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)

Human immunodeficiency virus type 1 (HIV-1)-infected CEM cells were treated by the HIV-1-specific inhibitors bis-heteroarylpiperazine (BHAP), 4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk][1,4]benzodiazepin-2(1 H)-on e (TIBO) R82913, nevirapine, and the N3-methylthymine derivative of [2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-ribofuranosyl]-3'-spiro- 5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide) (TSAO-m3T), as single agents or in combination, at escalating concentrations. When used individually, the compounds led to the emergence of drug-resistant virus strains within two to five subcultivations. The resulting strains were designated HIV-1/BHAP, HIV-1/TIBO, HIV-1/Nev, and HIV-1/TSAO-m3T, respectively. The mutant viruses showed the following amino acid substitutions in their reverse transcriptase (RT): Leu-100-->Ile for HIV-1/BHAP; Lys-103-->Asn for HIV-1/TIBO; Val-106-->Ala for HIV-1/Nev; and Glu-138-->Lys for HIV-1/TSAO-m3T. Both the Tyr-181-->Cys and Val-106-->Ala mutations were found in another mutant emerging following treatment with nevirapine at escalating concentrations. The BHAP-resistant virus remained fully sensitive to the inhibitory effects of nevirapine and TSAO-m3T, whereas the TSAO-m3T-resistant virus remained fully sensitive to the inhibitory effects of nevirapine and BHAP. When different pairs of nonnucleoside RT inhibitors (i.e., BHAP plus TSAO-m3T, nevirapine plus TSAO-m3T, TIBO plus TSAO-m3T, nevirapine plus TIBO, and BHAP plus nevirapine) were used, resistant virus emerged as fast as with single-drug therapy. In all cases the Tyr-181-->Cys mutation appeared; the virus showed markedly reduced sensitivity to all HIV-1-specific inhibitors but retained sensitivity to 2',3'-dideoxynucleoside analogs such as zidovudine, ddC, and ddI. Our findings argue against simultaneous combination of two different nonnucleoside RT inhibitors that are unable to inhibit HIV-1 mutant strains containing the Tyr-181-->Cys mutation when administered as single drugs.
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PMID:Treatment of human immunodeficiency virus type 1 (HIV-1)-infected cells with combinations of HIV-1-specific inhibitors results in a different resistance pattern than does treatment with single-drug therapy. 768 22

The effect of 3 drug combinations (AZT/FLT, AZT/ddI and FLT/ddI) upon the replication of AZT-sensitive and -resistant human immunodeficiency virus (HIV) was studied. The 3 combinations synergistically inhibited drug sensitive virus. However, AZT resistant virus showed an altered response to the combinations containing AZT: synergy was replaced by addition or antagonism. Thus, the susceptibility to a drug may affect the synergistic effect of combinations containing that drug. Other drug combinations may not be affected, since the AZT resistant virus retained a synergistic response to the combination of FLT/ddI. The synergistic effect could be regained upon reversion of resistance; a viral isolate taken after cessation of therapy, which had reverted to sensitivity to AZT, regained the synergistic response to drug combinations containing AZT. These results have implications for the use of combination chemotherapy to treat infection with HIV. Drug combinations will be most useful if the virus is sensitive to all components in the combination. It might be preferable to avoid the inclusion in combinations of drugs to which there is resistance, since we saw an antagonistic effect for combinations containing AZT in AZT resistant virus. Other combinations not containing the drug to which resistance has arisen may maintain their synergistic effect and remain good choices. Thus, a strategy of monitoring drug sensitivity and altering the combination therapy accordingly would appear to offer promise for the treatment of HIV infection.
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PMID:Effect of resistance on combination chemotherapy for human immunodeficiency virus infection. 768 90

3'-azido-3'deoxythymidine (AZT), a clinically used anti-HIV compound, was evaluated for antiviral effect on HIV infection in combination with other antiviral compounds in vitro. Interactions were evaluated by the median-effect principle and the isobologram technique. Synergistic effect was obtained by combining many evaluated antiviral agents with AZT. We observed a difference in the degree of synergism depending on the evaluated compound; the results indicate that compounds with the same target in the viral replicative cycle (ddI: 2',3'-dideoxyinosine, didanosine; d4T: 2',3'-dideoxy-2',3'-didehydrothymidine stavodine; TIBO: tetrahydro-imidazole-benzodiazepin) had a synergistic effect at all concentrations, agents that disturb the infectivity of virus (CAS: Castanospermine; AME: Amphotericin B Methyl Ester) exerted a strong synergistic effect at low concentrations, and finally compounds interfering with the adhesion/penetration process of virus (ConA: Concanavalin A; DS: dextran sulfate) were most potent with AZT when used in rather high concentrations. At this moment in the HIV epidemic, these observations suggest that combinations of antiviral compounds should be evaluated in clinical trials, with the major emphasis on nucleoside analogues and compounds influencing the infectivity of the virus.
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PMID:Evaluation of the combination effect of different antiviral compounds against HIV in vitro. 768 46

The reverse transcriptase enzyme of human immunodeficiency virus type 1 (HIV-1) is the target for many inhibitors. Amino-acid substitutions in functional regions of the enzyme that abolish reverse transcriptase activity also prevent HIV-1 replication. But selection pressure by drugs such as AZT (3'-azido-3'deoxythymidine, zidovudine), ddI (2',3'-dideoxyinosine) and non-nucleoside reverse transcriptase inhibitors (NNRTIs) causes outgrowth of resistant variants due to non-lethal mutations in the enzyme. Reports of synergy and lack of cross-resistance between reverse transcriptase inhibitors (refs 7, 9, 10, 12-14, 17, 18, 20, 21), plus the reversal of AZT resistance by mutations induced by ddI and NNRTIs, have indicated that specific drug combinations directed at reverse transcriptase might curtail resistance. Chow et al. extended this concept in a report that specific multiple combinations of resistance mutations in the reverse transcriptase can significantly impair HIV-1 replication. They concluded that evolutionary limitations may exist to prevent the emergence of multidrug resistance to inhibitors of reverse transcriptase. We report here that HIV-1 co-resistant to AZT, ddI and the NNRTI nevirapine can be readily selected in cell culture starting with dual AZT- and ddI-resistant virus. We found no evidence for 'replication incompatible' combinations of resistance mutations, although a mutation (M184-->V) conferring oxathiolane-cytosine nucleoside resistance in reverse transcriptase completely suppressed AZT resistance in a triple-resistant background. These in vitro observations suggest that triple drug combination therapy might ultimately result in co-resistant HIV-1, although they do not preclude assessment of such combinations for treatment of HIV-1 disease.
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PMID:Convergent combination therapy can select viable multidrug-resistant HIV-1 in vitro. 769 2

Thiazolobenzimidazole (NSC 625487) was a highly potent inhibitor of human immunodeficiency virus-induced cell killing and viral replication in a variety of human cell lines, as well as fresh human peripheral blood lymphocytes and macrophages. The compound was active against a panel of biologically diverse laboratory and clinical strains of HIV-1, including the AZT-resistant strain G910-6. However, the agent was inactive against HIV-2 and a pyridinone-resistant strain (A17) of HIV-1, a strain which is cross-resistant to several structurally diverse members of a common pharmacologic class of nonnucleoside reverse transcriptase inhibitors. The compound selectively inhibited HIV-1 reverse transcriptase but not HIV-2 reverse transcriptase. Combinations of thiazolobenzimidazole with either AZT or ddI synergistically inhibited HIV-1 induced cell killing in vitro. Thiazolobenzimidazole also inhibited the replication of the Rauscher murine leukemia retrovirus. Thus, thiazolobenzimidazole is a new active anti-HIV-1 chemotype and may represent a subclass of nonnucleoside reverse transcriptase inhibitors with an enhanced range of anti-retroviral activity.
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PMID:Thiazolobenzimidazole: biological and biochemical anti-retroviral activity of a new nonnucleoside reverse transcriptase inhibitor. 769 15

Methods for the absolute quantitation of nucleic acids present in small amounts in biological samples (competitive PCR and competitive reverse transcription PCR) were applied to the direct monitoring of specific anti-human immunodeficiency virus type 1 (HIV-1) therapy. With these techniques, different parameters of HIV-1 activity (including genomic RNA copy numbers in plasma, proviral and late transcript copy numbers in peripheral blood lymphocytes, and mean transcriptional activity per each HIV-1 provirus) were monitored during therapy with azidothymidine or ddI. In most of these treated patients, a direct response to the antiretroviral compounds employed was detected during the first few weeks of treatment, as documented by a fast decrease of all molecular indexes of HIV-1 activity. However, residual viral replication (albeit at minimal levels) was documented during therapy in all subjects monitored in this study. In a minority of the patients under study (3 of 12), the drug-dependent viral inhibition was maintained throughout the observation time (213 to 791 days), but in 9 patients a rebound in viremia level was detected during therapy with competitive reverse transcription PCR. Sequencing analysis of a portion of the HIV-1 gene pol from cell-free virions showed that circulating viral variants bearing at least two mutations compatible with azidothymidine or ddI resistance were detectable in the patients who exhibited a rebound in cell-free HIV-1 genomic RNA copy numbers in plasma but not in one patient who maintained (for 455 days) lowered levels of viral load during ddI treatment.
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PMID:Quantitative molecular monitoring of human immunodeficiency virus type 1 activity during therapy with specific antiretroviral compounds. 769 34

We attempted to detect drug-related HIV-1 pol gene mutations by selective polymerase chain reaction (PCR) using both proviral DNA and viral RNA isolated from patients (pts) with AIDS or ARC receiving antiretroviral therapy. Peripheral blood mononuclear cell (PBM)-associated proviral DNA and serum-derived viral RNA were obtained from eight patients before and after receiving an alternating regimen of AZT and ddC for 15-41 months or ddI monotherapy for 12-26 months. These specimens were examined for the presence of mutations at positions 70, 74, 215 and 219. We noted that selective PCR results can be ambiguous depending on the quantity of DNA template employed. We, therefore, used the minimal quantity of DNA templates that yielded evaluable PCR products in this study. For all the eight pairs of pre- and post-therapy proviral DNA samples, selective PCR results agreed with independently determined nucleotide sequences. Results of reverse transcription of serum-derived viral RNA followed by selective PCR differed in some cases from those using the proviral DNA. In particular, the use of serum viral RNA appeared to allow earlier detection of changes in drug-related mutations than the use of PBM-associated proviral DNA. We conclude that (i) selective PCR using the minimum and sufficient number of PBM-associated proviral DNA and serum viral RNA copies successfully detects the presence of known pol gene mutations; (ii) drug-related mutations may be distinguished earlier in virions in serum (or plasma) than in proviral DNA in PBM; and (iii) quantification of HIV-1 prior to selective PCR may be an important component in monitoring the therapy of HIV-1 infection.
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PMID:Identification of drug-related genotypic changes in HIV-1 from serum using the selective polymerase chain reaction. 771 Feb 71

To evaluate the safety and efficacy of didanosine (ddl) monotherapy and three different combinations of zidovudine (ZDV) and ddl in asymptomatic human immunodeficiency virus-1 (HIV-1) infection, we conducted an open-label, phase I/II study in 126 asymptomatic HIV-1-infected hemophilic and nonhemophilic subjects with a CD4 count of 200 to 500/mm3 stratified for prior zidovudine treatment and baseline CD4 count. Study arms included arm A, low-dose combination (ZDV 150 mg and ddl 134 mg, daily); arm B, moderate-dose combination (ZDV 300 mg and ddI 334 mg, daily); arm C, high-dose combination (ZDV 600 mg and ddl 500 mg, daily), and arm D, ddl monotherapy (ddl 500 mg, daily). Earlier, more frequent hepatotoxicity was experienced by hemophilic subjects (P = .008), but there were no differences in toxicity between treatment arms (P = .51), nor were there any differences in the rate of development of clinical endpoints by treatment (P = .41). Smaller median CD4 increases occurred over the first 12 weeks for arms A and D, 44/mm3 and 42/mm3, than arms B and C, 105/mm3 and 114/mm3, respectively, (P = .015). Hemophilia status (P = .0004) and prior ZDV experience (P = .044) independently predicted weaker CD4 responses during the first 12 weeks of treatment. Using a regression model and adjusting for hemophilia status, prior ZDV treatment, and baseline CD4, there was a significant reduction in quantitative viral load from baseline by week 12 for all treatment arms combined (P = .0001), with significantly lower median percent reduction for arm A (56.3%) than arms B, C, and D (94.6%, 98.5%, and 91.9%, respectively, P = .015). Although greater hepatoxicity and weaker CD4 responses occur in hemophilic subjects, didanosine monotherapy and combination therapy with zidovudine are safe and effective in asymptomatic HIV-1-infected patients.
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PMID:Randomized study of didanosine monotherapy and combination therapy with zidovudine in hemophilic and nonhemophilic subjects with asymptomatic human immunodeficiency virus-1 infection. AIDS Clinical Trial Groups. 772 68

Much controversy surrounds the use of antiretroviral drugs in HIV-infected patients. The many studies involving large numbers of patients that have been and are being conducted have raised as many questions as they have sought to answer. Given that no cure exists and that all clinically available drugs have only limited activity despite their high toxicity, the question of which drug (or combination of drugs) to use, and in whom, continues to vex both the clinician and the patient. Only three specific antiretroviral agents are currently licensed for use: zidovudine (ZDV), didanosine (dideoxyinosine, ddI) and zalcitabine (dideoxycytidine, ddC). This article reviews the major studies comparing the clinical efficacy of these drugs and the possible benefits of adding acyclovir to zidovudine therapy. The questions of when to begin antiretroviral therapy and the role of combination chemotherapy are discussed. Whenever possible, 'clinical' endpoints (death or clinical progression) are distinguished from 'softer' endpoints (surrogate markers of progression, such as the CD4 lymphocyte count) in the studies reviewed. Recommendations for the use of antiretroviral agents based on currently available published data are made.
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PMID:Controversies in anti-retroviral therapy of adults. 775 89

Treatment with antiviral drugs (zidovudine and ddI) has been reported to delay progression to AIDS, and may even possibly lower the infectiousness of the infectives. However, its effect on the community level is still uncertain. The latter is important since a successful community treatment program must meet both public health and individual health goals. Our study will focus on the effect of a community-wide treatment program initiated at the early stages of the disease as well as the long-term effect of the program. Using a simple mathematical model, we demonstrate that a community-wide treatment program could be instrumental in decreasing HIV incidence rate and eradicating the disease in the future if certain conditions on the parameters are met. On the other hand, when the above mentioned conditions on the parameters are not satisfied, we show that even if the treatment does improve survival in AIDS patients and decrease the rate at which HIV infection spreads in the community, it is still possible for the treatment program to have an adverse effect on the spread of AIDS in the population in the long run. Hence, a public health policy maker must exercise caution in order to design an effective treatment program for HIV/AIDS.
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PMID:Community treatment of HIV-1: initial stage and asymptotic dynamics. 777 24


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