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)

Suksdorfin (1), which is isolated from the fruit of Lomatium suksdorfii, was found to be able to inhibit HIV-1 replication in the T cell line, H9, with an average EC50 value of 2.6 +/- 2.1 microM. In addition, suksdorfin was also suppressive during acute HIV-1 infections of peripheral blood mononuclear cells, monocyte/macrophages and the promonocytic cell line, U937. Combinations of 1 and the anti-HIV nucleosides ddI and ddC demonstrated statistical synergy in inhibiting HIV-1 replication (ddC > ddI). However, the viral inhibition mediated by combining 1 with AZT was not statistically synergistic. Furthermore, the presence of suksdorfin did not antagonize the suppression mediated by the three nucleoside reverse transcriptase inhibitors. Comparison of the structure and activity of 1 with those of ten related compounds indicated that the dihydroseselin type of pyranocoumarin possessing a 4'-isovaleryl group is important to suksdorfin's enhanced anti-HIV activity.
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PMID:Suksdorfin: an anti-HIV principle from Lomatium suksdorfii, its structure-activity correlation with related coumarins, and synergistic effects with anti-AIDS nucleosides. 777 21

We have been isolated HIV strains from blood specimens of HIV infected individuals in Japan for these 6 years. The number of specimens tested reached approximately 1,700 that ninety percent of them were from hemophiliacs repeatedly injected blood products from the United States. More than 300 of field HIV were successfully isolated from the samples. The isolation rates has decreased to 30 percent in 1993 from 40 percent in 1992, suggesting that treatment with anti-HIV drugs such as AZT and/or ddI may be effective to HIV-infected individuals. Further, both of the viral and genomic sequences of HIV were classified to be clade B virus. The clinical isolates that expressed IHIGPGRAFY sequence at the center of the HIV-V3 domain were found to be neutralized by an anti-clade B-V3 monoclonal antibody, mu 5.5. By individual levels, when asymptomatic seropositives have progressed to disease-states, neutralization core motif of GPGR in approximately 6% of the viruses has changed to GPGG and hydrophilic amino acid changed to hydrophobic amino acid, correlating the loss of binding activity to PND-peptide of Japanese Consensus virus. Further, rapid progressors to HIV-induced diseases showed decreased activity of the binding antibody. By using the Japanese consensus sequence of HIV-1, we successfully constructed chimeric protein secretion vectors by selecting an appropriate insertion site of a carrier protein, and established the PND-peptide secretion system in BCG. The recombinant BCG inoculated guinea pigs were initially screened by delayed-type hypersensitivity (DTH) skin reactions to the PND peptide followed by passive transfer of the DTH by the systemic route.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Induction of protective immune responses by a chimeric soluble protein from a recombinant BCG vector candidate vaccine to HIV-1]. 778 47

1. Dideoxyinosine (ddI) has recently been approved for the treatment of patients with HIV infection. As increasing numbers of such patients are pregnant, we wished to define the rate and mechanism(s) of ddI transfer by the placenta to the foetus. Using isolated single perfused human term placental cotyledons, the drug was shown to cross the placenta from mother to foetus at a rate of 25% that of a freely diffusible marker, antipyrine, and at about half the rate of zidovudine (AZT). The transfer of ddI was similar in both directions (maternal to foetal and the reverse), equal to that of L-glucose, a passively transported sugar, and was not inhibited by excess inosine or uric acid (structural analogues of ddI). ddI did not cross to the foetus against a concentration gradient. The transport process appeared to be passive and it was not altered by AZT. 2. ddI was not metabolized in the Krebs Ringer buffer/albumin perfusate, and placental homogenates converted only 4% of ddI to hypoxanthine over the 4 h incubation. However, when maternal term or cord blood was incubated with ddI for 3 h, 50% of the drug was converted to hypoxanthine in maternal blood and to hypoxanthine and uric acid in cord blood. 3. Thus, ddI metabolism in maternal blood should decrease its net transfer to the foetus in vivo. In the foetal circulation, ddI will be further metabolized by erythrocytes to hypoxanthine and possibly to uric acid. Hence, the fraction of administered ddI delivered to foetal tissues should be much lower than that of AZT.
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PMID:Transfer of dideoxyinosine across the human isolated placenta. 782 25

A subclonal cl.1-14 cell was established from a monocytic cell line U937 by a limiting dilution method. The anti-HIV-1 activity of some antiviral compounds was evaluated in HIV-1-infected cl.1-14 cells. The results demonstrated that although AZT was a potent inhibitor of HIV-1 replication in cl.1-14 cells, its 50% effective concentration (EC50) values was 80 times higher than that in HIV-1 infected MT-4 cells; the EC50 of AZT was 0.16 microM and 0.002 microM in cl.1-14 and MT-4 cells, respectively. In contrast, the anti-HIV-1 activity of ddA, ddI and ddC in cl.1-14 cells was comparable to that in MT-4 cells. The antiviral activity of nevirapine, dextran sulfate, curdlan sulfate and T22 did not differ significantly between the cl.1-14 and MT-4 cells. The antiviral activity of several compounds in the HIV-1-infected cl.1-14 cells was similar to that in the HIV-1JR-FL-infected human peripheral macrophages. Our results suggest that cl.1-14 cell cultures are very useful for estimating antiviral activity and more advantageous than the use of peripheral blood macrophages.
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PMID:A novel assay system for anti-human immunodeficiency virus type 1 (HIV-1) activity using a subclone of a monocytic cell line, U937. 786 61

One of the hallmarks of human immunodeficiency virus type 1 (HIV-1) infection is the decline in CD4+ T lymphocytes which precedes the progression from an asymptomatic state to AIDS. Apoptosis (programmed cell death) is one of the mechanisms proposed to mediate this depletion. Infectious and inactivated preparations of HIV-1LAI were compared for their potential to induce apoptosis. Analysis with fluorescence-activated cell sorting using the DNA intercalative compound propidium iodide demonstrated that apoptosis occurred only with infectious HIV-1, implying that cell surface binding and signalling by the virus alone were insufficient to trigger apoptosis. Apoptosis was further confirmed by the presence of characteristic digestion of host cell DNA and morphologically by nuclear condensation observed by transmission electron microscopy. HIV infection of CD4+ T cell lines generated an accumulation of the cells in G2/M phase of the cell cycle and cells undergoing apoptosis appeared to originate from the pool of cells in the G1 phase. Inhibitors of HIV replication were used to identify the point in the virus replicative cycle at which apoptosis is induced. The reverse transcriptase inhibitor, ddI, or the HIV protease inhibitor, RO31-8959 (Saquinavir), were added either 2 h before or 6 h after HIV inoculation. Only ddI inhibited HIV-induced apoptosis when added before inoculation; however, neither treatment was effective in preventing HIV-induced apoptosis when applied 6 h after inoculation. These data indicate that apoptosis requires a single round of reverse transcription and the expression of virion proteins, but not the maturation of progeny virions. Two agents which compete with HIV for binding to CD4+ T cells, dextran sulphate and the anti-CD4 MAb Leu3a, were effective at preventing apoptosis when added 6 h after infection, implying that a subsequent gp120-CD4 interaction at the surface of an infected cell was required to complete the apoptotic process.
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PMID:Productive infection and subsequent interaction of CD4-gp120 at the cellular membrane is required for HIV-induced apoptosis of CD4+ T cells. 789 56

Patients infected with HIV, including those with AIDS-related complex and AIDS, and failing treatment with antiretroviral agents such as zidovudine, have been evaluated following addition of trichosanthin to the antiretroviral agent regimen. This ribosomal inhibitory protein is specifically cytotoxic for HIV-infected macrophages and lymphocytes. Ninety-three patients were treated with trichosanthin, using a schedule of weekly, then monthly, intravenous injections of 1.2 mg of drug in combination with antiretroviral agents, usually zidovudine. Side effects included myalgias, fevers, mild elevation in liver function tests, and mild-moderate anaphylactic reactions, which respond well to therapy with steroids and/or benedryl. Reversible mental status changes were noted in two patients, both receiving concomitant therapy with ddI. Clinical responses to trichosanthin treatment were monitored primarily by changes in laboratory parameters, particularly levels of CD4+ T lymphocytes. In the total population evaluated for efficacy (85 patients) there was a significant increase in CD4+ cell levels after initiation of trichosanthin therapy. A second analysis performed on 72 patients measured the rate of change of CD4+ cells during therapy, using an "area under the curve" analysis. During therapy there was a median increase of 1.2 cells/mm3/month. In patients in the top 25th percentile, this increase was greater than 8.4 cells/mm3/month. In 59 of the 72 patients, responses could also be monitored by comparing the rate of loss of CD4+ cell levels on antiretroviral agents (zidovudine or ddI) alone, during the year prior to initiation of trichosanthin, to the rate of change when trichosanthin was added to the treatment regimen. During the period before trichosanthin treatment (311 +/- 11.7 days) the median loss of CD4+ cells was 6.91 cells/mm3/month. Addition of trichosanthin to the treatment regimen resulted in a median gain of 1.1 CD4+ cells/mm3/month.
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PMID:A phase II study of effect of addition of trichosanthin to zidovudine in patients with HIV disease and failing antiretroviral agents. 791 24

(1) We evaluated efficacy of several treatments for HTLV-I-associated myelopathy (HAM) on the basis of our study on 254 HAM patients and of literature review. Improvement of motor disability more than fair response was obtained as follows: 82% in prednisolone, 69% in interferon-alpha, 92% in fosfomycin, 82% in high-dose vitamin C, 72% in blood purification therapy, 70% in heparin, 59% in salazosulfapyridine, 56% in thyrotropin-releasing hormone, 55% in erythromycin, 50% in mizoribine. (2) In the absence of clear guideline, the efficacy of zidovudine in the AIDS dementia complex has been demonstrated. There are also efficacy of amytriptylinein controlling HIV headache, corticosteroid in mononeuritis multiple and inflammatory myositis, hydrocortisone in autonomic neuropathy and plasmapheresis in distal sensory neuropathy respectively. Otherwise, it is emphasized that ddI, ddC and d4T have peripheral neuropathy as major, dose related side effect.
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PMID:[Therapy for HAM/TSP and AIDS]. 799 4

We have sequentially passaged both laboratory and clinical isolates of the human immunodeficiency virus type 1 (HIV-1) in MT-4 cells in the presence of increasing concentrations of different drugs to derive viral variants that are multiply resistant to various combinations of ddC, ddI, d4T and AZT. The EC50 values obtained for the viruses thus generated varied between 50-100 times above those of parental wild-type strains in the case of AZT, 20-30 times for d4T, but only 10-15 times for ddI and ddC. Cultivation of AZT-resistant viruses in the presence of increasing concentrations of ddI yielded viruses that were resistant to the latter compound, with no apparent decrease in susceptibility to AZT. Sometimes, viruses selected for resistance against ddI were cross-resistant as well against ddC, although most viruses selected for resistance to ddC were not cross-resistant to ddI. Combinations of two or three of these compounds inhibited replication of HIV variants that displayed resistance to the same drugs when tested individually. No emergence of drug resistance was demonstrable when combinations of drugs were employed simultaneously in these selection protocols or when single drugs were used in concert with interferon-2 alpha or high dilutions of virus-neutralizing antisera. Cloning and sequencing of some viruses resistant to each of AZT, ddI, and ddC revealed the simultaneous presence of mutations at sites 41, 74, 184 and 215 within the HIV pol gene open reading frame.
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PMID:Generation of multiple drug resistance by sequential in vitro passage of the human immunodeficiency virus type 1. 800 79

It is shown that ddA bis(SATE)phosphotriester is one of the most potent anti-HIV agents in cell culture. Compared with the parent nucleoside, ddA, an increase of 3 orders of magnitude was observed in the EC50, which makes this compound as active as AZT. This can be tentatively explained if one considers that direct ddAMP intracellular delivery shunts the well established ddA/ddI metabolism pathway.
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PMID:Equal inhibition of the replication of human immunodeficiency virus in human T-cell culture by ddA bis(SATE)phosphotriester and 3'-azido-2',3'-dideoxythymidine. 804 11

Because of the importance of macrophages in the pathogenesis of the disease caused by HIV, we investigated the efficacy of various anti-HIV drugs in human primary macrophages acutely or chronically infected by this virus. The results obtained for acutely infected macrophages show that dideoxynucleosides (AZT, ddI, and ddC), interferon-alpha and -gamma, mismatched double-stranded RNA, Tat inhibitor, phosphorothioate antisense, and inhibitors of HIV protease, all significantly inhibit virus replication at concentrations far below those toxic for the cells. However, in macrophages in which proviral DNA is already integrated (chronically infected macrophages), only the three inhibitors of HIV protease induced significant virus inhibition at concentrations 100 or more times higher than those effective in acutely infected macrophages. Treatment of macrophages with macrophage colony-stimulating factor does not affect the anti-HIV efficacy of protease inhibitors. These results suggest that therapeutic strategies with activity for macrophages, including inhibitors of HIV protease, are worth pursuing in patients with HIV infection.
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PMID:In vitro activity of inhibitors of late stages of the replication of HIV in chronically infected macrophages. 808 12


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