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)

Although anti-human immunodeficiency virus type 1 (HIV-1) therapy has prolonged the lives of patients, drug resistance is a significant problem. Of particular concern are mutations that cause cross-resistance to a particular class of drugs. Among the mutations that cause resistance to several nucleoside analogs are the insertion of amino acids in the fingers subdomain of HIV-1 reverse transcriptase (RT) at positions 69 and 70. These insertions are usually associated with changes in the flanking amino acids and with a change to F or Y at position 215. We have proposed that the T215F/Y mutation makes the binding of ATP to HIV-1 RT more effective, which increases the excision of 3-azido-3'-deoxythymidine-5'-monophosphate (AZTMP) in vitro and increases zidovudine (AZT) resistance in vivo. Although the mechanism of AZT resistance involves enhanced excision, resistance to 3TC involves a block to incorporation of the analog. We measured the effects of fingers insertion mutations on the misincorporation and excision of several nucleoside analogs. RT variants with the amino acid insertions in the fingers and T215Y have a decreased level of misincorporation of ddATP and 3TCTP. These mutants also have the ability to excise AZTMP by ATP-dependent pyrophosphorylysis. However, unlike the classic AZT resistance mutations (M41L/D67N/K70R/T215Y or F/K219E or Q), the combination of the amino acid insertions in the fingers and the T215Y mutation allows efficient excision of ddTMP and d4TMP, even when relatively high levels of deoxynucleoside triphosphates are present in the reaction. Although the dideoxynucleoside analogs of other nucleosides were excised more slowly than AZTMP, ddTMP, and d4TMP, the mutants with the fingers insertion and T215Y excised all of the nucleoside analogs that were tested more efficiently than wild-type RT or a mutant RT carrying the classical AZT resistance mutations. In the ternary complex (RT/template-primer/dNTP), the presence of the bound dNTP prevents the end of the primer from gaining access to the nucleotide binding site (N site) where excision occurs. Gel shift analysis showed that the amino acid insertions in the fingers destabilized the ternary complex compared to wild-type HIV-1 RT. If the ternary complex is unstable, the end of the primer can gain access to the N site and excision can occur. This could explain the enhanced excision of the nucleoside analogs.
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PMID:Nucleoside analog resistance caused by insertions in the fingers of human immunodeficiency virus type 1 reverse transcriptase involves ATP-mediated excision. 1218 98

During a conference held in The Hague, in 1999, to review 5-year progress in attaining the goals of the 1994 International Conference on Population and Development, the head of the technical branch of the UN Population Fund noted the importance of developing an inexpensive vaginal microbicidal agent that women could insert prior to sexual intercourse to prevent HIV infection. Major drug firms are not focusing on the necessary research, however, because they do not believe such microbicides would be a source of profit and because of liability concerns. The need for women to have access to such protection has been made urgent by the fact that most new HIV infections are occurring in women. At the moment, approximately 20 microbicide products are in some stage of development. Clinical trials will soon begin for the Population Council's product, PC512, and for PRO 2000 Gel, developed by a Massachusetts-based firm. It is believed that, to be effective, a microbicide must combine several active ingredients.
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PMID:Promising HIV preventive may put women in control. 1229 35

In the US, legislation has been introduced in Congress for increased funding for research and development of microbicides, which protect against HIV and sexually transmitted diseases. Vaginal microbicides act by creating a barrier between the pathogen and the vagina, thus blocking infection, killing or immobilizing pathogens, and preventing a virus from replicating once it has infected the cells that line the vaginal wall. Proceedings from the first international conference on microbicides are to be published in the journal AIDS. Two microbicide products available in the US market (Conceptrol Gel and Advantage-S) are on their phase III trials to examine their effectiveness.
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PMID:Push is on for increased microbicide R&D funds. 1229 24

OmniComm Systems, Inc. (OMCM), Miami, Florida, announced it is partnering with Optima WorldWide, Ltd., to launch US testing of a vaginal gel for the potential prevention of pregnancy and the most common sexually transmitted diseases (STDs). Surete Gel, which is already being sold in China as a vaginal disinfectant and contraceptive, is being tested as a potential preventive agent for most STDs, including HIV. The concept of an antimicrobial product that prevents infectious sexual diseases has long been awaited by experts at the WHO and the US National Institutes of Health as an important weapon in preventing the global STD and HIV epidemics. OmniComm's Internet electronic data capture system, TrialMaster, and its web portal for trial investigators and participants, WebIPA.com, will manage long-term testing of Surete Gel worldwide. Stephen Drake, Optima, is hailing the partnership with OmniComm as a big step forward. "We are very pleased with this alliance as we complete trials on Surete Gel. This brings us closer to bringing a microbicide gel to the important US market while our vaginal disinfectant and contraceptive is already being introduced abroad". Optima is awaiting approval to sell Surete Gel in India and Thailand, as well as in several African and European nations. OmniComm is expanding its trial investigator base for Surete clinic trials in the US by enrolling experienced US investigators in the field of gynecology. A number of trial participants will be needed to take part in extensive testing before the product can be considered for approval in the US as more than a contraceptive. Surete complies with the US Food and Drug Administration monograph as a contraceptive. Anyone interested in taking part in those clinical trials--investigators or participants--must register thru OmniComm's web portal, WebIPA.com.
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PMID:U.S. trials on contraceptive gel begin via the Internet. 1229 7

Procept, Cambridge, Massachusetts, announced preclinical results demonstrating the contraceptive efficacy of its PRO 2000 topical microbicide gel. In a program of late-breaking discoveries presented at the National Conference on Women and HIV, held in Pasadena, California, Procept scientists described the results of studies recently conducted with PRO 2000. The in vitro results showed that PRO 2000 was contraceptive when rabbits were dosed intravaginally with a gel containing a 4% concentration of PRO 2000. At a concentration about 10 times lower, PRO 2000 did not appear to affect the rabbit pregnancy rate. Results of preclinical tests have indicated that both concentrations prevent HIV infection, suggesting that contraceptive and noncontraceptive formulations of this drug may be developed. "The potential of this compound as an advancement in the area of women's health is significant," said Stanley C. Erck, Procept. "We believe that the contraceptive properties demonstrated by PRO 2000 Gel will complement the anti-HIV/STD activity we will be evaluating in clinical trials." "More than 70% of all HIV infections worldwide follow heterosexual intercourse. A major problem confounding efforts to prevent AIDS in women has been the lack of effective, female-controlled barrier methods. PRO 2000 Gel has been identified as a topical microbicide well suited for use by women to prevent HIV infection. In laboratory studies, PRO 2000 blocked infection by a wide variety of HIV strains and also was active against herpes simplex virus." Clinical studies currently are underway to assess the safety of PRO 2000 Gel in healthy female volunteers. Assuming the results of these studies are positive, additional studies will be conducted to demonstrate safety and efficacy in populations at high risk for HIV infection.
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PMID:Data complement anti-STD activity of PRO 2000 gel. Contraceptives. 1232 Aug 75

A standardized protocol was used to compare cellular toxicities and anti-human immunodeficiency virus type 1 (HIV-1) activities of candidate microbicides formulated for human use. The microbicides evaluated were cellulose acetate phthalate (CAP), Carraguard, K-Y plus nonoxynol-9 (KY-N9), PRO 2000 (0.5 and 4%), SPL7013 (5%), UC781 (0.1 and 1%), and Vena Gel, along with their accompanying placebos. Products were evaluated for toxicity on cervical and colorectal epithelial cell lines, peripheral blood mononuclear cells (PBMCs), and macrophages (MPhi) by using an ATP release assay, and they were tested for their effect on transepithelial resistance (TER) of polarized epithelial monolayers. Anti-HIV-1 activity was evaluated in assays for transfer of infectious HIV-1 from epithelial cells to activated PBMCs and for PBMC and MPhi infection. CAP, Carraguard, PRO 2000, SPL7013, and UC781 along with their placebos were 20- to 50-fold less toxic than KY-N9 and Vena Gel. None of the nontoxic product concentrations disrupted the TER. Transfer of HIV-1(Ba-L) from epithelial cells to PBMCs and PBMC and MPhi infection with laboratory-adapted HIV-1(Ba-L) and HIV-1(LAI) isolates were inhibited by all products except Carraguard, KY-N9, and Vena Gel. KY-N9, Vena Gel, and Carraguard were not effective in blocking PBMC infection with primary HIV-1(A), HIV-1(C), and HIV-1(CRF01-AE) isolates. The concordance of these toxicity results with those previously reported indicates that our protocol may be useful for predicting toxicity in vivo. Moreover, our systematic anti-HIV-1 testing provides a rational basis for making better informed decisions about which products to consider for clinical trials.
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PMID:In vitro comparison of topical microbicides for prevention of human immunodeficiency virus type 1 transmission. 1538 43

A microbicide is designed to coat the vaginal epithelium and prevent transmission of HIV. Complete coverage is desired for optimal protection. In vivo factors affecting coverage have not yet been studied. This randomized crossover trial evaluates the effect of gel volume and patient activity upon vaginal epithelial coating. Gynol II gel was mixed with a magnetic resonance imaging (MRI) contrast agent. Ten women self-inserted, on separate visits, 3 or 5 mL of gel and underwent serial MRI scanning both before and after simulated intercourse. Gel spread was dependent upon time and volume. There was modest spread during the first hour and greater spread 6 h after insertion. Five milliliters of gel resulted in statistically significantly greater coverage immediately following insertion, within the first 30 min and at 6 h after insertion. Simulated intercourse greatly enhances gel spread. After simulated intercourse, the distribution of the gel at each volume was similar. Less leakage of gel was reported with the smaller volume.
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PMID:In vivo distribution of a vaginal gel: MRI evaluation of the effects of gel volume, time and simulated intercourse. 1554 13

Gag protein oligomerization, an essential step during virus assembly, results in budding of spherical virus particles. This process is critically dependent on the spacer p2, located between the capsid and the nucleocapsid proteins. P2 contributes also, in association with NCp7, to specific recognition of the HIV-1 packaging signal resulting in viral genome encapsidation. There is no structural information about the 20 last amino acids of the C-terminal part of capsid (CA[CTD]) and p2, in the molecular mechanism of Gag assembly. In this study the structure of a peptide encompassing the 14 residues of p2 with the upstream 21 residues and the downstream 13 residues was determined by (1)H NMR in 30% trifluoroethanol (TFE). The main structural motif is a well-defined amphipathic alpha-helix including p2, the seven last residues of the CA(CTD), and the two first residues of NCp7. Peptides containing the p2 domain have a strong tendency to aggregate in solution, as shown by gel filtration analyses in pure H(2)O. To take into account the aggregation phenomena, models of dimer and trimer formed through hydrophobic or hydrophilic interfaces were constructed by molecular dynamic simulations. Gel shift experiments demonstrate that the presence of at least p2 and the 13 first residues of NCp7 is required for RNA binding. A computer-generated model of the Gag polyprotein segment (282-434)Gag interacting with the packaging element SL3 is proposed, illustrating the importance of p2 and NCp7 in genomic encapsidation.
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PMID:Helical structure determined by NMR of the HIV-1 (345-392)Gag sequence, surrounding p2: implications for particle assembly and RNA packaging. 1565 70

Despite the key role played by the RNase H of human immunodeficiency virus-1 reverse transcriptase (HIV-1 RT) in viral proliferation, only a few inhibitors of RNase H have been reported. Using in vitro combinatorial selection methods and the RNase H domain of the HIV RT, we have selected double-stranded DNA thioaptamers (aptamers with selected thiophosphate backbone substitutions) that inhibit RNase H activity and viral replication. The selected thioaptamer sequences had a very high proportion of G residues. The consensus sequence for the selected thioaptamers showed G clusters separated by single residues at the 5'-end of the sequence. Gel electrophoresis mobility shift assays and nuclear magnetic resonance spectroscopy showed that the selected thioaptamer binds to the isolated RNase H domain, but did not bind to a structurally similar RNase H from Escherichia coli. The lead thioaptamer, R12-2, showed specific binding to HIV-1 RT with a binding constant (K(d)) of 70 nM. The thioaptamer inhibited the RNase H activity of intact HIV-1 RT. In cell culture, transfection of thioaptamer R12-2 (0.5 microg/mL) markedly inhibited viral production and exhibited a dose response of inhibition with R12-2 concentrations ranging from 0.03 to 2.0 microg/mL (IC(50) < 100 nM). Inhibition was also seen across a wide range of virus inoculum, ranging from a multiplicity of infection (moi) of 0.0005 to 0.05, with a reduction of the level of virus production by more than 50% at high moi. Suppression of virus was comparable to that seen with AZT when moi <or= 0.005.
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PMID:Combinatorial selection, inhibition, and antiviral activity of DNA thioaptamers targeting the RNase H domain of HIV-1 reverse transcriptase. 1604 16

Lentiviral vectors have been demonstrated as efficient tools for gene delivery to the CNS. We describe a novel approach for vector delivery using the thermoresponsive Gel, Pluronic F127 as a carrier. A HIV-1 lentiviral vector expressing GFP was contained in various concentrations of gel (15, 30 and 40%) and applied to cultures of 293T cells. FACS analysis of cells transduced with 8ng of lentiviral vector revealed a similar transduction efficiency for each Gel concentration compared to vector added to cells without PF127. Primary Rat CNS mixed glial cultures were also transduced with lentiviral vector in 15% Pluronic F127 and results demonstrated a similar transduction efficiency of astrocytes compared to virus without gel and no evidence of cell toxicity or death. Stereotaxic delivery of viral vector in 15% PF127 to the rat brain resulted in transduction of cells, predominantly astrocytes close to the injection site. Pluronic F127 gel delivery of viral vectors to the CNS may provide a platform for localised release particularly in areas of brain or spinal cord injury.
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PMID:Delivery of a lentiviral vector in a Pluronic F127 gel to cells of the central nervous system. 1615 31


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