electron microscopy. Kidneys of 13 HIV-2-infected animals contained a pattern of cellular injury, which was characterized by (1) nuclear swelling with an ultrastructural morphology different from apoptotic nuclei, (2) sharply demarcated areas of renal cells with chromatin nicks (TUNEL positive) and single-stranded DNA, (3) absence of an inflammatory or proliferative response, (4) upregulation of p53 and loss of at least one cellular differentiation marker (Wilms' tumor suppressor gene-1), (5) a tight correlation with the diagnosis of renal TMA, and (6) a contrast between profound changes in the renal cellular morphology and the apparently unaffected clinical condition of the host. This pattern of injury, which shares some features of both apoptotic and oncotic necrosis, might be involved in the pathogenesis of HIV-associated renal TMA in this model.
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PMID:Cellular injury associated with renal thrombotic microangiopathy in human immunodeficiency virus-infected macaques. 1180 64

The HIV epidemic in the Asian subcontinent has a significant impact on India. Patients with AIDS have an increased risk of developing non-Hodgkin lymphoma (NHL). In this study, we have investigated the pattern of distribution of lymphoid neoplasms and also studied the Epstein-Barr virus (EBV)-association and p53 expression in 35 HIV-positive patients from India. The biopsy samples were studied for histology and for expression of CD20, CD3, CD15, CD30, light chains, CD138, bcl-6, epithelial membrane antigen, EBV-latent membrane protein-1, and p53 protein. In situ hybridization was performed with digoxigenin-labeled anti-sense EBV-encoded nuclear RNA-1 (EBER-1) probe. Polymerase chain reaction (PCR) was performed on DNA extracted from paraffin sections for EBV-subtype analysis. The 35 cases included 7 cases of Hodgkin disease (HD), 4 cases of plasmacytoma (PL), and 24 cases of NHL. Among the cases of NHL, 3 were Burkitt lymphoma (BL), 4 were diffuse large B-cell lymphoma (DLBL) of centroblastic type (CBL), 10 were DLBL of immunoblastic type (IBL), 4 were high-grade B-cell lymphoma (unspecified) and the rest were other subtypes. EBV-association was noted in all cases of HD, 2 of 3 BL, and 3 of 10 IBL. PCR analysis of the EBNA-3C gene revealed amplimers corresponding to type A. A p53 protein overexpression was noted in 6 of 10 IBLs, 1 of 3 BLs, 2 of 3 CBLs, and 5 of 7 cases of HD. This is the first reported study of lymphoid malignancies in HIV-positive individuals from India.
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PMID:Lymphoid neoplasms in HIV-positive individuals in India. 1183 89

The nef gene product of human immunodeficiency virus type 1 (HIV-1) is important for the induction of AIDS, and key to its function is its ability to manipulate T-cell function by targeting cellular signal transduction proteins. We reported that Nef coprecipitates a multiprotein complex from cells which contains tumor suppressor protein p53. We now show that Nef interacts directly with p53. Binding assays showed that an N-terminal, 57-residue fragment of Nef (Nef 1-57) contains the p53-binding domain. Nef also interacted with p53 during HIV-1 infection in vitro. As p53 plays a critical role in the regulation of apoptosis, we hypothesized that Nef may alter this process. Nef inhibited UV light-induced, p53-dependent apoptosis in MOLT-4 cells, with Nef 1-57 being as effective as its full-length counterpart. The inhibition by Nef of p53 apoptotic function is most likely due its observed ability to decrease p53 protein half-life and, consequently, p53 DNA binding activity and transcriptional activation. These data show that HIV-1 Nef may augment HIV replication by prolonging the viability of infected cells by blocking p53-mediated apoptosis.
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PMID:Human immunodeficiency virus type 1 Nef binds to tumor suppressor p53 and protects cells against p53-mediated apoptosis. 1186 36

Infection with human immunodeficiency virus type 1 (HIV-1) is associated with dramatic depletion of CD4(+) T cells, the major HIV-1-induced pathogenesis. Apoptosis has been suggested to play an important role for the T cell depletion and a number of mechanisms have been proposed for the apoptosis in T cells. Here, we compared the levels for apoptosis induction in primary peripheral blood mononuclear cells (PBMCs) among several laboratory strains and primary isolates of the HIV-1 subtypes B and E. The results showed that apoptosis in infected PBMCs, preferentially in CD4+ T cell population, became detectable around the time for virus production by flow cytometric terminal transferase dUTP nick end labeling (TUNEL) technique and staining with the nuclear dye Hoechst 33342. The abilities to induce apoptosis in PBMCs were highly variable in individual isolates. The increase of p53 protein in infected PBMCs, which was initiated before virus production, was observed in infected PBMCs and the levels of p53 protein were almost proportional to the rates of the isolates to induced apoptosis. The cells infected and cultured in the presence of Z-VAD-FMK had significantly decreased cell mortalities, indicating that activated caspases also played a significant role in the apoptosis. Thus, HIV-1-induced apoptosis in primary T cells was accompanied by the p53 protein and caspase activation at varied levels in primary isolates.
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PMID:Ability to induce p53 and caspase-mediated apoptosis in primary CD4+ T cells is variable among primary isolates of human immunodeficiency virus type 1. 1195 87

Immunization with wild-type sequence (wt) p53 epitopes represents a novel therapeutic strategy for cancer patients with tumors accumulating mutant p53. To evaluate usefulness of p53-derived peptides as future cancer vaccines, frequencies of wt p53(264-272) peptide-specific CD8+ T cells were determined in the peripheral circulation of patients with squamous cell carcinoma of the head and neck (SCCHN). T cells of 30 HLA-A2.1+ patients and 31 HLA-A2.1+ healthy individuals were evaluated by multicolor flow cytometry analysis using peptide-HLA-A2.1 complexes (tetramers). T cells specific for an influenza matrix peptide (a model recall antigen) or an HIV reverse transcriptase peptide (a model novel antigen) were studied in parallel. Patients with SCCHN had a significantly higher mean frequency of CD8+ T cells specific for wt p53(264-272) than normal donors (P = 0.0041). Surprisingly, the frequency of epitope-specific T cells in the circulation of patients did not correlate with p53 accumulation in the tumor. In patients whose tumors had normal p53 expression or had p53 gene mutations preventing presentation of this epitope, high frequencies of wt p53(264-272)-specific CD8+ T cells were found, of which many were memory T cells. In contrast, patients whose tumors accumulated p53 had low frequencies of wt p53(264-272)-specific CD8+ T cells, which predominantly had a naive phenotype and were unable to proliferate ex vivo in response to the epitope, as reported by us previously (T. K. Hoffmann, J. Immunol., 165: 5938-5944, 2000). This seemingly contradictory relationship between the high frequency of epitope-specific T cells and wt p53 expression in the tumor suggests that other factors may contribute to the observed anti-p53 responses. Human papillomavirus-16 E6/E7 expression is common in SCCHN, and E6 is known to promote presentation of wt p53 epitopes. Although human papillomavirus-16 E6/E7 expression was detected in 46% of the tumors, it did not correlate with the frequency of wt p53(264-272)-specific CD8+ T cells or with p53 expression in the tumor. These findings emphasize the complexity of interactions between the tumor and the host immune system, and, thus, have particularly important implications for future p53-based immunization strategies.
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PMID:Frequencies of tetramer+ T cells specific for the wild-type sequence p53(264-272) peptide in the circulation of patients with head and neck cancer. 1206 99

The targeted delivery of genes whose products arrest the cell cycle and/or induce apoptosis represent an important tool for the understanding and controlling forms of unregulated cell growth. The vpr gene product of HIV-1 has been reported to interfere with cell growth and induce apoptosis, but the mechanism of its action is not clearly understood. In order to study these important properties of Vpr, we created a recombinant adenovirus H5.010CMV-vpr (adCMV-vpr) as a tool to deliver the vpr gene to various cell lines to examine its biology. Vpr protein expression was confirmed by Western blot analysis in adCMV-vpr infected cells. We tested the effects of adCMV-vpr on cell growth of several tumor cell lines. Infection of both p53 positive and p53 deficient tumor cell lines with adCMV-vpr resulted in dramatic induction of cell death in short-term assays. We observed that apoptosis was induced through the mitochondrial pathway as we observed changes in the cytochrome c content accompanied by caspase 9 activation. As Bcl-2 is reported to interfere with apoptosis through the mitochondrial pathway, we examined the effect of adCMV-vpr in Bcl-2 over expressing cell lines. We observed that Bcl-2 overexpression does not inhibit adCMV-vpr induced apoptosis. The properties of adCMV-vpr inducing apoptosis through caspase 9 in a p53 pathway independent manner suggest that this is an important reagent. Such a vector may give insight into approaches designed to limit the growth of pathogenic human cells.
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PMID:Adenovirus encoding HIV-1 Vpr activates caspase 9 and induces apoptotic cell death in both p53 positive and negative human tumor cell lines. 1209 38

Potent and safe vaccinia virus vectors inducing cell-mediated immunity are needed for clinical use. Replicating vaccinia viruses generally induce strong cell-mediated immunity; however, they may have severe adverse effects. As a vector for clinical use, we assessed the defective vaccinia virus system, in which deletion of an essential gene blocks viral replication, resulting in an infectious virus that does not multiply in the host. The vaccinia virus Lister/Elstree strain, used during worldwide smallpox eradication, was chosen as the parental virus. The immunogenicity and safety of the defective vaccinia virus Lister were evaluated without and with the inserted human p53 gene as a model and compared to parallel constructs based on modified vaccinia virus Ankara (MVA), the present "gold standard" of recombinant vaccinia viruses in clinical development. The defective viruses induced an efficient Th1-type immune response. Antibody and cytotoxic-T-cell responses were comparable to those induced by MVA. Safety of the defective Lister constructs could be demonstrated in vitro in cell culture as well as in vivo in immunodeficient SCID mice. Similar to MVA, the defective viruses were tolerated at doses four orders of magnitude higher than those of the wild-type Lister strain. While current nonreplicating vectors are produced mainly in primary chicken cells, defective vaccinia virus is produced in a permanent safety-tested cell line. Vaccines based on this system have the additional advantage of enhanced product safety. Therefore, a vector system was made which promises to be a valuable tool not only for immunotherapy for diseases such as cancer, human immunodeficiency virus infection, or malaria but also as a basis for a safer smallpox vaccine.
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PMID:Immunogenicity and safety of defective vaccinia virus lister: comparison with modified vaccinia virus Ankara. 1209 85

A retrospective study was performed to characterize malignant lymphomas of 16 Simian immunodeficiency virus (SIV)-infected rhesus monkeys (Macaca mulatta), 2-9 years of age, on the basis of clinical data, histologic and immunophenotypic results, and cell death indices compiled with the TdT-mediated X-duTP nick end labeling method. We particularly focused on providing immunohistochemical evidence of expression products of EBNA2, Bc12, c-Myc, P21, P53, and Bc16. Results were compared with data from the literature on human HIV-associated lymphomas. According to the updated Kiel classification, the lymphomas were classified as 11 centroblastic lymphomas, three immunoblastic lymphomas, one Burkitt-like lymphoma, and one immunocytoma. Using antibodies to CD20, the B-cell origin of tumor cells was demonstrated. SIV antigen was not demonstrated in the tumor cells. Infection with rhesus lymphocryptovirus was present in 94% of the monkeys. Lymphomas revealed expression of Bc12 in 15/16 (94%), c-Myc in 14/16 (88%), P21 in 10/ 16 (63%), P53 in 12/16 (75%), and Bc16 in 1/16 (6%) monkeys. This study provided evidence that the expression of these gene products, which are thought to play an important role in cell proliferation and apoptosis in HIV- and non-HIV-associated lymphomas, are also involved in the pathogenesis of lymphomas in SIV-infected rhesus monkeys. A tentative relationship between the described gene products and the cell death indices was established for the expression of Bc12. The present primate model represents a suitable animal model for studying the pathogenesis of AIDS-associated lymphomas.
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PMID:SIV-associated lymphomas in rhesus monkeys (Macaca mulatta) in comparison with HIV-associated lymphomas. 1210 18

Precursor lesions in the GIT include flat dysplasias, adenomas, dysplasia superimposed on nonneoplastic polyps, endocrine cell dysplasia, ACF, and condyloma accuminatum. Interobserver variability can be a problem in reporting dysplasia, and ancillary techniques including flow cytometry, image analysis, proliferation markers, and examination for p53 expression can help in this task. Squamous dysplasia seen in the esophagus and anus is graded on either a two-tiered or three-tiered system largely based on the extent of mucosal involvement. Glandular dysplasia is morphologically similar whether seen as an adenomatous polyp or within the setting of Barrett's esophagus, atrophic gastritis, or idiopathic inflammatory bowel disease. The distinction between LGD and HGD in glandular mucosa is based on the severity of cytologic and architectural distortion. Type I dysplasia is the classic adenomatous pattern seen most commonly and recognized by the presence of elongate hyperchromatic stratified nuclei. Type II, the nonadenomatous variant, contains vesicular nuclei and alteration in nuclear size and shape. Nonantral endocrine dysplasia in the stomach is seen in the setting of corporal predominant atrophic chronic gastritis and Zollinger-Ellison syndrome with Multiple Endocrine Neoplasia syndrome type I. Condyloma accuminatum is a HPV-related lesion most commonly seen in men practicing anal intercourse. Superimposed squamous dysplasia can be seen with HGD most frequently in the HIV-positive population. Recognition of the different classification systems of dysplasia, the most frequent settings in which these lesions are found, and their natural history is important for all practicing gastroenterologists and pathologists.
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PMID:Histologic precursors of gastrointestinal tract malignancy. 1213 10


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