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

Whether or not Japanese encephalitis virus (JEV) is an important causative agent of acute encephalitis in Cambodia remains unclear. This study was carried out to determine the cause of encephalitis syndrome among children and adults admitted to Takeo Provincial Hospital from October 1999 to September 2000. Ninety-nine cases were included in the study: 52 pediatric cases (12 were fatal) and 47 adult cases (10 were fatal). A causative agent such as human herpesvirus (HHV-3 or HHV-4), Cryptococcus neoformans, or Mycobacterium tuberculosis had been identified in 8 of the 11 adults who had human immunodeficiency virus type 1 (HIV-1). An infectious agent was identified in 35 (40%) of 88 HIV-1-seronegative patients (60% of the causes remains unidentified). These comprised 11 bacterial infections, 1 fungal infection, and 23 viral infections. The viral infections were 1 fatal HHV-4 infection, 5 dengue virus infections (2 fatal), 1 coinfection with flavivirus and alphavirus, and 16 presumptive infections JEV (no virus detected), one case of which was fatal. Infection with JEV, the principal cause identified in the 99 encephalitis syndromes, concerned 16 (31%) of 52 children.
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PMID:Etiology of encephalitis syndrome among hospitalized children and adults in Takeo, Cambodia, 1999-2000. 1213 94

Despite spectacular progress in the eradication of infectious diseases, malaria and tuberculosis are making a comeback in many parts of the world. After years of decline, plague, diphtheria, dengue, meningococcal meningitis, yellow fever, and cholera have reappeared as public health threats. In the last 20 years [before 1997] more than 30 new and highly infectious diseases have been identified, including Ebola-type hemorrhagic fever, HIV/AIDs, and hepatitis C. Antibiotic resistance has also emerged during this period, and fewer new antibiotics are being produced because of high development costs and licensing. Drugs no longer offer protection or cure for many infectious diseases, and consequently more people need hospitalization with higher treatment costs. The causes of the appearance of new diseases and the resurgence of old ones include the rapid increase in international travel, the growth of mega-cities with high population densities, inadequate safe water and sanitation, food-borne diseases by the globalization of trade, and human penetration into remote animal and insect habitats. Meanwhile, resources for public health are being reduced, with the result that either the appearance of new diseases or resistance to drugs go unnoticed. A recent example is the human immunodeficiency virus, which went unrecognized until a large number of people got infected. For this very reason the 1997 World Health Day featured the theme of emerging infectious diseases and global response. Such forums are held to help countries rebuild the foundations of disease surveillance and control, while the public and private sectors may be encouraged to develop better techniques for surveillance to confront a common global threat.
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PMID:Emerging infectious disease: global response, global alert. 1234 2

Previously, we studied the envelope (E) gene of dengue virus and reported that dengue-3 virus is present as a quasispecies. To investigate the extent of intrahost sequence variation of other dengue viral genes, we examined in this study the capsid (C) gene and the nonstructural gene, NS2B, derived directly from plasma dengue viruses from 18 confirmed dengue-3 patients. Using reverse transcription-PCR, multiple clones of a 360-nucleotide region covering the C gene and of a 404-nucleotide region covering the NS2B gene from each patient were completely sequenced and analyzed. Our findings of the intrahost sequence variation of the C and the NS2B genes (mean pairwise p-distance: 0.12 to 1.02%, and 0.16 to 1.20%, respectively) demonstrate the quasispecies structure of dengue virus in vivo. A linear relationship was found between the extent of sequence variation of the C and NS2B proteins, suggesting that intrahost sequence variation of dengue-3 virus is likely to reflect genetic drift. The extent of intrahost sequence variation observed is in the same range as that of acute human immunodeficiency virus or hepatitis C virus infection, indicating that the random mutation frequency of dengue virus is similar to that of other RNA viruses in vivo. Consistent with a previous report of the E gene, the observations of genome-defective clones in both the C and the NS2B genes (3.9 and 5.0% of the clones, respectively) suggest a higher frequency of defective viruses in vivo. These findings would add to our understanding of the evolution of dengue-3 virus.
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PMID:Sequence diversity of the capsid gene and the nonstructural gene NS2B of dengue-3 virus in vivo. 1248 70

Rather than the expected increase in human immunodeficiency virus type 1 (HIV-1) load, there was transient suppression of HIV-1 replication during acute dengue infection in a 29-year-old Thai woman. Acute-phase (but not convalescent-phase) serum samples obtained from an HIV-1-uninfected patient with dengue fever reduced HIV-1 infectivity, as determined by a peripheral blood mononuclear cell assay, suggesting the possibility that HIV-1 replication is suppressed during acute dengue fever, as occurs during some cases of scrub typhus infection and measles.
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PMID:Decrease in human immunodeficiency virus type 1 load during acute dengue fever. 1268 21

Seven polyoxotungstates substituted with vanadium or titanium atoms were examined for their activity against Flaviviridae (Dengue fever virus, DFV), Orthomyxoviridae (influenza virus type A, fluV-A), Paramyxoviridae (respiratory syncytial virus, RSV, parainfluenza virus type 2, PfluV-2 and canine distemper virus, CDV) and Lentiviridae (human immunodeficiency virus type 1, HIV-1) families. Among the seven polyoxotungstates examined, PM-43 [K(5)[SiVW(11)O(40)]], PM-47 [K(7)[BVW(11)O(40)]], and PM-1001 [K(10)Na(VO)(3)(SbW(9)O(33))(2)]26H(2)O contained vanadium. PM-1002 had the same core structure of (VO)(3)(SbW(9)O(33))(2) as PM-1001; however, three V atoms of PM-1001 consisted of two V(IV) and one V(V) and those of PM-1002 consisted of three V(IV). On the other hand, PM-518 [[Et(2)NH(2)](7)[PTi(2)W(10)O(40)]], PM-520 [Pri(2)NH(2)](5)[PTiW(11)O(40)] and PM-523 [PriNH(3)](6)H[PTi(2)W(10)O(38)(O(2))(2)]H(2)O all contained titanium. All compounds showed broad spectrum antiviral activity against all viruses examined except for PMs-43, -518 and -523 which did not exhibit inhibitory activity at >/=50 microM against PfluV-2, CDV and DFV, respectively. All compounds were inhibitory against HIV replication at an EC(50) of less than 2.0 microM. Among them, PMs-1001 and -1002 showed the most potent inhibition. The compounds were not toxic for MDCK, HEp-2 and Vero cells at a concentration of 200 microM. For the exponentially growing MT-4 cells, the vanadium containing polyoxometalates (PMs-43, 47, 1001, 1002) showed toxicity at concentrations between 41 and 47 microM. On the other hand, titanium containing polyoxometalates (PMs-518, -520, -523) were not toxic at 100 microM. The mechanism of anti-HIV action of PM-1001 was analyzed: it affected the binding of HIV to the cell membrane and syncytium formation between HIV-infected and uninfected cells.
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PMID:Broad spectrum anti-RNA virus activities of titanium and vanadium substituted polyoxotungstates. 1276 74

The synthesis of the structurally unusual heterotricyclic compound 1-[3-hydroxy-5-(hydroxymethyl)-2-methyl-4-pyridinyl]-2,8,9-trioxaadamantane-3,5,7-triol (trivially named bananin, BN) from pyridoxylidenephloroglucinol and a theoretical prospect on possible biological activities of BN are presented in this report. Pyridoxylidenephloroglucinol is synthesized by Knoevenagel condensation of the vitamin B6 aldehyde pyridoxal with phloroglucinol. Pyridoxylidenephloroglucinol rearranges to light-yellow (4'RS)-1',4'-dihydrobananin by refluxing in 5M hydrochloric acid. Air oxidation subsequently forms BN in the heat which immediately yields orange-yellow (4'RS)-4'-chloro-1',4'-dihydrobananin by 1,4-addition of hydrogen chloride. This intermediate could be isolated but, interestingly, not a BN hydrochloride. Brown BN is finally achieved by base-catalyzed elimination of hydrogen chloride from (4'RS)-4'-chloro-1',4'-dihydrobananin. Regarding possible biological activities, it was demonstrated that BN acts as zinc (Zn2+) chelator. Therefore, a target of interest could be the human immunodeficiency virus type 1 (HIV-1) zinc finger HIV-1 RNA-binding nucleocapsid protein p7 (NCp7). Through suggested zinc ejection from HIV-1 genomic RNA psi-element-binding and HIV-1-RNA-duplex packaging NCp7 by BN, thus rendering NCp7 functionally obsolete, it is deduced that HIV-1 replication and effective infectious virion encapsidation could be inhibited by BN. Furthermore, theoretical and structural considerations propose that BN is converted into bananin 5'-monophosphate (BNP) by the cell type-ubiquitous human enzyme pyridoxal kinase (EC 2.7.1.35). Together with the putative antilentiviral retinoid vitamin A-vitamin B6 conjugate analogue B6RA (Kesel, A. J. Biochem. Biophys. Res. Comm. 2003, 300, 793), BNP is postulated to serve as effector in a system of protein target sequences RX(D/E) of RNA virus components. Human immunodeficiency Retroviridae (HIVs) could possibly be influenced by B6RA and BNP. In addition, candidate targets of B6RA and BNP could be adsorption, transcription and/or viral RNA replication of an interestingly wide RNA virus selection including Picornaviridae (poliovirus, human coxsackievirus, hepatitis A virus), Flaviviridae (yellow fever virus, Dengue virus, West Nile virus, Kunjin virus, St. Louis encephalitis virus, hepatitis C virus), Togaviridae (rubella virus), Coronaviridae (human coronavirus, human SARS-associated coronavirus), Rhabdoviridae (rabies virus), Paramyxoviridae (human parainfluenza virus, measles virus, human respiratory syncytial virus), Filoviridae (Marburg virus, Ebola virus), Bornaviridae (Borna disease virus), Bunyaviridae (Hantaan virus), Arenaviridae (Lassa virus), and Reoviridae (human rotavirus). The postulated scope of 'metabolically trapped' BNP might resemble the antiviral spectrum of the RNA-viral virustatic ribavirin.
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PMID:A system of protein target sequences for anti-RNA-viral chemotherapy by a vitamin B6-derived zinc-chelating trioxa-adamantane-triol. 1452 57

RNA interference (RNAi) is a sequence-specific gene-silencing mechanism in eukaryotes, which is believed to function as a defence against viruses and transposons. Since its discovery, RNAi has been developed into a widely used technique for generating genetic knock-outs and for studying gene function by reverse genetics. Additionally, inhibition of virus replication by means of induced RNAi has now been reported for numerous viruses, including several important human pathogens such as human immunodeficiency virus type 1, hepatitis C virus, hepatitis B virus, dengue virus, poliovirus and influenza virus A. In this review, we will summarize the current data on RNAi-mediated inhibition of virus replication and discuss the possibilities for the development of RNAi-based antiviral therapeutics.
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PMID:Inhibition of virus replication by RNA interference. 1457 63

The processes of mutation and nucleotide substitution contribute to the observed variability in virulence, transmission and persistence of viral pathogens. Since most viruses evolve many times faster than their human hosts, we are in the unusual position of being able to measure these processes directly by comparing viral genes that have been isolated and sequenced at different points in time. The analysis of such data requires the use of specific statistical methods that take into account the shared ancestry of the sequences and the randomness inherent in the process of nucleotide substitution. In this paper we describe the various statistical methods for estimating evolutionary rates, which can be classified into three general approaches: linear regression, maximum likelihood, and Bayesian inference. We discuss the advantages and shortcomings of each approach and illustrate their use through the analysis of two example viruses; human immunodeficiency virus type 1 and dengue virus serotype 4. Reliable estimates of viral substitution rates have many important applications in population genetics and phylogenetics, including dating evolutionary events and divergence times, estimating demographic parameters such as population size and generation time, and investigating the effect of natural selection on molecular evolution.
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PMID:Inference of viral evolutionary rates from molecular sequences. 1471 Oct 90

Ampligen [polyI:polyC12U] is a mismatched double-stranded RNA that acts by inducing interferon production (immunomodulator) and by activating an intracellular enzyme (RNase-L) against viral RNA transcripts (antiviral). Ampligen, currently under development by Hemispherx Biopharma in the US, acts on the immunological system through T-lymphocyte stimulation and is indicated for the treatment of chronic fatigue syndrome and acquired immunodeficiency deficiency syndrome (AIDS), as part of the combined therapy. Ampligen is available for licensing worldwide. In February 2004, Fujisawa Deutschland GmbH, a subsidiary of Fujisawa Pharmaceutical Co., entered into an option agreement with Hemispherx Biopharma with the intent of becoming a distributor for Ampligen for the potential treatment of chronic fatigue syndrome in Germany, Switzerland and Austria. An option fee of 400,000 euros was paid pursuant to the terms of the option agreement and upon execution of the Distribution Agreement, Fujisawa will pay Hemispherx fees and milestone payments with a potential worth of several millions of dollars. In September 2003, Hemispherx Biopharma Inc. entered into an agreement with Guangdong Medicine Group Corporation to organise clinical trials, marketing, sales and distribution for both of its lead compounds, Ampligen and Alferon N in the People's Republic of China. The agreement stipulates that the Guangdong Medicine Group Corporation (GMC) will conduct clinical trials with Ampligen for the treatment of HIV. All costs related to the trials are to be covered by GMC. Additionally, GMC has to develop and implement marketing and promotional programmes. In May 2003, Hemispherx Biopharma and the Center for Cell and Gene Therapy entered into a research project agreement that will see Ampligen implemented in a protocol used in patients with relapsed EBV-positive Hodgkin's Lymphoma. In March 2002, Esteve and Hemispherx Biopharma entered into a collaborative agreement under which Esteve will be the sole distributor of Ampligen in Spain, Portugal and Andorra for the treatment of chronic fatigue syndrome. Under this agreement, in addition to other terms, Esteve will also collaborate in the drug product development by conducting clinical studies in Spain in patients coinfected with HIV/HCV. In July 2001 Hemispherx Biopharma announced that it had formed a strategic alliance with Empire Health Resources for clinical trials of Ampligen in the treatment of HIV and hepatitis C virus infections. Empire Health Resources, a healthcare management firm, will be responsible for accrual and retention of patients for HIV trials, and protocols for trials in patients with hepatitis C or both HIV and hepatitis C infections. Hemispherx has entered into a collaboration with RED Laboratories, and RED Laboratories NV expects that this will facilitate the continued development of Ampligen. Hemispherx has also entered into an agreement with Schering Plough to use a Schering facility as its principal manufacturing platform in the US. This agreement may be expanded to include other territories. Hemispherx and AOP Orphan Pharmaceuticals have signed a marketing agreement for Ampligen for the treatment of chronic fatigue syndrome for Austria, the Czech Republic, Poland and Hungary. In an arrangement between Hemispherx and Bioclones, Bioclones has certain marketing rights for Ampligen in the Southern Hemisphere, UK and Ireland. In the US, Ampligen has been granted orphan drug status for the treatment of AIDS, renal cell carcinoma (phase II, completed), chronic fatigue syndrome (phase III) and invasive/metastatic malignant melanoma (phase II). In August 2004, Hemispherx announced that it intends to use the proceeds from the private placement of company stock to complete the clinical work for its immunotherapeutics/ antivirals Ampligen and Oragens. Previously, Hemispherx submitted an application to the EMEA for the approval of Ampligen for the treatment of chronic fatigue syndrome; the first stage of th;) for the treatment of chronic fatigue syndrome; the first stage of the regulatory review has been cleared. In 2000, Hemispherx Europe (Hemispherx) obtained orphan drug status for Ampligen for the treatment of chronic fatigue syndrome in the EU, providing Hemispherx with 10 years of marketing exclusivity following the launch of the drug, as well as potential financial research benefits for the agent. In February 2000, Crystaal Corporation (now Biovail Pharmaceuticals Canada) acquired exclusive marketing rights to Ampligen in Canada, where it submitted an NDA for the agent for the treatment of chronic fatigue syndrome. In the meantime, Ampligen has been available since May 1996 under the Canadian Emergency Drug Release Programme for the treatment of chronic fatigue syndrome and immune dysfunction syndrome by Rivex Pharma (Helix BioPharma). Bioclones has initiated clinical studies with Ampligen for the treatment of chronic fatigue syndrome in Australia. The active substance for Ampligen is manufactured by F.H. Faulding Ltd. Clinical treatment programmes for chronic fatigue syndrome in other Pacific Rim countries are planned. Ampligen is available for severe chronic fatigue syndrome on a named patient, cost-recovery basis in South Africa. Hemispherx has developed a 'ready-to-use' liquid formulation of the drug and has begun treating patients with chronic fatigue syndrome in ongoing clinical trials. Hemispherx has also developed an oral version of the drug (Oragen), which is undergoing preclinical evaluation. In February 2001, Hemispherx Biopharma announced that it was initiating phase II/III trials of Ampligen in the treatment of late-stage, multidrug-resistant strains of HIV in the European Union. Patients treated in these studies will have exhausted all other treatment options. In July 2001, Hemispherx stated that Ampligen was being evaluated in a phase IIb trial in patients with HIV in the US. The trial, comprising two studies, REARMI and REARMII (Research/Evaluation of Ampligen for Retroviral Mutations I and II), will evaluate the ability of Ampligen to prevent the emergence of mutated, drug-resistant strains of the virus. 'Several hundred' patients currently on antiretroviral therapy and at risk of viral relapse will be enrolled at centres in Connecticut, New York, Florida and California. A second phase IIb study evaluating the effect of Ampligen on structured treatment interruptions (STI) is also underway. Final results from this study were reported in December 2002. NIH sponsored studies of potential therapies for SARS have identified Ampligen as having unusually high and consistent antiviral activity against human coronavirus, the pathogen implicated as the causative agent of the disease. Ampligen demonstrated very high potency at very low concentrations (0.4 microg/mL) and had a favourable safety profile. In October 2003, Hemispherx announced that, based on these promising new results, the company will stockpile injectible and/or oral formats of Ampligen and Alferon N. Independent researchers have demonstrated the antiviral activity of Ampligen against flaviviruses (West Nile virus, Equine Encephalitis virus, Dengue fever virus and Japanese Encephalitis virus) as well as virus classes associated with bioterrorism. In an animal study, Ampligen was shown to prevent destruction of nerve cells, reduce virus concentrations in the brain and blood stream and increase survival rates. Researchers at the Rega Institute in Belgium have published results from an animal study demonstrating that Ampligen was superior at protecting mice against coxsackie B3 virus-induced myocarditis compared with pegylated interferon. In May 2004 Hemispherx announced that it had filed an expanded US patent application covering the use of Ampligen for the potential treatment and prevention of severe acute respiratory syndrome (SARS) and dreaded emerging viruses.
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PMID:Mismatched double-stranded RNA: polyI:polyC12U. 1535 29

Several sulfated seaweed polysaccharides show high antiviral activity against enveloped viruses, including important human pathogens such as human immunodeficiency virus, herpes simplex virus, human cytomegalovirus, dengue virus and respiratory syncytial virus. They can be obtained in major amounts and at low costs, have low toxicity and in some cases, lack anticoagulant effects. Even if the systemic applications have many drawbacks, their structure and mode of action indicate potential for topical uses to prevent virus infection. The herpes simplex viruses attach to cells by an interaction between the envelope glycoprotein C and the cell surface heparan sulfate (HS). The virus-cell complex is formed by ionic interactions between the anionic (mainly sulfate) groups in the polysaccharide and basic amino acids of the glycoprotein, and non-ionic ones depending on hydrophobic amino acids interspersed between the basic ones in the glycoprotein-binding zone. Hypothesis are advanced of the corresponding hydrophobic structures in the polysaccharides. The antiviral activity of the sulfated seaweed polysaccharides is based on the formation of formally similar complexes that block the interaction of the viruses with the cells. Correlations are established between different structural parameters and antiviral activity. The minimal, ionic and hydrophobic, structures in the seaweed polysaccharides were hypothesized by comparison of the polysaccharides with the known minimal binding structure in HS/heparin, together with a correlation between those structures of the polysaccharides and their antiviral activity.
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PMID:Sulfated seaweed polysaccharides as antiviral agents. 1537 5


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