Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0021051 (immunodeficiency)
71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inhibitors of human immunodeficiency virus type 1 attachment (CD4-immunoglobulin G subclass 2), CCR5 usage (PRO 140), and fusion (T-20) were tested on diverse primary cell types that represent the major targets both for infection in vivo and for the inhibition of trans infection of target cells by virus bound to dendritic cells. Although minor cell-type-dependent differences in potency were observed, each inhibitor was active on each cell type and trans infection was similarly vulnerable to inhibition at each stage of the fusion cascade.
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PMID:Human immunodeficiency virus type 1 attachment, coreceptor, and fusion inhibitors are active against both direct and trans infection of primary cells. 1255 19

The diketo acid L-708,906 has been reported to be a selective inhibitor of the strand transfer step of the human immunodeficiency virus type 1 (HIV-1) integration process (D. Hazuda, P. Felock, M. Witmer, A. Wolfe, K. Stillmock, J. A. Grobler, A. Espeseth, L. Gabryelski, W. Schleif, C. Blau, and M. D. Miller, Science 287:646-650, 2000). We have now studied the development of antiviral resistance to L-708,906 by growing HIV-1 strains in the presence of increasing concentrations of the compound. The mutations T66I, L74M, and S230R emerged successively in the integrase gene. The virus with three mutations (T66I L74M S230R) was 10-fold less susceptible to L-708,906, while displaying the sensitivity of the wild-type virus to inhibitors of the RT or PRO or viral entry process. Chimeric HIV-1 strains containing the mutant integrase genes displayed the same resistance profile as the in vitro-selected strains, corroborating the impact of the reported mutations on the resistance phenotype. Phenotypic cross-resistance to S-1360, a diketo analogue in clinical trials, was observed for all strains. Interestingly, the diketo acid-resistant strain remained fully sensitive to V-165, a novel integrase inhibitor (C. Pannecouque, W. Pluymers, B. Van Maele, V. Tetz, P. Cherepanov, E. De Clercq, M. Witvrouw, and Z. Debyser, Curr. Biol. 12:1169-1177, 2002). Antiviral resistance was also studied at the level of recombinant integrase. Single mutations did not appear to impair specific enzymatic activity. However, 3' processing and strand transfer activities of the recombinant integrases with two (T66I L74M) and three (T66I L74M S230R) mutations were notably lower than those of the wild-type integrase. Although the virus with three mutations was resistant to inhibition by diketo acids, the sensitivity of the corresponding enzyme to L-708,906 or S-1360 was reduced only two- to threefold. As to the replication kinetics of the selected strains, the replication fitness for all strains was lower than that of the wild-type HIV-1 strain.
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PMID:Development of resistance against diketo derivatives of human immunodeficiency virus type 1 by progressive accumulation of integrase mutations. 1455 31

Viral entry inhibitors represent an emerging mode of therapy for human immunodeficiency virus type 1 (HIV-1) infection. PRO 542 (CD4-immunoglobulin G2) is a tetravalent CD4-immunoglobulin fusion protein that broadly neutralizes primary HIV-1 isolates. PRO 542 binds to the viral surface glycoprotein gp120 and blocks attachment and entry of virus into CD4(+) cells. Previously, PRO 542 demonstrated antiviral activity without significant toxicity when tested at single doses ranging to 10 mg/kg. In this study, 12 HIV-infected individuals were treated with 25-mg/kg single-dose PRO 542 and then monitored for safety, antiviral effects, and PRO 542 pharmacokinetics for 6 weeks. The study examined two treatment cohorts that differed in the extent of HIV-1 disease progression. PRO 542 at 25 mg/kg was well tolerated and demonstrated a serum half-life of 3 days. Statistically significant acute reductions in HIV-1 RNA levels were observed across all study patients, and greater antiviral effects were observed in the cohort of patients with more advanced HIV-1 disease. In advanced disease (HIV-1 RNA > 100,000 copies/ml; CD4 lymphocytes < 200 cells/mm(3)), PRO 542 mediated an 80% response rate and statistically significant approximately 0.5 log(10) mean reductions in viral load for 4 to 6 weeks posttreatment. Similar findings were obtained in an analysis of all (n = 11) advanced disease patients treated to date with single doses of PRO 542 ranging from 1 to 25 mg/kg. In addition, a significant correlation was observed between antiviral effects observed in vivo and viral susceptibility to PRO 542 in vitro. The findings support continued development of PRO 542 for salvage therapy of advanced HIV-1 disease.
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PMID:Treatment of advanced human immunodeficiency virus type 1 disease with the viral entry inhibitor PRO 542. 1474 90

Topical microbicides designed to prevent acquisition of sexually transmitted infections are urgently needed. Nonoxynol-9, the only commercially available spermicide, damages epithelium and may enhance human immunodeficiency virus transmission. The observation that herpes simplex virus (HSV) and human immunodeficiency virus bind heparan sulfate provided the rationale for the development of sulfated or sulfonated polymers as topical agents. Although several of the polymers have advanced to clinical trials, the spectrum and mechanism of anti-HSV activity and the effects on soluble mediators of inflammation have not been evaluated. The present studies address these gaps. The results indicate that PRO 2000, polystyrene sulfonate, cellulose sulfate, and polymethylenehydroquinone sulfonate inhibit HSV infection 10,000-fold and are active against clinical isolates, including an acyclovir-resistant variant. The compounds formed stable complexes with glycoprotein B and inhibit viral binding, entry, and cell-to-cell spread. The effects may be long lasting due to the high affinity and stability of the sulfated compound-virus complex, as evidenced by surface plasmon resonance studies. The candidate microbicides retained their antiviral activities in the presence of cervical secretions and over a broad pH range. There was little reduction in cell viability following repeated exposure of human endocervical cells to these compounds, although a reduction in secretory leukocyte protease inhibitor levels was observed. These studies support further development and rigorous evaluation of these candidate microbicides.
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PMID:Candidate topical microbicides bind herpes simplex virus glycoprotein B and prevent viral entry and cell-to-cell spread. 1515 95

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

Poly(styrene 4-sulfonate), cellulose sulfate, polymethylenehydroquinone, and PRO 2000 are sulfated or sulfonated polymers (SPs) under development as topical microbicides. They are presumed to work through similar mechanisms of action, although to date there has been no extensive comparison of their anti-human immunodeficiency virus activities. To determine whether any of these candidate microbicides offers a potential advantage, their in vitro activities, mechanisms of action, stabilities in biological secretions, and toxicities were compared. All four compounds were found to be active against X4, R5, and dualtropic primary isolates and against X4 and R5 laboratory-adapted strains in CD4+ T cells, macrophages, and single-coreceptor cell lines. Our single-cycle experiments using pseudotyped virus suggest that all four SPs function at the binding and entry stages of the viral life cycle but differ in degree of postentry effect. Surface plasmon resonance analyses demonstrate that SPs bind to X4 and R5 monomeric glycoprotein 120 with similar high binding affinities. When mixed with cervicovaginal lavage fluid, SPs maintain inhibitory activity at concentrations achievable in formulations.
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PMID:Candidate sulfonated and sulfated topical microbicides: comparison of anti-human immunodeficiency virus activities and mechanisms of action. 1612 29

A human colorectal explant culture was developed to assess the safety and efficacy of topical microbicides proposed for use in humans. Because any product marketed for vaginal application will likely be used for anal intercourse, it is important to evaluate these products in colorectal explant tissue. Microbicides tested included cellulose acetate 1,2-benzenedicarboxylate (CAP), PRO 2000, SPL7013, Vena Gel, and UC781, along with their accompanying placebos. Colorectal tissues were exposed to microbicides overnight and either fixed in formalin to evaluate toxicity by histological analysis or placed in 1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan (MTT) to quantitatively determine tissue viability. Histological analysis showed minimal toxicity for CAP, UC781, and Vena Gel. Shedding of epithelium with intact lamina propria occurred for the PRO 2000 and SPL7013 products, and shedding of epithelium and necrosis of the lamina propria occurred in explants cultured with nonoxynol-9. The MTT assay confirmed these results for PRO 2000 (4% and 0.5%), SPL7013 (and placebo), and nonoxynol-9 but also demonstrated reduced viability for CAP. However, viability of tissues treated with all products was not significantly different from that of the medium control. Efficacy of the microbicides was evaluated by measuring human immunodeficiency virus type 1 (HIV-1) infection of explants in the absence or presence of products. All microbicide formulations tested were highly effective in preventing HIV infection. However, explants treated with some of the placebo formulations also exhibited a lower level of infection. Most of the products developed for vaginal application showed minimal toxicity and were effective in reducing HIV-1 infection in colorectal tissues. These results suggest that this model is useful for evaluating the safety and efficacy of topical microbicides when used rectally.
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PMID:A human colorectal explant culture to evaluate topical microbicides for the prevention of HIV infection. 1620 69

Prevention of genital herpes and other sexually transmitted infections (STI) is a critical health priority because of the overwhelming impact on women and infants and the epidemiological association with human immunodeficiency virus (HIV)/AIDS. Small animal models are essential for evaluating strategies for prevention or treatment of STI. Neither the murine nor the guinea pig model of genital herpes fully recapitulates human disease. We demonstrate that herpes simplex virus type 2 (HSV-2) readily infects inbred cotton rats (Sigmodon hispidus). Consistent infection does not require pretreatment with medroxyprogesterone, and primary disease resembles that observed in humans. The animals develop genital lesions and fully recover. During primary infection, viral DNA is also detected in liver, lungs, brain, and kidneys. Clinical self-limited recurrences occur spontaneously but may also be induced by dexamethasone. Pretreatment of cotton rats with PRO 2000 gel, a candidate vaginal microbicide being evaluated in clinical trials to prevent HSV and HIV, protects cotton rats from HSV. Together, these studies suggest that the cotton rat may provide an excellent model to study genital herpes and to evaluate preventive strategies.
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PMID:The cotton rat provides a novel model to study genital herpes infection and to evaluate preventive strategies. 1628 63

The chemokine receptor CCR5 provides a portal of entry for human immunodeficiency virus type 1 (HIV-1) into susceptible CD4(+) cells. Both monoclonal antibody (MAb) and small-molecule CCR5 inhibitors have entered human clinical testing, but little is known regarding their potential interactions. We evaluated the interactions between CCR5 MAbs, small-molecule CCR5 antagonists, and inhibitors of HIV-1 gp120, gp41, and reverse transcriptase in vitro. Inhibition data were analyzed for cooperative effects using the combination index (CI) method and stringent statistical criteria. Potent, statistically significant antiviral synergy was observed between the CCR5 MAb PRO 140 and the small-molecule CCR5 antagonists maraviroc (UK-427,857), vicriviroc (SCH-D), and TAK-779. High-level synergy was observed consistently across various assay systems, HIV-1 envelopes, CCR5 target cells, and inhibition levels. CI values ranged from 0.18 to 0.64 and translated into in vitro dose reductions of up to 14-fold. Competition binding studies revealed nonreciprocal patterns of CCR5 binding by MAb and small-molecule CCR5 inhibitors, suggesting that synergy occurs at the level of receptor binding. In addition, both PRO 140 and maraviroc synergized with the chemokine RANTES, a natural ligand for CCR5; however, additive effects were observed for both small-molecule CCR5 antagonists and PRO 140 in combination with other classes of HIV-1 inhibitors. The findings provide a rationale for clinical exploration of MAb and small-molecule CCR5 inhibitors in novel dual-CCR5 regimens for HIV-1 therapy.
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PMID:Potent antiviral synergy between monoclonal antibody and small-molecule CCR5 inhibitors of human immunodeficiency virus type 1. 1700 7

A human cervical explant culture was utilized for the preclinical assessment of anti-human immunodeficiency virus type 1 (HIV-1) activity and tissue toxicity of formulated, candidate topical microbicides. Products tested included cellulose acetate 1,2-benzene dicarboxylate (CAP), a carrageenan-based product (PC-515), a naphthalene sulfonate polymer (PRO 2000), a lysine dendrimer (SPL7013), a nonnucleoside reverse transcriptase inhibitor (UC781), and an antimicrobial peptide (D2A21), along with their placebos. Cervical explants were cultured overnight with HIV-1 with or without product, washed, and monitored for signs of HIV-1 infection. HIV-1 infection was determined by p24gag levels in the basolateral medium and by immunohistochemical analysis of the explant. Product toxicity was measured by the MTT [1-(4,5-dimethylthiazol-2-yl)-3,5-diphenylformazan] assay and histology. CAP, PRO 2000, SPL7013, and UC781 consistently prevented HIV-1 infection in all explants tested. PC-515 and D2A21 prevented HIV-1 infection in 50% or fewer of the explants tested. Placebos did not prevent infection in any of the explants tested. With the exception of PRO 2000 (4%), the MTT assay and histological analysis of the other products and placebos showed minimal toxicity to the epithelium and submucosa. Collectively, these data suggest that this culture system can be used for evaluating the safety and efficacy of topical microbicides designed for vaginal use.
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PMID:Preclinical testing of candidate topical microbicides for anti-human immunodeficiency virus type 1 activity and tissue toxicity in a human cervical explant culture. 1735 37


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