Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By studying the infection of rhesus macaques with simian immunodeficiency virus (SIVmac) the potential of nucleic acid immunisation against AIDS can be evaluated. As a first step towards the development of suitable expression constructs, the levels and the durations of expression elicited by the house-keeping gene promoters of the murine phospho-glycerate kinase (PGK) gene and rat proto-ras 1Ha, a lentiviral LTR and the CMV-intron A promoter were tested in BALB/c mice intramuscularly inoculated with marker gene constructs encoding luciferase. The expression levels achieved by the CMV-intron A and the lentiviral promoter were comparably high, and also the PGK promoter induced a high level of expression for at least 64 days. Following the inoculation of plasmids comprising single or multiple genes of SIV, the induction of specific antibodies directed against SIV antigens was demonstrated. We previously showed in vitro that int- and nef-defective mutants of SIVmac were able to initiate a limited and self-abortive infection of permissive cells in the absence of chromosomal integration of the viral DNA. Intramuscular inoculations in monkeys using int-defective proviral DNA of SIV will show whether an increased immune response may be induced by expression of viruses undergoing a self-limited replication in vivo.
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PMID:Induction of antibodies against SIV antigens after intramuscular nucleic acid inoculation using complex expression constructs. 871 87

The demonstration that RNA can be cleaved by cis or trans ribozymes (catalytic RNAs, RNA enzymes) has potentially important therapeutic implications. Since their discovery in the 1980s, the biochemistry and conserved sequences of ribozymes have been well characterized. Ribozymes are effective modulators of gene expression because of their simple structure, sitespecific cleavage activity, and catalytic potential. The targets of ribozyme-mediated gene modulation have ranged from cancer cells to foreign genes that cause infectious diseases. Additional target sites for ribozymes are in initial phases of development and design. Ribozymes have been targeted against a myriad of genes, including oncogenes (ras, BCR-ABL, c-fos) and drug resistance genes, as well as the human immunodeficiency virus-type I genome. These ribozymes have cleaved the target RNAs in vitro and altered the cellular pathology. Currently, the therapeutic application of ribozymes to human diseases is limited by gene transfer systems. It is anticipated that ribozymes ultimately will play an important role in human gene therapy.
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PMID:Therapeutic applications of ribozymes. 871 70

The incidence of non-Hodgkin's lymphoma is greatly increased in human immunodeficiency virus (HIV)-infected individuals. Most are clinically aggressive B-cell lymphomas exhibiting Burkitt-type, immunoblastic or large-cell morphology. Approximately 80% arise systemically (nodal or extranodal), and the remaining 20% arise in the central nervous system. A small proportion are body cavity-based (primary effusion) lymphomas associated with Kaposi's sarcoma-associated herpesvirus (KSHV) infection. Possible factors contributing to lymphoma development include HIV-induced immunosuppression, chronic antigenic stimulation, and cytokine overproduction. These phenomena are associated with the development of oligoclonal B-cell expansions. The appearance of malignant lymphoma is characterized by the presence of a monoclonal B-cell population displaying a variety of genetic lesions including Epstein-Barr virus (EBV) infections, c-myc gene rearrangement, bcl-6 gene rearrangement, ras gene mutations, and p53 gene mutations/deletions. The number and type of genetic lesions varies according to anatomic site of origin and histopathology. In the case of Burkitt-type lymphoma, virtually 100% exhibit c-myc gene rearrangement, two thirds display p53 gene mutations, one third contain EBV, and none exhibit bcl-6 gene rearrangements. In contrast, in the case of immunoblastic lymphoma, virtually 100% contain EBV, 25% display c-myc gene rearrangements, 20% display bcl-6 gene rearrangements, and few exhibit p53 gene mutations. These findings suggest that more than one pathogenetic mechanism is operational in the development and progression of acquired immunodeficiency syndrome (AIDS)-related lymphoma. Further work is necessary to develop a thorough understanding of the origin and pathogenesis of malignant lymphoma in the setting of HIV infection. AIDS-related lymphoma remains an important biologic model for investigating the development and progression of high-grade non-Hodgkin lymphomas as well as malignant lymphomas that develop in immune-deficient hosts.
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PMID:Molecular pathology of acquired immunodeficiency syndrome-related non-Hodgkin's lymphoma. 904 11

We have previously reported that the human immunodeficiency virus type 1 (HIV-1) regulatory gene vpr induces differentiation of rhabdomyosarcoma (embryonal muscle tumor cell line) cells, an effect that is accompanied by reduced proliferative capacity of the transfected cells. In this report, we examine the effect of Vpr expression on several different tumor cell lines derived from unique lineages. These tumor cells display different patterns of modulated oncogenes including both ras and p53 mutations. Here we demonstrate that the growth of tumor cells in vitro and in vivo is arrested by the expression of HIV-1 Vpr. Expression of Vpr in several human tumor cell lines upon transfection resulted in an accumulation of cells in the G2/M phase of cell cycle with altered cellular morphology, including an increase in adherence, and growth arrest, consistent with a differentiated phenotype. Vpr expression in B78/H1 cells results in a marked reduction in colony formation in vitro and an associated reduction in melanin synthesis by the cells. Vpr-transfected melanoma cells inoculated into syngenic C57BL/6 mice showed a markedly reduced ability to form tumors in vivo. These results suggest that this retroviral regulatory gene has broad tumor suppressor effects, likely mediated by transcriptional regulation of the state of the host cell.
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PMID:In vitro and in vivo tumor growth suppression by HIV-1 Vpr. 905 34

Lymphocytes employ a complex assembly of signaling elements that have been organized on a spatiotemporal map to define their role in stimulating both proliferation and apoptosis. The antigen/major histocompatibility complex (MHC) initiates the sequence by organizing the assembly of an active T-cell receptor (TCR) complex responsible for transmitting information down various signaling cassettes (e.g., the IP3/Ca2+, DAG/PKC, ras/MAPK, and the PI 3-K pathways). It is proposed that CD28 may exert its costimulatory action by facilitating the assembly of an effective scaffold of signaling elements within the TCR complex. The absence of costimulation through CD28 seems to result in the assembly of a defective scaffold that reverses slowly and may thus account for the state of unresponsiveness responsible for peripheral T-cell tolerance. The signaling cassettes activated by the TCR and CD28 then engage cytosolic factors that transmit information into the nucleus to activate the genes that code for the IL-2 and Fas signaling pathways. The IL-2 and Fas receptors employ additional signaling cassettes (e.g., the JAK/STAT and the sphingomyelinase/ceramide pathways) to mediate their effects on proliferation and apoptosis, respectively. Information concerning these signaling systems is beginning to provide therapeutic strategies to manipulate the immune system to overcome human immunodeficiency virus (HIV) infection, autoimmune diseases, and graft rejection.
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PMID:Lymphocyte activation in health and disease. 909 51

A T-lymphoid cell line termed 221 was derived from a rhesus monkey infected with herpesvirus saimiri. Growth of 221 cells was dependent on the addition of interleukin-2 (IL-2) to the culture medium. In the absence of IL-2, 221 cells arrested in G0-G1 but did not die. Simian immunodeficiency virus (SIV) replicated efficiently in IL-2-stimulated 221 cells whether or not the nef gene was present. In the absence of IL-2, nef-containing SIV replicated 8 to 100 times more efficiently in 221 cells than did the same virus lacking nef. nef-containing virus preferentially stimulated the production of IL-2 from 221 cells. HIV-1 nef and v-ras genes, but not the c-ras gene, were shown to substitute functionally for SIV nef when tested as recombinant viruses in this assay system. These results demonstrate a role for natural nef in causing lymphoid cell activation, and they provide a system for delineating the biochemical mechanisms responsible for this activation.
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PMID:A role for natural simian immunodeficiency virus and human immunodeficiency virus type 1 nef alleles in lymphocyte activation. 922 3

A new virus named hepatitis G virus (HGV) has been detected recently. Until now, no assays for the detection of antibodies against different HGV proteins have been commercially available. Therefore, a strip immunoblot assay has been established to investigate seroreactivity against recombinant structural (core) and nonstructural proteins (NS3 and NS4) of HGV produced in Escherichia coli. Seropositivity for HGV was evaluated and concordanced with HGV polymerase chain reaction (PCR) results in 709 subjects. These individuals were classified into a nonrisk or a risk group, on the basis of infection with human immunodeficiency virus (HIV) or hepatitis C virus (HCV) or frequent parenteral exposure, including hemophilia, intravenous drug addiction, receipt of blood transfusion, or hemodialysis. The nonrisk group consisted of 257 healthy blood donors with normal alanine transaminase (ALT) levels (ALT < 30 U/L) and 154 patients with suspected non-A-E hepatitis (ALT > 45 U/L). In the group of healthy blood donors, 1.9% (5 of 257) had detectable HGV viremia and 15.9% (41 of 257) showed antibody response to HGV. In the collective of patients with suspected non-A-E hepatitis, results from 1.9% of patients (3 of 154) were positive by HGV PCR, and 15.6% of patients (24 of 154) showed seropositivity against the recombinant HGV proteins. In six groups of patients (n = 298) with different risk factors, the prevalence of both HGV viremia (V) and serological reactivity (SR) was higher compared with that of the nonrisk group: V, 6.80%-35.2%; serological reactivity (SR), 25.4%-52.9%. The following conclusions can be derived from our data. HGV infection is widespread in the general population. The prevalence of antibodies against HGV or detectable HGV viremia is higher in patients with risk factors for parenteral viral transmission than in those without risk factors. The majority of HGV infections (70.2%) is self-limiting and not persistent in our collective of patients. We found no correlation between HGV viremia and clinical or biochemical signs of hepatitis in individuals without risk factors for acquiring parenterally transmitted agents.
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PMID:Distribution of hepatitis G viremia and antibody response to recombinant proteins with special regard to risk factors in 709 patients. 925 64

CD4 molecules are the primary receptors for human immunodeficiency virus (HIV) and bind the envelope glycoprotein gp120 of HIV with high-affinity. We have previously shown that cross-linking of CD4 molecules (CD4XL) in normal peripheral blood mononuclear cells (PBMC) results in secretion of cytokines tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma), but not of interleukin-2 (IL-2) or IL-4. To investigate the intracellular signaling events associated with CD4-gp120 interaction, we incubated CD4+ T cells from peripheral blood of HIV-negative healthy donors with HIV envelope protein gp160 alone or performed CD4XL with gp160 and anti-gp160 antibody. This procedure resulted in tyrosine phosphorylation of intracellular substrates p59fyn, zap 70, and p95vav and also led to ras activation, as assessed by conversion of rasGDP to rasGTP. The role of ras in CD4 signaling was further investigated using CD4+ Jurkat cells transfected with a dominant negative ras mutant. CD4+ T cells expressing dn-ras secreted significantly reduced levels of TNF-alpha in response to CD4XL. These studies indicate that interaction of HIV gp160 with CD4 molecules activates the ras pathway in T cells, which may result in the cells becoming unresponsive to subsequent stimulation.
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PMID:CD4 cross-linking (CD4XL) induces RAS activation and tumor necrosis factor-alpha secretion in CD4+ T cells. 926 77

Identifying infectious organisms, quantitating gene expression, and sequencing genomic DNA on chips all rely on the detection of nucleic acid hybridization. Described here is a novel assay for detection of the hybridization of products of the polymerase chain reaction using electron transfer from guanine to a transition-metal complex. The hybridization assay was modeled in solution by monitoring the cyclic voltammetry of Ru(bpy)3(2+) (bpy = 2,2'-bipyridine) in the presence of a probe strand containing only A, T, and C prior to and after hybridization to a complement that contained seven guanines, which led to high catalytic current due to the oxidation of guanine by Ru(bpy)3(3+). To allow recognition of all four bases in the target sequence, it was shown that inosine 5'-monophosphate was 3 orders of magnitude less reactive than guanosine 5'-monophosphate, suggesting that effective hybridization sensors could be realized by immobilization of probe strands in which inosine was substituted for guanosine; hybridization to guanosine-containing target strands would then provide high catalytic currents. A sensor design was tested in a model system for the detection of a synthetic 21-mer oligonucleotide patterned on the sequence of the ras oncogene, which gave an increase in charge collected of 35 +/- 5 microC after hybridization and of only 8 +/- 5 microC after exposure to noncomplementary DNA. Independent quantitation of probe and target by radiolabeling showed that the hybridized electrode contained 3.0 +/- 0.3 ng of target. New sensor electrodes were then prepared for the detection of PCR-amplified genomic DNA from herpes simplex virus type II, genomic DNA from Clostridium perfringens, and genomic RNA from human immunodeficiency virus and gave an additional charge of 35-65 microC for hybridization to complementary amplicon and of only 2-10 microC after exposure to noncomplementary DNA.
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PMID:Probing biomolecule recognition with electron transfer: electrochemical sensors for DNA hybridization. 940 65

Ribozymes are catalytic RNA molecules that recognize their target RNA in a highly sequence-specific manner. They can therefore be used to inhibit deleterious gene expression (by cleavage of the target mRNA) or even repair mutant cellular RNAs. Targets such as the mRNAs of oncogenes (resulting from base mutations or chromosome translocations, eg, ras or bcr-abl) and viral genomes and transcripts (human immunodeficiency virus-type 1 [HIV-1]) are ideal targets for such sequence-specific agents. The aim of this review is therefore to introduce the different classes of ribozymes, highlighting some of the chemistry of the reactions they catalyze, to address the specific inhibition of genes by ribozymes, the problems yet to be resolved, and how new developments in the field give hope to the future for ribozymes in the therapeutic field.
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PMID:The therapeutic potential of ribozymes. 942 89


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