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PubMedDate not supplied

[Inhibition of HIV reproduction in cultured cells using proteolysis inhibitors].

Treatment of AIDS is a complicated problem since there is a limited set of preparations tested and most of them appear to be ineffective. Their main target is HIV reverse transcriptase. The data presented show that proteolysis inhibitors are able to inhibit HIV reproduction in cell culture. The compounds used in this study, gordox and kontrikal, are officinal drugs and therefore it is worthwhile to study their effect in patients with AIDS.

Aprotinin↗
PubMedDate not supplied

[The antiviral action of recombinant forms of the human T-lymphocyte CD4 receptor].

A recombinant protein containing the first 179 N-terminus amino acids of human T-lymphocyte CD4-receptor was synthesized in E. coli cells. This recombinant protein was shown to interact with OKT4A and Leu3a monoclonal antibodies competing with HIV gp120 glycoprotein for binding with the native CD4 receptor. Experiments in vitro in human T-lymphocyte cultures showed that the recombinant CD4-protein in concentrations of 1 to 10 micrograms/ml inhibited the virus-induced syncytium formation, HIV replication in cell culture, synthesis of HIV reverse transcriptase and other virus-specific proteins, that is, behaved as a HIV inhibitor.

Antibodies, Monoclonal↗
PubMed1992

[2',5'-Bis-O-(tert-butyldimethylsilyl)]-3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide) (TSAO) derivatives of purine and pyrimidinenucleosides as potent and selective inhibitors of human immunodeficiency virus type 1.

The [2',5'-bis-O-(tert-butyldimethylsilyl)]-3'-spiro-5''-(4''-amino- 1'',2''-oxathiole-2'',2''-dioxide) (TSAO) derivatives of ribofuranosylthymine, uridine, 5-bromouridine, 5-methylcytidine, inosine, and adenosine are potent and selective inhibitors of human immunodeficiency virus type 1 (HIV-1) but not of other retroviruses (HIV-2, simian immunodeficiency virus, or Moloney murine sarcoma virus). The 50% effective concentration (EC50) of the most active TSAO congeners for inhibition of HIV-1 replication ranged from 0.034 to 0.44 microgram/ml. The 50% cytotoxic concentration (CC50) affecting the viability of MT-4 cells ranged from 2.35 to 18 micrograms/ml. The TSAO thymine derivative proved to be a highly selective inhibitor of HIV-1 reverse transcriptase but not of HIV-2 reverse transcriptase and DNA polymerase alpha. Introduction of an alkyl or alkenyl function at N3 of the thymine ring markedly decreased cytotoxicity but did not affect the antiviral activity of the compounds. The most potent (EC50, 0.034 microgram/ml) and most selective (CC50/EC50, 4088) inhibitor of HIV-1 replication proved to be the N3-methyl derivative of (1-[2',5'-bis-O-(tert-butyldimethylsilyl)beta-D-ribofuranosyl]thymine)- 3'-spiro-5''-(4''-amino-1'',2''-oxathiole-2'',2''-dioxide). This compound should be considered as a promising drug candidate for the treatment of HIV-1 infections.

Antiviral Agents↗
PubMed2000

The role of steric hindrance in 3TC resistance of human immunodeficiency virus type-1 reverse transcriptase.

Treating HIV infections with drugs that block viral replication selects for drug-resistant strains of the virus. Particular inhibitors select characteristic resistance mutations. In the case of the nucleoside analogs 3TC and FTC, resistant viruses are selected with mutations at amino acid residue 184 of reverse transcriptase (RT). The initial change is usually to M184I; this virus is rapidly replaced by a variant carrying the mutation M184V. 3TC and FTC are taken up by cells and converted into 3TCTP and FTCTP. The triphosphate forms of these nucleoside analogs are incorporated into DNA by HIV-1 RT and act as chain terminators. Both of the mutations, M184I and M184V, provide very high levels of resistance in vivo; purified HIV-1 RT carrying M184V and M184I also shows resistance to 3TCTP and FTCTP in in vitro polymerase assays. Amino acid M184 is part of the dNTP binding site of HIV-1 RT. Structural studies suggest that the mechanism of resistance of HIV-1 RTs carrying the M184V or M184I mutation involves steric hindrance, which could either completely block the binding of 3TCTP and FTCTP or allow binding of these nucleoside triphosphate molecules but only in a configuration that would prevent incorporation. The available kinetic data are ambiguous: one group has reported that the primary effect of the mutations is at the level of 3TCTP binding; another, at the level of incorporation. We have approached this problem using assays that monitor the ability of HIV-1 RT to undergo a conformational change upon binding a dNTP. These studies show that both wild-type RT and the drug-resistant variants can bind 3TCTP at the polymerase active site; however, the binding to M184V and M184I is somewhat weaker and is sensitive to salt. We propose that the drug-resistant variants bind 3TCTP in a strained configuration that is salt-sensitive and is not catalytically competent.

Amino Acid Substitution↗
PubMed2005

In vitro HIV type 1 reverse transcriptase inhibitory activities of Thai medicinal plants and Canna indica L. rhizomes.

Water and 80% ethanol extracts of 20 Thai medicinal plants used to treat AIDS were tested for their HIV type 1 reverse transcriptase inhibitory activity. The water extracts of Ipomoea carnea subsp. fistulosa (aerial parts), Vitex glabrata (branch), Vitex trifolia (aerial part), Vitex negundo (aerial part), Canna indica (rhizome), and Justicia gendarussa (aerial part) showed HIV-1 RT inhibition ratio (% IR) higher than 90% at a 200 microg/ml concentration. The water extract of Canna indica rhizomes (IC(50) 22.56 microg/ml) was selected for further study, i.e. for its HIV-1 RT inhibition activity and the purification and characterization of the active proteins. Proteins in water extract were fractionated by ammonium sulfate precipitation and separated by sodium dodecyl sulfate acrylamide gel electrophoresis (SDS-PAGE), yielding two proteins, Cip31 (31 kDa) and Cip14 (14 kDa) with IC50 of 17.41 and 19.25 microg/ml and isoelectric point (pI) of 3.5 and 6.35, respectively. Both proteins showed significant HIV-1 RT inhibition.

HIV Reverse Transcriptase↗
PubMed1996

Antiviral activity and mechanism of action of calanolide A against the human immunodeficiency virus type-1.

Calanolide A, recently discovered in extracts from the tropical rainforest tree, Calophyllum lanigerum, is a novel inhibitor of the human immunodeficiency virus (HIV) type 1. The compound is essentially inactive against strains of the less common HIV type 2. The present study focused on the further characterization of the selective antiviral activity and mechanism of action of calanolide A. The compound inhibited a wide variety of laboratory strains of HIV type 1, with EC50 values ranging from 0.10 to 0.17 microM. The compound similarly inhibited promonocytotropic and lymphocytotropic isolates from patients in various stages of HIV disease, as well as drug-resistant strains. Viral life-cycle studies indicated that calanolide A acted early in the infection process, similar to the known HIV reverse transcriptase (RT) inhibitor 2', 3'-dideoxycytidine. In enzyme inhibition assays, calanolide A potently and selectively inhibited recombinant HIV type 1 RT but not cellular DNA polymerases or HIV type 2 RT within the concentration range tested. Serial passage of the virus in host cells exposed to increasing concentrations of calanolide A yielded a calanolide A resistant virus strain. RT from the resistant virus was not inhibited by calanolide A but retained sensitivity to other nonnucleoside as well as nucleoside RT inhibitors, including 3'-azido-2',3'-dideoxythymidine triphosphate and nevirapine. The study substantially supports the conclusion that calanolide A represents a novel subclass of nonnucleoside RT inhibitor which merits consideration for anti-HIV drug development.

Anti-HIV Agents↗
PubMed1994

Synthesis, hydrolytic behavior, and anti-HIV activity of selected acyloxyalkyl esters of trisodium phosphonoformate (foscarnet sodium).

The synthesis and anti-HIV activity of selected (acyloxy)alkyl esters of trisodium phosphonoformate (foscarnet sodium) are described. The conversion of bis(trimethylsilyl) (alkoxycarbonyl)phosphonates 11a-d to the corresponding disilver salts 12a-d and their subsequent reaction with iodoalkyl acrylates 4a-c gave the desired bis(acyloxyalkyl) phosphonates 6-9(a-c). Of the analogs tested, only the dichlorophenyl analog 9a showed a dose-dependent inhibition of HIV activity in H9 cells. Using 31P-NMR, bioreversibility has been investigated in an attempt to rationalize these results.

Antiviral Agents↗
PubMed2004

Adaptation to the deleterious effects of antimicrobial drug resistance mutations by compensatory evolution.

Compensatory mutations, due to their ability to mask the deleterious effects of another mutation, are important for the adaptation and evolution of most organisms. Resistance to antibiotics, antivirals, antifungals, herbicides and insecticides is usually associated with a fitness cost. As a result of compensatory evolution, the initial fitness costs conferred by resistance mutations (or other deleterious mutations) can often be rapidly and efficiently reduced. Such compensatory evolution is potentially of importance for (i) the long-term persistence of drug resistance, (ii) reducing the rate of fitness loss associated with the accumulation of deleterious mutations in small asexual populations, and (iii) the evolution of complexity of cellular processes.

Amino Acid Sequence↗
PubMed2003

Change to abacavir-lamivudine-tenofovir combination treatment in patients with HIV-1 who had complete virological suppression.

Patients who have not received previous antiretroviral treatment (ART) have a high failure rate on the combination treatment of abacavir, lamivudine, and tenovir. We assessed the virological failure rate in eight patients with HIV-1 who switched to this combination after having complete virological suppression from their previous long-term ART (median 8.0 months, range 7.5-18.0). Five of the eight patients showed virological failure. Four of these five patients had either the K65R mutation, the M184V/I mutation, or both. This combination of drugs cannot therefore be recommended as alternative treatment in patients with HIV-1 who are fully virologically suppressed.

Adenine↗
PubMed2002

Design, synthesis, structure-activity relationships, and molecular modeling studies of 2,3-diaryl-1,3-thiazolidin-4-ones as potent anti-HIV agents.

Starting from 1H,3H-thiazolo[3,4-a]benzimidazoles (TBZs), we performed the design, synthesis, and the structure-activity relationship studies of a series of 2,3-diaryl-1,3-thiazolidin-4-ones. Some derivatives proved to be highly effective in inhibiting HIV-1 replication at nanomolar concentrations with minimal cytotoxicity, thereby acting as nonnucleoside HIV-1 RT inhibitors (NNRTIs). Computational studies were used to delineate the ligand-RT interactions and to probe the binding of the ligands to HIV-1 RT.

Anti-HIV Agents↗
PubMedDate not supplied

A new class of anti-HIV-1 oligonucleotide targeted to the polypurine tract of viral RNA.

The PPT is highly conserved among the known HIV-1 strains, and is a possible target for triplex formation. We show triple-helix formation by a two-strand-system (FTFOs, DsDGloopT5-37) targeted to the polypurine tract (PPT) of HIV-1. In HIV-1 infected MOLT-4 cells, the FTFOs containing phosphorothioate groups at the antisense strand and guanosine rich parts within the third Hoogsteen base pairing sequence inhibit the replication of HIV-1 more effectively than the antisense phos-phorothioate oligonucleotides indicating sequence-specific inhibition of HIV-1 replication for 62 days. However, AZT, treated cells expressed high levels of p 24 products after 46 days.

Anti-HIV Agents↗
PubMed2005

Comparison of two human immunodeficiency virus (HIV) RNA surrogate assays to the standard HIV RNA assay.

Human immunodeficiency virus (HIV) RNA testing is the gold standard for monitoring antiretroviral therapy in HIV-infected patients. However, equipment and reagent costs preclude widespread use of the assay in resource-limited settings. The Perkin-Elmer Ultrasensitive p24 assay and the Cavidi Exavir Load assay both offer potentially simpler, less costly technologies for monitoring viral load. These assays were compared to the Roche Amplicor HIV-1 Monitor Test, v1.5, using panels of clinical samples (subtype B) from HIV-positive subjects and HIV-spiked samples (subtypes A, C, D, CRF_01AE, CRF_02AG, and F). The Ultrasensitive p24 assay detected 100% of the spiked samples with virus loads of >250,000 copies/ml and 61% of the clinical samples with virus loads of 219 to 288,850 copies/ml. Detection rates were improved substantially if an external lysis buffer was added to the procedure. The Cavidi assay detected 54 to 100% of spiked samples with virus loads >10,000 copies/ml and 68% of the clinical samples. These detection rates were also greatly improved with a newly implemented version of this kit. Coefficients of variation demonstrate good reproducibility for each of these kits. The results from the Cavidi v1.0, Cavidi v2.0, and Perkin-Elmer, and the Perkin-Elmer Plus external buffers all correlated well with the results from the Roche Monitor Test (r = 0.83 to 0.96, r = 0.84 to 0.99, r = 0.58 to 0.67, and r = 0.59 to 0.95, respectively). Thus, the use of these two assays for monitoring patients, together with less-frequent confirmation testing, offers a feasible alternative to frequent HIV RNA testing in resource-limited settings.

HIV Core Protein p24↗
PubMed2002

Origin of human immunodeficiency virus type 1 quasispecies emerging after antiretroviral treatment interruption in patients with therapeutic failure.

The emergence of antiretroviral (ARV) drug-resistant human immunodeficiency virus type 1 (HIV-1) quasispecies is a major cause of treatment failure. These variants are usually replaced by drug-sensitive ones when the selective pressure of the drugs is removed, as the former have reduced fitness in a drug-free environment. This was the rationale for the design of structured ARV treatment interruption (STI) studies for the management of HIV-1 patients with treatment failure. We have studied the origin of drug-sensitive HIV-1 quasispecies emerging after STI in patients with treatment failure due to ARV drug resistance. Plasma and peripheral blood mononuclear cell samples were obtained the day of treatment interruption (day 0) and 30 and 60 days afterwards. HIV-1 pol and env were partially amplified, cloned, and sequenced. At day 60 drug-resistant variants were replaced by completely or partially sensitive quasispecies. Phylogenetic analyses of pol revealed that drug-sensitive variants emerging after STI were not related to their immediate temporal ancestors but formed a separate cluster, demonstrating that STI leads to the recrudescence and reemergence of a sequestrated viral population rather than leading to the back mutation of drug-resistant forms. No evidence for concomitant changes in viral tropism was seen, as deduced from env sequences. This study demonstrates the important role that the reemergence of quasispecies plays in HIV-1 population dynamics and points out the difficulties that may be found when recycling ARV therapies with patients with treatment failure.

Adult↗
PubMed2004

HIV-1 inhibitory compounds from Calophyllum brasiliense leaves.

The hexane, acetone and methanol extracts of Calophyllum brasiliense leaves were fractionated following a three bioassay guide: high HIV-1 RT inhibition, low cytotoxicity on MT2 cells and high inhibition of HIV-1 IIIb/LAV replication. This led to the isolation of three anti HIV-1 dipyranocoumarins: calanolides A and B and soulattrolide. In contrast, other isolated compounds such as apetalic acid, isoapetalic acid, a structural isomer of isoapetalic acid, friedelin, canophyllol and amentoflavone were devoid of HIV-1 RT inhibitory activity. Calanolide C was also obtained as a natural product and showed moderate inhibitory properties.

Anti-HIV Agents↗