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At least 1,459 records · Page 81Linked to original sources
PubMed1992

Constituents of Eriobotrya japonica. A study of their antiviral properties.

The CHCl3 extract of Eriobotrya japonica from an Italian source was shown to contain four new triterpene esters, namely, 23-trans-p-coumaroyltormentic acid [1], 23-cis-p-coumaroyltormentic acid [2], 3-O-trans-caffeoyltormentic acid [3], and 3-O-trans-p-coumaroylrotundic acid [4], in addition to three common ursolic acid derivatives 5, 6, and 7. An investigation of the antiviral properties of compounds 1-7 revealed that only 3 significantly reduced rhinovirus infection. The compounds were ineffective towards human immunodeficiency virus type 1 (HIV-1) and Sindbis virus replication.

Antiviral Agents↗
PubMed1995

Turnover of circulating virion RNA and of cell-associated viral DNA reflects active viral replication in human immunodeficiency virus type 1-infected individuals.

A quantitative assessment of human immunodeficiency virus type 1 turnover in patient cell-free virion and infected-cell compartments under the dynamic conditions imposed by an effective antiviral therapy was performed. The turnover was rapid, and following a temporal lag, the extent of viral population replacement was eventually similar in both compartments. Each compartment therefore reflects considerable active virus replication.

Antiviral Agents↗
PubMed1996

Antiviral roundup.

Explore the source record for details and available documents.

CD4 Lymphocyte Count↗
PubMed1990

Pharmacodynamics of 2',3'-dideoxycytidine: an inhibitor of human immunodeficiency virus.

The incidence of acquired immunodeficiency syndrome and the number of people infected with the human immunodeficiency virus (HIV) is likely to increase into the 1990s and perhaps beyond. Zidovudine, a 2',3'-dideoxynucleoside approved for the treatment of acquired immunodeficiency syndrome, provides immunologic, virologic, and survival benefits. However, because its hematologic toxicity can be dose-limiting, investigations are ongoing with other 2',3'-dideoxynucleosides. After zidovudine, the first of these agents to be tested was 2',3'-dideoxycytidine (ddC), the most potent inhibitor of HIV reverse transcriptase among the dideoxynucleosides tested thus far. Concentrations of ddC as low as 0.5 microM provide protection against HIV in cultured T cells (and monocytes), even at high multiplicities of infection. Like the other dideoxynucleosides, activation of ddC is dependent on intracellular phosphorylation to its 5'-triphosphate form. Efforts are under way to alter enzymatically the intracellular ratio of ddC-5'-triphosphate to deoxycytidine-5'-triphosphate, its endogenous counterpart. ddC has relatively straightforward pharmacokinetics; it has a plasma half-life of about 1.2 hours and an oral bioavailability of about 87 percent. Approximately 75 percent of the drug is excreted unchanged in the urine. Patients treated with ddC have experienced both immunologic and virologic benefit, although long-term high doses are limited by the development of painful peripheral neuropathy. Significant hematologic toxicity is not evident in most patients; low-dose regimens of ddC alone, as well as alternating or in combination with zidovudine, are being tested in an effort to retain antiviral activity while minimizing treatment toxicities.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Antiviral therapy in human immunodeficiency virus infections. Current status (Part II).

Part I of this article reviewed the targets against which anti-HIV drugs can be directed, problems in assessing active compounds (e.g. resistance development and use of surrogate end-points). and nucleoside analogues effective against HIV reverse transcriptase. Intensive research is currently being undertaken in laboratories and hospitals to design and evaluate new inhibitors of HIV. In this work, combining different drugs is one important approach, both to decrease toxicity and to offset the rate of resistance development, which seems to be a major problem associated with therapy directed against the ever-changing HIV. Therapeutic vaccines and immunomodulators are other modalities being actively evaluated against HIV and AIDS, although this effort has not yet yielded any licensed treatment. It appears likely that new antiviral drugs and immunotherapies will be forthcoming during the next 5 years, that they will be used in a variety of combinations, and that the treatment options available for opportunistic infections will increase. These developments should improve the survival and the quality of life of patients with HIV infection.

Antiviral Agents↗
PubMed1988

Antiviral therapy.

The complicated machinery used by HIV for multiplication offers several targets for therapy and the viral enzymes appear to be particularly appropriate targets. For the HIV reverse transcriptase, this has been demonstrated by the clinical effect of zidovudine, but less toxic drugs are needed. The HIV protease is another viral enzyme against which inhibitors are likely to be developed. As the function and structure of HIV proteins are understood in more detail, it will become possible to construct more selective inhibitors. It is necessary to evaluate new HIV inhibitors in animal models to facilitate the rapid selection of suitable compounds and combinations for further clinical evaluation. It appears likely that several drugs preventing HIV replication will be required, and that these will appear during the next few years, but it is also apparent that the elimination of HIV from a patient remains a remote possibility.

Acquired Immunodeficiency Syndrome↗
PubMed2000

Inhibition of the initiation of HIV-1 reverse transcription by 3'-azido-3'-deoxythymidine. Comparison with elongation.

Initiation of human immunodeficiency virus-1 reverse transcription requires formation of a complex containing the viral RNA, primer tRNA(3)(Lys), and reverse transcriptase. Initiation, corresponding to addition of the first six nucleotides to tRNA(3)(Lys), is distinguished from elongation by its high specificity and low efficiency (processivity). Here, we compared the inhibition of initiation and elongation of reverse transcription by 3'-azido-3'-deoxythymidine 5'-triphosphate (AZTTP), the active form of 3'-azido-3'-deoxythymidine. We report the first detailed study of nucleotide binding, discrimination, and pyrophosphorolysis by the authentic initiation complex. We showed that the initiation and elongation complexes bound AZTTP and dTTP with the same affinity, while the polymerization rates were reduced by 148-160-fold during initiation. The pyrophosphorolysis rate of dTTP was reduced by the same extent, indicating that the polymerization equilibrium is the same in the two phases. The efficient unblocking of the 3'-azido-3'-deoxythymidine 5'-monophosphate (AZTMP)-terminated primer by pyrophosphorolysis significantly relieved inhibition of DNA synthesis during elongation in the presence of physiological pyrophosphate concentrations. Remarkably, although pyrophosphorolysis of dTMP and AZTMP were equally efficient during elongation, reverse transcriptase was almost totally unable to unblock the AZTMP-terminated primer during initiation. As a result, inhibition of reverse transcription by AZTTP was more efficient during initiation than elongation of reverse transcription, despite a reduced selectivity of incorporation.

Base Sequence↗
PubMed2006

Analysis of polymorphism in the protease and reverse transcriptase genes of HIV type 1 CRF02-AG subtypes from drug-naive patients from Saint-Etienne, France.

SUMMARY: : The proportion of non-B HIV-1 variants is increasing in Western Europe. The impact of the high polymorphism in the protease and reverse transcriptase genes, as recently described for CRF02-AG isolates of African origin, on antiretroviral resistance is still disputed. We first examined the polymorphism of these genes in CRF02-AG strains recovered from drug-naive patients followed at the University Hospital of Saint-Etienne in France, most of these of French origin and harboring a clonal strain as elicited by phylogenic analysis. The first plasma sample detected positive from 31 CRF02-AG and 23 B strains was used to compare sequences with their respective subtype consensus strain. The overall number of mutations was dramatically higher for CRF02-AG strains than for B strains in both protease and reverse transcriptase genes (P < 0.0001 and 0.009, respectively). In addition, no statistically significant difference in the number of therapeutic failures, mean CD4 cell count, and viral load was observed between 22 and 45 patients infected with CRF02-AG or B strains, respectively, during a mean treatment period of 25.5 months. Even if no striking antiretroviral failure linked to this polymorphism was observed during short-term follow-up, its impact on long-term therapy will have to be extensively evaluated in patients infected by non-B HIV-1 variants.

Adult↗
PubMed1993

Mechanisms of the inhibition of reverse transcription by unmodified and modified antisense oligonucleotides.

We demonstrated that unmodified and modified (phosphorothioate) oligonucleotides prevent cDNA synthesis by AMV or HIV reverse transcriptases. Antisense oligonucleotide/RNA hybrids specifically arrest primer extension. The blockage involves the degradation of the RNA fragment bound to the antisense oligonucleotide by the reverse transcriptase-associated RNase H activity. However, the phosphorothioate oligomer inhibited polymerization by binding to the AMV RT rather than to the template RNA, whereas there was no competitive binding of the phosphorothioate oligomer on the HIV RT during reverse transcription.

Animals↗
PubMed1999

Initiation of minus-strand DNA synthesis by human immunodeficiency virus type 1 reverse transcriptase.

The initiation of (-) strand DNA synthesis by HIV-1 reverse transcriptase was examined using a transient kinetic approach and a physiologically relevant RNA 18-mer/RNA 36-mer primer-template substrate. HIV-1 reverse transcriptase (RT) was found to bind with reasonably high affinity to the RNA/RNA substrate (K(d) = 90 nM), although the affinity for DNA/RNA and DNA/DNA substrates is higher (K(d) approximately 5 nM). A pre-steady-state burst of deoxynucleotide incorporation (k(obsd) = 1.0 s(-)(1)) into the RNA duplex was observed followed by a slower steady-state release of the elongated primer-template product (k(ss) = 0.58 s(-)(1)). The observation of a burst provides evidence that the release of the product is most likely the rate-limiting step in the overall kinetic pathway for the enzymatic reaction during a single deoxynucleotide incorporation event. Furthermore, the release of this product was 5-fold faster than that for elongated DNA/RNA and DNA/DNA products. Single-turnover experiments showed that there is a hyperbolic dependence of the rate of deoxynucleotide incorporation on the concentration of dCTP and demonstrated that the maximum rate of dCTP incorporation (k(pol) = 1.4 s(-)(1)) is 33- and 12-fold slower than the values for DNA/RNA and DNA/DNA primer-template substrates, respectively, while the affinity of dCTP (K(d) = 780 microM) for the HIV-1 RT.RNA/RNA complex is 56- and 71-fold weaker than the affinities for HIV-1 RT.DNA/RNA and HIV-1 RT.DNA/DNA complexes, respectively. Consequently, the overall efficiency of dCTP incorporation (k(pol)/K(d)) into the RNA/RNA substrate is approximately 1800- and 800-fold less than that for DNA/RNA and DNA/DNA substrates, respectively. These findings provide evidence which suggests that the HIV-1 RT.RNA/RNA.dCTP ternary complex exists in a significantly different conformation compared to ternary complexes involving DNA/RNA and DNA/DNA substrates. A model summarizing these results is presented, and implications for the molecular mechanism of initiation of (-) strand DNA synthesis by RT are discussed.

Binding Sites↗
PubMed2002

Hypersusceptibility to non-nucleoside reverse transcriptase inhibitors in HIV-1: clinical, phenotypic and genotypic correlates.

OBJECTIVE: The routine use of phenotypic drug resistance testing in patient management has revealed that many HIV-1 strains possess significantly increased drug sensitivity, or 'hypersusceptibility' compared with wild-type viruses. This study describes hypersusceptibility to non-nucleoside reverse transcriptase inhibitors (NNRTI) and was designed to determine the prevalence of and viral characteristics associated with NNRTI hypersusceptibility in patient-derived viruses. METHODS: Retrospective analyses were performed on a large clinical laboratory dataset containing phenotypic drug susceptibility and genotypic sequence results from HIV-1 patient isolates. Genetically engineered viruses were used to confirm the role of certain nucleoside reverse transcriptase inhibitor (NRTI)-resistance mutations in NNRTI hypersusceptibility. RESULTS: Hypersusceptibility to delavirdine, efavirenz and nevirapine was detected in 10.7, 10.8 and 8.0% of more than 17,000 consecutive plasma samples submitted for phenotypic susceptibility testing. In analyses limited to a subset of viruses derived from patients with known treatment histories, NNRTI hypersusceptibility was observed significantly more frequently among viruses from NRTI experienced/NNRTI-naive patients compared with viruses from NRTI/NNRTI-naive patients. Significant inverse correlations between NRTI and NNRTI susceptibility exist among the viruses from NRTI-experienced patients. Analyses of viruses classified according to their NNRTI susceptibility identified 18 positions in reverse transcriptase where substitutions were significantly associated with NNRTI hypersusceptibility. CONCLUSIONS: NNRTI hypersusceptibility is common among patient HIV-1 isolates, especially in NRTI-resistant viruses. Genotypic correlates of hypersusceptibility are complex and not easily defined by a simple analysis of NRTI-associated resistance mutations. NNRTI hypersusceptibility may provide an explanation for the superior virologic response to NNRTI-containing salvage regimens observed in NRTI-experienced patients in several clinical trials.

Anti-HIV Agents↗
PubMed2006

Anti-HIV therapy: Current and future directions.

Although combinations of drugs that target the HIV reverse transcriptase and protease enzymes have clearly revolutionized the treatment of HIV/AIDS, problems with these agents, such as viral escape mutants, persistence of viral reservoirs, poor patient compliance due to complicated regimens, and toxic side effects, have emphasized the need for development of new drugs with novel mechanisms of action, as well as an HIV vaccine. Recently two new classes of drugs have been identified that interfere with the membrane fusion reaction required for HIV entry of target cells. Two such agents, T-20 (enfuvirtide) and T-1249, which have been approved by the Food and Drug Administration (FDA), block the action of the fusogenic envelope glycoprotein gp41. Others target the HIV coreceptors CCR5 and CXCR4, and are now in clinical trials. Also under development are novel agents that target the HIV integrase and HIV regulatory gene products as well as immunomodulators such as IL-12 and IL-2. This article will focus on these and other novel approaches to HIV therapeutics.

Anti-HIV Agents↗
PubMed1998

Sulfated glycoglycerolipid from archaebacterium inhibits eukaryotic DNA polymerase alpha, beta and retroviral reverse transcriptase and affects methyl methanesulfonate cytotoxicity.

A sulfated glycoglycerolipid, 1-O-(6'-sulfo-alpha-D-glucopyranosyl)-2,3-di-O-phytanyl- sn-glycerol (KN-208), a derivative of the polar lipid isolated from an archaebacterium, strongly inhibited DNA polymerase (pol) alpha and pol beta in vitro among 5 eukaryotic DNA polymerases (alpha, beta, gamma, delta, and epsilon). It also inhibited Escherichia coli DNA polymerase I Klenow fragment (E. coli pol I) and human immunodeficiency virus reverse transcriptase (HIV RT). The mode of inhibition of these polymerases was competitive with the DNA template primer and was non-competitive with the substrate dTTP. KN-208 inhibited pol beta most strongly, with a Ki value of 0.05 microM, 10-fold lower than that for pol alpha (0.5 microM) and 60- or 140-fold lower than that for HIV RT (3 microM) or for E. coli pol I (7 microM), respectively. The loss of sulfate on the 6'-position of glucopyranoside of this compound completely abrogated inhibition. However, the hydrophilic part of KN-208, glucose 6-sulfate alone, showed no inhibition. Other sulfated compounds containing different hydrophobic structures, such as dodecyl sulfate and cholesterol sulfate, exhibited a much weaker inhibition. Our results suggest that the whole molecular structure of KN-208 is required for inhibition. KN-208 was shown to be modestly cytotoxic for the human leukemic cell line K562. Interestingly, a subcytotoxic dose of KN-208 increased the sensitivity of the human leukemic cells to an alkylating agent, methyl methanesulfonate, while it did not potentiate the effects of ultraviolet light or of cisplatin.

Archaea↗
PubMed2006

Clinical and genotypic correlates of mutation K65R in HIV-infected patients failing regimens not including tenofovir.

The mutation RT-K65R confers resistance to tenofovir (TDF). Although its prevalence is increasing with the use of this drug, clinical and genotypic correlates of K65R occurrence have yet to be fully identified. Clinical, virological and immunological and genotypic data of patients naïve for TDF who failed HAART regimens and underwent genotypic resistance test (GRT) during 1999-2003 were collected in a database and analyzed retrospectively. Out of 1392 GRT performed for 771 patients, 12 TDF-naïve patients had the K65R mutation with an overall prevalence of 1.6%. Previous AIDS, the use of abacavir, and treatment with efavirenz at GRT were independently associated with a greater risk of expressing K65R, while patients with longer exposure to lamivudine were less likely to present the mutation. Among genotypic correlates, the presence of M184V and NAMs seems to be protective for the emergence of K65R, while a strong positive correlation was found with the Q151M complex mutation. Moreover, the L100I mutation was independently associated with a higher probability of presenting K65R. The selection of mutation K65R in patients failing without TDF is rare. However, exposure to abacavir and/or efavirenz, presence of Q151M and/or L100I, and prior AIDS may favor the selection of this mutation. Conversely, long 3TC exposure, and the presence of M184V or NAMs seem to be protective.

Adenine↗
PubMed2004

Novel nevirapine-like inhibitors with improved activity against NNRTI-resistant HIV: 8-heteroarylthiomethyldipyridodiazepinone derivatives.

A series of 8-heteroarylthiomethyldipyridodiazepinone derivatives were prepared and evaluated for their antiviral profile against wild type virus and the important K103N/Y181C mutant as an indicator for broad activity. 2,6-Dimethylpyridine derivative 16 was found to have a good pharmacokinetic profile in spite of poor metabolic stability in rat liver microsomes.

Animals↗