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)

In Japan, 1531 out of 4171 hemophiliacs (36.7%) are human immunodeficiency virus (HIV)-infected, and up to 31 December 1991, 324 (21.2%) of these patients had developed AIDS. The Research Committee estimated the peak of the seroconversion period of hemophiliacs in Japan as January 1983, having presumed that new cases of seroconversion would not arise after heat treated concentrates came into general use in 1985. However, after a long 5 years window period starting in 1985, cases of seroconversion are being reported. The present mean rate of reduction in cluster difference 4 (CD4) counts of HIV infected hemophiliacs has been increasing since 1990. At present (1991), the proportion of HIV infected hemophiliacs below 20 years is believed to be approximately 40%. Concomitantly with the aging of this group, the incidence of AIDS is expected to increase in the future. Although the aforesaid factors are conducive to a rising incidence of AIDS, the rate of increase of AIDS incidence among hemophiliacs in Japan is actually decelerating. This can, hopefully, be attributed to the commencement of widespread use of periodic pentamidine inhalation therapy, or the administration of drugs such as AZT (zidovudine) or ddI (didanosine) to AIDS related complex (ARC) cases, or to asymptomatic carrier (AC) cases with CD4 counts below 350 cells for the prophylactic treatment against developing to AIDS. Oral administration of didanosine at a dosage of 400 mg/day, or didanosine at a dosage of 334 mg to 500 mg/day, has been found effective for the treatment of hemophiliacs with AIDS.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pathological status and therapy of HIV-infected hemophiliacs in Japan. 136 5

It is recognized that high-level resistance to 3'-azido-3'-deoxythymidine (AZT, zidovudine, or Retrovir) is conferred by the presence of four mutations in the human immunodeficiency virus (HIV) reverse transcriptase [RT; deoxynucleoside-triphosphate:DNA deoxynucleotidyltransferase (RNA-directed), EC 2.7.7.49] coding sequence. However, a number of clinical isolates have been observed that exhibit high-level resistance but contain only three of the four identified mutations (Asn-67, Arg-70, and Tyr-215). Construction of a molecular clone with this genotype gave rise to only a partially resistant virus, raising the possibility that an additional mutation existed in some clinical isolates. Using an HIV marker rescue system, we have mapped and identified a fifth mutation conferring resistance to zidovudine, namely, methionine to leucine at codon 41 of HIV RT. An infectious molecular clone containing this mutation together with three previously identified mutations in the RT coding sequence yielded highly resistant HIV after transfection of T cells. Direct detection of the fifth mutation in DNA samples from cocultured peripheral blood lymphocytes by the PCR revealed that it occurred relatively early in the development of zidovudine resistance. However, this mutation was only detected after the appearance of the codon 215 change in the RT coding sequence. Identification of this mutation in addition to the other known mutations conferring resistance enables rapid and direct correlation between an RT genotype and sensitivity of the virus.
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PMID:Fifth mutation in human immunodeficiency virus type 1 reverse transcriptase contributes to the development of high-level resistance to zidovudine. 137 86

Multiple mutations in the reverse transcriptase (RT) gene were observed in a drug-resistant isolate of human immunodeficiency virus type 1 (HIV1) from an individual having prolonged (greater than 2 years) zidovudine (AZT) therapy. The virus replicated in PBMC's in the presence of very high concentrations of AZT (125 microM). Drug-sensitive strains were curtailed by 0.01 microM AZT. Eleven defined mutations were observed as compared with published sequences of RT for eight strains of HIV1. Eight of these mutations were found in the domain involved in nucleotide recognition and enzyme function. Only one of the mutations, giving a Thr--Tyr change at amino acid 215, matched those previously ascribed (67, 70, 215, and 219) to the generation of high-level resistance to AZT. Therefore additional amino acid changes may have significance in the emergence of super-resistant viruses.
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PMID:Sequence analysis of an HIV-1 isolate which displays unusually high-level AZT resistance in vitro. 137 91

The rate of reversion from azidothymidine (zidovudine; AZT) resistance was studied by direct sequencing of human immunodeficiency virus type 1 (HIV-1) virion RNA in sera from four patients who discontinued long-term treatment. Before cessation of treatment, all four patients harbored HIV-1 with multiple mutations reported to confer AZT resistance. In three patients, slow reversions of these mutations starting after 9, 9, and 18 months were detected. The slow reversions indicate that AZT-resistant HIV-1 variants are likely to have an unaltered replicative capacity and pathogenic potential. Furthermore, there were discrepancies between the in vivo RNA sequences and the sequences of virus isolates, indicating that the isolation procedure may select for nonrepresentative virus variants.
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PMID:Persistence of azidothymidine-resistant human immunodeficiency virus type 1 RNA genotypes in posttreatment sera. 138 98

Various 3-substituted 3'-azido-3'-deoxythymidine analogs (2a-i) were prepared by the reaction of 3'-azido-3'-deoxythymidine (1), AZT with N,N-dimethylformamide dialkylacetal or alkyl bromide in the presence of base and their activities against human-immunodeficiency virus type-1 (HIV-1) were evaluated. The corresponding 5'-triphosphate analogs (9) were also synthesized in order to examine inhibition of HIV-1 reverse transcriptase activity. Beyond expectation, some N3-derivatives of AZT were found to reserve the anti-HIV-1 activity to some extent. Among the compounds (2a-i) obtained, 3-allyl-AZT (2e) was the most active against HIV-1 replication in MT-4 cells in vitro with an EC50 value of 0.9 microM. 3-Allyl-AZT 5'-triphosphate (9e), however, exhibited no inhibition of HIV-1 reverse transcriptase activity.
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PMID:Synthesis and anti-human immunodeficiency virus type 1 (HIV-1) activity of 3-substituted derivatives of 3'-azido-3'-deoxythymidine (AZT), and inhibition of HIV-1 reverse transcriptase by their 5'-triphosphates. 138 96

Ro 5-3335, 7-chloro-5-(2-pyrryl)-3H-1,4-benzo-diazepin-2-(H)-one, has been shown to inhibit gene expression controlled by the human immunodeficiency virus-1 (HIV-1) LTR promoter. The inhibition was specific for the viral transcriptional transactivator Tat. The compound did not inhibit the basal activity of the HIV-1 LTR or the activity of promoters not responsive to Tat. Consistent with its mode of action, Ro 5-3335 inhibited HIV-1 replication (IC50 = 0.1-1 microM) by reducing viral RNA synthesis in acutely, as well as chronically, infected cells in vitro. The compound was active against HIV-1 and HIV-2, and AZT-resistant clinical isolates.
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PMID:Discovery and characterization of an HIV-1 Tat antagonist. 139 54

Deoxynucleoside analogs, AZT and/or ddN, are the therapeutic agents currently utilized to inhibit the human immunodeficiency virus (HIV) reverse transcriptase. The effects of their anabolic products, AZT-triphosphate (AZT-TP) and ddCTP on human cellular DNA metabolic processes were studied using highly purified, structurally and enzymatically defined forms of the two major human host DNA polymerases, alpha and beta, and compared to those of the reverse transcriptase purified from HIV viron. Human DNA polymerase alpha during processive DNA synthesis is able to incorporate AZT-monophosphate (AZT-MP) but not ddCMP into DNA, causing chain termination. During its initial encounter with a primer terminus, polymerase alpha is able to incorporate both AZT-MP and ddCMP into DNA chains. Polymerase beta is able to incorporate AZT-MP and ddCMP into DNA, causing chain termination in both modes of DNA synthesis. Steady state kinetic analyses demonstrate that polymerase alpha inserts one AZT-MP molecule into DNA for every 2500 dTMP molecules incorporated. Polymerase beta incorporates ddCMP with efficiency nearly equal to that of dCMP. HIV reverse transcriptase prefers to incorporate AZT-MP and ddCMP rather than dTMP and dCMP, respectively. The findings described here raise the concern that the capability of the two major host DNA polymerases to incorporate AZT-MP or ddCMP into DNA might cause adverse side effects on human DNA metabolism and mutation in the genomes of patients under long term continuous treatment with AZT and ddC.
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PMID:Human DNA polymerases alpha and beta are able to incorporate anti-HIV deoxynucleotides into DNA. 140 Apr 58

3'-Deoxythymidine (3dT) is a weakly active dideoxynucleoside in human immunodeficiency virus (HIV)-infected cells because of its slow phosphorylation by cellular thymidine kinase. 3dT diphosphate dimyristoylglycerol (3dTDP-DMG), a phospholipid prodrug, was synthesized and found in vitro to be 18- to 50-fold more effective than 3dT in CEM and HT4-6C cells. In CEM cells, the selectivity index of 3dTDP-DMG was 270 versus 48 for 3dT, an increase of 5.6-fold. In thymidine kinase-deficient mutant CEM cells infected with HIV, 3dT and zidovudine (AZT) were virtually inactive but 3dTDP-DMG retained substantial activity, suggesting that its greatly increased antiviral activity is due in part to bypass of thymidine kinase. 3dTDP-DMG was 14- to 37-fold more active than 3dT in AZT-sensitive and AZT-resistant clinical isolates of HIV; no cross-resistance with AZT was noted. The results suggest that lipid prodrugs may be utilized in some cases to confer unique metabolic advantages over the corresponding free nucleoside; in the case of 3dTDP-DMG, an 18- to 50-fold increase in antiretroviral activity was observed in LAV-infected cells. The strategy would seem to be especially useful for antiviral nucleosides which are poorly phosphorylated.
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PMID:Greatly enhanced inhibition of human immunodeficiency virus type 1 replication in CEM and HT4-6C cells by 3'-deoxythymidine diphosphate dimyristoylglycerol, a lipid prodrug of 3'-deoxythymidine. 141 96

It is proposed that the new American and European AIDS epidemics are caused by recreational and anti-HIV drugs rather than by human immunodeficiency virus (HIV). Chronologically, the AIDS epidemic in the 1980s followed a massive escalation in the consumption of recreational drugs that started in the 1960s and 70s. Epidemiologically, both epidemics derive about 80% of their victims from the same groups of 20-44 year-olds, of which 90% are males. In America 32% of these are intravenous drug users and their children, about 60% are male homosexuals who are long-term users of oral aphrodisiac drugs and an unknown percentage are prescribed the cytotoxic DNA chain terminator AZT, as inhibitor of HIV. Direct evidence indicates that these drugs are necessary for HIV-positives and sufficient for HIV-negatives to develop AIDS diseases. The drug-AIDS hypothesis predicts correctly that: (i) AIDS is new in the US, because the drug epidemic is new, while the HIV epidemic is old--fixed at a constant 1 million Americans since 1985; (ii) despite an increase in venereal diseases, AIDS remains restricted to long-term drug users and small groups with clinical deficiencies; (iii) over 72% of AIDS occurs in 20-44 year-old males, because they make up over 80% of hard psychoactive drug use; (iv) distinct AIDS diseases correlate with the use of distinct drugs, eg Kaposi's sarcoma with nitrite inhalants, tuberculosis with intravenous drugs, and leukopenia, anemia, and nausea with AZT; (v) AIDS diseases are only acquired after long-term drug consumption, rather than after single contacts as the virus-hypothesis predicts. The drug hypothesis can be tested epidemiologically and experimentally in animals. It predicts that most AIDS can be prevented by stopping the consumption of drugs, and provides a rational basis for therapy.
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PMID:The role of drugs in the origin of AIDS. 142 Oct 32

Tachyplesin and polyphemusin are antimicrobial peptides recently isolated from the hemocytes of horseshoe crabs (Tachypleus tridentatus and Limulus polyphemus). We synthesized them and their analogs and examined their antiviral activity against human immunodeficiency virus (HIV) type 1 in vitro. The infection of human T cells with the virus was markedly inhibited by some of them at low concentrations. In this structure-activity study, we found that [Tyr5,12, Lys7]-polyphemusin II, which was designated as T22, had extremely high anti-HIV activity. Its 50% inhibitory concentration (EC50) was 0.008 micrograms/ml, while its 50% cytotoxic concentration (CC50) was 54 micrograms/ml and these values were comparable to those of AZT. This result indicates that T22 would be a potential candidate for the therapy of HIV infection.
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PMID:A novel anti-HIV synthetic peptide, T-22 ([Tyr5,12,Lys7]-polyphemusin II). 147 56


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