Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Topical microbicides (cellulose acetate 1,2 benzene dicarboxylate [CAP], PRO 2000, SPL7013, and UC781) are being investigated to reduce the sexual transmission of human immunodeficiency virus type 1 (HIV-1). These products were shown to prevent the transfer of infectious HIV-1 from urogenital and colorectal epithelial cell lines to peripheral blood mononuclear cells. However, it was unclear if the topical microbicides rendered the virus noninfectious and/or reduced the binding to the epithelial cells. To test this, epithelial cells were cultured with HIV-1 in the presence or absence of topical microbicides or their placebos. The cells were washed, RNA lysates were made, and real-time PCR was performed for HIV-1. PRO 2000 and SPL7013 significantly (P < 0.0001) reduced the amount of bound HIV-1 to the colorectal epithelial cell line across clades A, B, C, and CRF01-AE. While none of the products reduced the binding of HIV-1 clades A and C to the urogenital cell line, CAP, PRO 2000, and SPL7013 significantly (P </= 0.002) reduced the binding of clades B and CRF01-AE. In general, PRO 2000 and SPL7013 placebos significantly (P < 0.0001) reduced the amount of bound HIV-1 but were less than the active products. UC781, its placebo, and hydroxyethyl cellulose (placebo for CAP) minimally affected the amount of bound HIV-1. These results suggest that rendering HIV-1 noninfectious may not correlate to the amount of HIV-1 bound to epithelial cells and possible shedding into mucosal secretions. Therefore, functional virological assays in addition to measuring viral RNA should be included when clinically evaluating topical microbicide use by infected persons.
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PMID:Effect of topical microbicides on infectious human immunodeficiency virus type 1 binding to epithelial cells. 1740 8

Several CCR5 ligands, including small molecules and monoclonal antibodies (MAbs), are being developed as therapies for infection with strains of human immunodeficiency virus type 1 (HIV-1) that use CCR5 for entry (R5 viruses). The efficacy of such therapies could be influenced by inter-individual differences in host factors, such as CCR5 expression levels. To study this, we used peripheral blood mononuclear cells (PBMCs) from humans and rhesus macaques. The half-maximal inhibitory concentrations (IC(50)) of the small-molecule CCR5 ligands CMPD167, UK427,857 and SCH-D, and of the PRO 140 MAb, differ by >2 logs in a donor-dependent manner. We studied this variation by using flow cytometry to measure CCR5 expression on PBMCs from six of the human donors: the IC(50) values of both SCH-D and PRO 140 correlated with CCR5 expression (R(2)=0.64 and 0.99, respectively). We also determined the efficacy of the CCR5 ligands against HIV-1 infection of HeLa-derived cell lines that express CD4 at the same level but vary 2-fold in CCR5 expression (JC.48 and JC.53 cells). The moderately greater CCR5 expression on the JC.53 than the JC.48 cells was associated with proportionately higher median IC(50) values for all four CCR5 ligands but not for a soluble CD4-based inhibitor or a non-nucleoside reverse transcriptase inhibitor. We conclude that differences in CCR5 expression on human PBMCs, which can be affected by CCL3L1 gene dose, may influence the antiviral potency of CCR5 ligands in vitro, but other host factors are also likely to be involved. These host factors may affect the clinical activity of CCR5 inhibitors, including their use as topical microbicides to prevent HIV-1 transmission.
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PMID:Cell surface expression of CCR5 and other host factors influence the inhibition of HIV-1 infection of human lymphocytes by CCR5 ligands. 1742 18

Topical microbicides are self-administered, prophylactic products for protection against sexually transmitted pathogens. A large number of compounds with known anti-human immunodeficiency virus type 1 (HIV-1) inhibitory activity have been proposed as candidate topical microbicides. To identify potential leads, an in vitro screening algorithm was developed to evaluate candidate microbicides in assays that assess inhibition of cell-associated and cell-free HIV-1 transmission, entry, and fusion. The algorithm advances compounds by evaluation in a series of defined assays that generate measurements of relative antiviral potency to determine advancement or failure. Initial testing consists of a dual determination of inhibitory activity in the CD4-dependent CCR5-tropic cell-associated transmission inhibition assay and in the CD4/CCR5-mediated HIV-1 entry assay. The activity is confirmed by repeat testing, and identified actives are advanced to secondary screens to determine their effect on transmission of CXCR4-tropic viruses in the presence or absence of CD4 and their ability to inhibit CXCR4- and CCR5-tropic envelope-mediated cell-to-cell fusion. In addition, confirmed active compounds are also evaluated in the presence of human seminal plasma, in assays incorporating a pH 4 to 7 transition, and for growth inhibition of relevant strains of lactobacilli. Leads may then be advanced for specialized testing, including determinations in human cervical explants and in peripheral blood mononuclear cells against primary HIV subtypes, combination testing with other inhibitors, and additional cytotoxicity assays. PRO 2000 and SPL7013 (the active component of VivaGel), two microbicide products currently being evaluated in human clinical trials, were tested in this in vitro algorithm and were shown to be highly active against CCR5- and CXCR4-tropic HIV-1 infection.
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PMID:Development of a comprehensive human immunodeficiency virus type 1 screening algorithm for discovery and preclinical testing of topical microbicides. 1831 28

Without an effective vaccine against human immunodeficiency virus (HIV) infection, topical microbicide development has become a priority. The sulfonated polyanion PRO 2000, a candidate topical microbicide now in phase II/III clinical trials, blocks HIV infection of cervical tissue in vitro. Dendritic cells (DC) are among the first cell types to contact HIV in the genital tract and facilitate the spread of the virus. Thus, interfering with virus-DC interactions is a desirable characteristic of topical microbicides as long as that does not interfere with the normal function of DC. PRO 2000 present during capture of the replication-defective HIV(JRFL) reporter virus or replication-competent HIV(BaL) by monocyte-derived DC (MDDC) inhibited subsequent HIV transfer to target cells. Continuous exposure to PRO 2000 during MDDC-target cell coculture effectively inhibited HIV infection of target cells. PRO 2000 inhibited HIV capture by MDDC. In addition, the compound blocked R5 and X4 HIV envelope-mediated cell-cell fusion. Interestingly, simultaneous exposure to PRO 2000 and lipopolysaccharide attenuated the cytokine production in response to stimulation, suggesting that the compound altered DC function. While efficient blocking of MDDC-mediated virus transfer and infection in the highly permissive MDDC-T-cell environment reinforces the potential value of PRO 2000 as a topical microbicide against HIV, the impact of PRO 2000 on immune cell functions warrants careful evaluation.
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PMID:Inhibitory effect of PRO 2000, a candidate microbicide, on dendritic cell-mediated human immunodeficiency virus transfer. 1833 74

The small molecule CCR5 inhibitors are a new class of drugs for treating infection by human immunodeficiency virus type 1 (HIV-1). They act by binding to the CCR5 co-receptor and preventing its use during HIV-1-cell fusion. Escape mutants can be raised against CCR5 inhibitors in vitro and will arise when these drugs are used clinically. Here, we have assessed the responses of CCR5 inhibitor-resistant viruses to other anti-retroviral drugs that act by different mechanisms, and their sensitivities to neutralizing antibodies (NAbs). The rationale for the latter study is that the resistance pathway for CCR5 inhibitors involves changes in the HIV-1 envelope glycoproteins (Env), which are also targets for NAbs. The escape mutants CC101.19 and D1/85.16 were selected for resistance to AD101 and vicriviroc (VVC), respectively, from the primary R5 HIV-1 isolate CC1/85. Each escape mutant was cross-resistant to other small molecule CCR5 inhibitors (aplaviroc, maraviroc, VVC, AD101 and CMPD 167), but sensitive to protein ligands of CCR5: the modified chemokine PSC-RANTES and the humanized MAb PRO-140. The resistant viruses also retained wild-type sensitivity to the nucleoside reverse transcriptase inhibitor (RTI) zidovudine, the non-nucleoside RTI nevirapine, the protease inhibitor atazanavir and other attachment and fusion inhibitors that act independently of CCR5 (BMS-806, PRO-542 and enfuvirtide). Of note is that the escape mutants were more sensitive than the parental CC1/85 isolate to a subset of neutralizing monoclonal antibodies and to some sera from HIV-1-infected people, implying that sequence changes in Env that confer resistance to CCR5 inhibitors can increase the accessibility of some NAb epitopes. The need to preserve NAb resistance may therefore be a constraint upon how escape from CCR5 inhibitors occurs in vivo.
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PMID:Neutralizing antibody and anti-retroviral drug sensitivities of HIV-1 isolates resistant to small molecule CCR5 inhibitors. 1851 43

The human T-cell lymphotropic virus type 1 (HTLV-1) is the cause of adult T-cell leukemia and inflammatory diseases including HTLV-1-associated myelopathy/tropical spastic paraparesis. HTLV-1 can be transmitted through sexual contact, mother-to-child transmission, and exposure to contaminated blood. Microbicides are agents that interfere with microbial infectivity at mucous membranes, and candidates are under development for use against sexually transmitted viruses such as human immunodeficiency virus type 1. We previously demonstrated that cell surface polyanionic heparan sulfate proteoglycans bind the HTLV-1 envelope glycoprotein surface subunit gp46, facilitating cell-cell and cell-free virus spread in vitro. We now show, using assays for Env-receptor binding inhibition, Env-induced cell-cell fusion, cell-cell virus spread, and pseudotype HTLV-1 infectivity, that the soluble polyanions PRO 2000 and dextran sulfate are potent inhibitors of HTLV-1 spread in vitro, with PRO 2000 being the more promising candidate. The results of these studies suggest that candidate topical microbicides may be of use in reducing HTLV-1 sexual transmission.
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PMID:Candidate polyanionic microbicides inhibit human T-cell lymphotropic virus type 1 receptor interactions, cell-free infection, and cell-cell spread. 1904 54

Polyanion-based microbicides have been developed to prevent the sexual transmission of human immunodeficiency virus (HIV). Recent data suggest that polyanions have the capacity to enhance HIV type 1 (HIV-1) replication at threshold antiviral concentrations. Evaluation of the microbicide candidates SPL7013 and PRO 2000 revealed no specific enhancement of two CCR5 HIV-1 strains in human peripheral blood mononuclear cells compared to enfuvirtide (Fuzeon). The enhancement effect is likely to be a function of the assay conditions and is not an intrinsic property of these polyanions.
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PMID:Enhancement of human immunodeficiency virus type 1 replication is not intrinsic to all polyanion-based microbicides. 1952 84

Microbicide candidates with promising in vitro activity are often advanced for evaluations using human primary tissue explants relevant to the in vivo mucosal transmission of human immunodeficiency virus type 1 (HIV-1), such as tonsil, cervical, or rectal tissue. To compare virus growth or the anti-HIV-1 efficacies of candidate microbicides in tissue explants, a novel soft-endpoint method was evaluated to provide a single, objective measurement of virus growth. The applicability of the soft endpoint is shown across several different ex vivo tissue types, with the method performed in different laboratories, and for a candidate microbicide (PRO 2000). The soft-endpoint method was compared to several other endpoint methods, including (i) the growth of virus on specific days after infection, (ii) the area under the virus growth curve, and (iii) the slope of the virus growth curve. Virus growth at the assay soft endpoint was compared between laboratories, methods, and experimental conditions, using nonparametric statistical analyses. Intra-assay variability determinations using the coefficient of variation demonstrated higher variability for virus growth in rectal explants. Significant virus inhibition by PRO 2000 and significant differences in the growth of certain primary HIV-1 isolates were observed by the majority of laboratories. These studies indicate that different laboratories can provide consistent measurements of anti-HIV-1 microbicide efficacy when (i) the soft endpoint or another standardized endpoint is used, (ii) drugs and/or virus reagents are centrally sourced, and (iii) the same explant tissue type and method are used. Application of the soft-endpoint method reduces the inherent variability in comparisons of preclinical assays used for microbicide development.
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PMID:Multisite comparison of anti-human immunodeficiency virus microbicide activity in explant assays using a novel endpoint analysis. 1972 2

Infection by the human immunodeficiency virus type 1 (HIV-1) is an ordered, multistep process involving binding and entry, reverse transcription, integration, viral gene transcription, translation, processing, and finally assembly. Numerous therapeutic and preventive compounds, which are currently available for clinical use or are under preclinical and clinical development, act on at least one of these steps. Polyanionic HIV-1 inhibitors comprise a family of compounds that are generally considered entry inhibitors. The main mechanism of anti-HIV-1 activity associated with these compounds involves electrostatic interactions with HIV-1 glycoprotein 120 that ultimately prevent binding of the virus to target cells. A number of these compounds have been considered for systemic use and for use as microbicides, which are products designed to prevent sexual HIV-1 transmission. These compounds have been studied extensively using in vitro assays of activity, cytotoxicity, and mechanism of action, ex vivo models of HIV-1 transmission, and animal models of in vivo efficacy and toxicity. Three of these polyanionic compounds - cellulose sulfate, carrageenan, and PRO 2000 - were advanced into clinical trials of microbicide safety and efficacy. Although phase I and phase II clinical trials showed these compounds to be safe and well tolerated, none of the phase III trials provided any evidence that these compounds were effective against heterosexual HIV-1 transmission. Furthermore, clinical and in vitro results suggest enhancement of HIV-1 infection in the presence of polyanionic compounds. We discuss the preclinical development of polyanionic HIV-1 inhibitors, the clinical trials of polyanionic compounds used systemically and as topical vaginal microbicides, and the prospects for the future development of these compounds as inhibitors of HIV-1 infection.
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PMID:The rise and fall of polyanionic inhibitors of the human immunodeficiency virus type 1. 2143 25

The development of safe topical microbicides that effectively prevent human immunodeficiency virus (HIV) infection is a major goal in curbing the human immunodeficiency virus pandemic. A number of past failures resulting from mucosal toxicity or lack of efficacy have informed the field. Products that caused toxicity to the female genital tract mucosa, and thereby increased the likelihood of HIV acquisition, included nonoxynol 9, cellulose sulfate, and C31 G vaginal gel Savvy. Topical products that were ineffective in preventing HIV infection include BufferGel, Carraguard, and PRO 2000. Antiretroviral drugs such as tenofovir and dapivirine formulated into microbicide products have shown promise, but there is much to learn about ideal product formulation and acceptability, and drug distribution and disposition (pharmacokinetics). Current formulations for water-soluble molecules include vaginally or rectally applied gels, vaginal rings, films and tablets. Dosing strategies (e.g. coitally dependent or independent) will be based on the pharmacokinetics of the active ingredient and the tolerance for less than perfect adherence.
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PMID:Formulation, pharmacokinetics and pharmacodynamics of topical microbicides. 2230 23


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