16 results on '"Ray, Neelanjana"'
Search Results
2. The Second-Generation Maturation Inhibitor GSK3532795 Maintains Potent Activity Toward HIV Protease Inhibitor-Resistant Clinical Isolates.
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Ray, Neelanjana, Tianbo Li, Zeyu Lin, Protack, Tricia, van Ham, Petronella Maria, Hwang, Carey, Krystal, Mark, Nijhuis, Monique, Lataillade, Max, and Dicker, Ira
- Abstract
Background: Protease inhibitor (PI)-resistant HIV-1 isolates with primary substitutions in protease (PR) and secondary substitutions in Gag could potentially exhibit cross-resistance to maturation inhibitors. We evaluated the second-generation maturation inhibitor, GSK3532795, for activity toward clinical isolates with genotypic and phenotypic characteristics associated with PI resistance (longitudinal). Methods: Longitudinal clinical isolates from 15 PI-treated patients and 7 highly PI-resistant (nonlongitudinal) viruses containing major and minor PI resistance-associated mutations were evaluated for GSK3532795 sensitivity. Phenotypic sensitivity was determined using the PhenoSense Gag/PR assay (Monogram Biosciences) or in-house single- and multiple-cycle assays. Changes from baseline [CFB; ratio of post- to pre-treatment FC-IC50 (fold-change in IC50 versus wild-type virus)] <3 were considered to be within the no-effect level. Results: All nonlongitudinal viruses tested were sensitive to GSK3532795 (FC-IC50 range 0.16-0.68). Among longitudinal isolates, all post-PI treatment samples had major PI resistance-associated mutations in PR and 17/21 had PI resistance-associated changes in Gag. Nineteen of the 21 post-PI treatment samples had GSK3532795 CFB <3. Median (range) CFB was 0.83 (0.05-27.4) [Monogram (11 patients)] and 1.5 (1.0-2.2) [single-cycle (4 patients)]. The 2 post-PI treatment samples showing GSK3532795 CFB >3 (Monogram) were retested using single- and multiple-cycle assays. Neither sample had meaningful sensitivity changes in the multiple-cycle assay. Gag changes were not associated with an increased GSK3532795 CFB. Conclusions: GSK3532795 maintained antiviral activity against PI-resistant isolates with emergent PR and/or Gag mutations. This finding supports continued development of GSK3532795 in treatment-experienced patients with or without previous PI therapy. [ABSTRACT FROM AUTHOR]
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- 2017
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3. Prediction of Virological Response and Assessment of Resistance Emergence to the HIV-1 Attachment Inhibitor BMS-626529 During 8-Day Monotherapy With Its Prodrug BMS-663068.
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Ray, Neelanjana, Hwang, Carey, Healy, Matthew D., Whitcomb, Jeannette, Lataillade, Max, Wind-Rotolo, Megan, Krystal, Mark, and Hanna, George J.
- Abstract
BMS-663068 is the phosphonooxymethyl prodrug of BMS-626529, a small-molecule attachment inhibitor that targets the HIV-1 envelope glycoprotein gp120 preventing it from binding to CD4+ T cells. In vitro investigations have demonstrated considerable variation in susceptibility of different HIV-1 isolates to BMS-626529. BMS-663068 monotherapy in HIV-1-infected subjects produced a mean maximum change from baseline of -1.64 log10 copies per milliliter, but the response was variable.In this analysis, baseline and day 8 samples were analyzed for susceptibility to BMS-626529 and the presence of known HIV-1 attachment inhibitor resistance mutations. In addition, predictors of virological response (maximal HIV-1 RNA decline ≥1 log10 copies per milliliter) and resistance selection were investigated.The only factor associated with reduced virological response was low baseline susceptibility to BMS-626529. There was no apparent relationship between virological response and baseline treatment experience, coreceptor tropism, plasma HIV-1 RNA level, or CD4+ T-cell count. Examination of all positions with known BMS-626529 resistance mutations based on in vitro selection studies showed that gp120 M426L was the primary substitution most clearly associated with nonresponse to BMS-663068. There was minimal change in susceptibility to BMS-626529 over the course of the study and no clear evidence of emergence of a known HIV-1 attachment inhibitor resistance mutation in the majority of subjects as measured by standard population-based phenotypic and genotypic approaches.Nonresponse to BMS-663068 was associated with low baseline susceptibility to BMS-626529 and the presence of M426L. In this short-term trial, there was minimal evidence of selection for BMS-626529 high-level resistance over 8 days of monotherapy with BMS-663068 by population-based approaches. [ABSTRACT FROM AUTHOR]
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- 2013
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4. Study of Andes virus entry and neutralization using a pseudovirion system
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Ray, Neelanjana, Whidby, Jillian, Stewart, Shaun, Hooper, Jay W., and Bertolotti-Ciarlet, Andrea
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VIRION , *HANTAVIRUSES , *HANTAVIRUS pulmonary syndrome , *G proteins , *VIRAL proteins , *BIOLOGICAL assay , *RENILLA luciferase - Abstract
Abstract: Andes virus (ANDV), a member of the Hantavirus genus in the family Bunyaviridae, causes an acute disease characteristic of New-World hantaviruses called hantavirus pulmonary syndrome (HPS). HPS is a highly pathogenic disease with a case-fatality rate of 40%. ANDV is the only hantavirus reported to spread directly from human-to-human. The aim of the present study was to develop a quantitative and high-throughput pseudovirion assay to study ANDV infection and neutralization in biosafety level 2 facilities (BSL-2). This pseudovirion assay is based on incorporation of ANDV glycoproteins onto replication-defective vesicular stomatitis virus (VSV) cores in which the gene for the surface G protein has been replaced by that encoding Renilla luciferase. Infection by the pseudovirions can be quantified by luciferase activity of infected cell lysates. ANDV pseudovirions were neutralized by ANDV-specific antisera, and there was good concordance between specificity and neutralization titers of ANDV hamster sera as determined by our pseudovirion assay and a commonly used plaque reduction neutralization titer (PRNT) assay. In addition, the pseudovirions were used to evaluate the requirements for ANDV entry, like pH dependency and the role of β3 integrin, the reported receptor for other pathogenic hantaviruses, on entry. [Copyright &y& Elsevier]
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- 2010
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5. Inefficient entry of vicriviroc-resistant HIV-1 via the inhibitor-CCR5 complex at low cell surface CCR5 densities
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Pugach, Pavel, Ray, Neelanjana, Klasse, Per Johan, Ketas, Thomas J., Michael, Elizabeth, Doms, Robert W., Lee, Benhur, and Moore, John P.
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HIV , *HOST-virus relationships , *VIRUS diseases , *GENE expression , *CELL receptors , *GENETIC transcription , *TRANSCRIPTION factors - Abstract
Abstract: HIV-1 variants resistant to small molecule CCR5 inhibitors such as vicriviroc (VVC) have modified Env complexes that can use both the inhibitor-bound and -free forms of the CCR5 co-receptor to enter target cells. However, entry via the inhibitor-CCR5 complex is inefficient in some, but not all, cell types, particularly cell lines engineered to express CCR5. We investigated the effect of increasing CCR5 expression, and hence the density of the inhibitor-CCR5 complex when a saturating inhibitor (VVC) concentration was present, by using 293-Affinofile cells, in which CCR5 expression is up-regulated by the transcriptional activator, ponasterone. When CCR5 expression was low, the resistant virus entered the target cells to a lesser extent when VVC was present than absent. However, at a higher CCR5 level, there was much less entry inhibition at a constant, saturating VVC concentration. We conclude that the relative decrease in entry of a VVC-resistant virus in some cell types results from its less efficient use of the VVC-CCR5 complex, and that increasing the CCR5 expression level can compensate for this inefficiency. [Copyright &y& Elsevier]
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- 2009
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6. HR-2 Mutations in Human Immunodeficiency Virus Type 1 gp41 Restore Fusion Kinetics Delayed by HR-1 Mutations That Cause Clinical Resistance to Enfuvirtide.
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Ray, Neelanjana, Blackburn, Leslie A., and Doms, Robert W.
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ANTIVIRAL agents , *HIV , *VIRAL proteins , *GENETIC mutation , *DYNAMICS , *IMMUNE system - Abstract
Enfuvirtide (ENF) prevents the entry of human immunodeficiency virus type 1 (HIV-1) into cells by binding to the HR-1 region of the viral envelope (Env) protein gp41 subunit. Resistance to ENF arises via mutations in the drug binding site in HR-1. In addition, HR-2 mutations are commonly observed in ENF-resistant Env proteins, though their role remains unclear. We explored the mechanistic basis for clinical resistance to ENF and the role of HR-2 mutations. Using panels of ENF resistance-associated mutants for two patients, we found that mutations in HR-1 slowed the fusion kinetics and that mutations in HR-2 restored fusion rates. We assessed the differences in the rates of fusion of these mutants from a temperature-arrested state and observed similar trends, suggesting that the step of delay occurs after coreceptor engagement. Sensitivity to neutralizing antibodies was unchanged by the HR-1 and HR-2 mutants in each panel. Since this result was in contrast to those of a previous in vitro analysis where enhanced sensitivity to neutralization was demonstrated for heterologous Envs with ENF resistance-associated HR-1 changes, we examined the context dependence of HR-1 and HR-2 mutations by transferring the mutations seen in one patient into the Env context of another. These studies revealed that some, but not all, HR-1 mutations, when placed out of context (i.e., in a patient Env where they did not originally arise), enhance sensitivity to neutralizing antibodies. However, in most cases, HR-1 mutations in ENF-treated patients evolve in a manner that preserves pretreatment neutralization sensitivity so as to evade the pressures of the immune system. [ABSTRACT FROM AUTHOR]
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- 2009
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7. Cyclooxygenase-1 and -2 Are Required for Production of Infectious Pseudorabies Virus.
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Ray, Neelanjana, Bisher, Margaret E., and Enquist, L.W.
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AUJESZKY'S disease virus , *CYCLOOXYGENASES , *GENETIC transcription , *HERPES simplex virus , *FIBROBLASTS , *LABORATORY rats , *MESSENGER RNA - Abstract
We have recently shown that cyclooxygenase-2 (COX-2) transcription is markedly induced after herpes simplex virus type 1 and pseudorabies virus (PRV) infections of rat embryonic fibroblast (REF) cells (N. Ray and L. W. Enquist, J. Virol. 78:3489-3501, 2004). For this study, we investigated the role of cyclooxygenase induction in the replication and growth of PRV. We demonstrate here a concordant increase in COX-2 mRNA and protein levels after the infection of REF cells. Inhibitors blocking the activity of cyclooxygenases caused a dramatic reduction in PRV growth. Viral growth could be restored if prostaglandin E2, the final product of COX-2 activity, was added simultaneously with the COX inhibitors. Immediate-early protein IE180, major capsid protein VP5, and glycoprotein expression were slightly reduced in the presence of COX-2 inhibitors, but expression of the early protein EP0 was not affected by COX inhibition. Viral DNA replication was marginally reduced in the presence of a COX-½ inhibitor, but there was no defect in viral DNA cleavage. Electron microscopy analysis revealed an increased number of unusual empty capsid structures in the nuclei of cells infected with PRV in the presence of a COX-½ inhibitor. These capsid structures shared some characteristics with procapsids but had a novel appearance by negative staining. Our data establish a role for COX-1 and COX-2 in facilitating the efficient growth and replication of PRV in primary cells. [ABSTRACT FROM AUTHOR]
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- 2004
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8. Transcriptional Response of a Common Permissive Cell Type to Infection by Two Diverse Alphaherpesviruses.
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Ray, Neelanjana and Enquist, L.W.
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HERPESVIRUSES , *DNA viruses , *VIRUSES , *VIRUS diseases , *VIROLOGY , *MICROBIOLOGY - Abstract
Pseudorabies virus (PRV) and herpes simplex virus type 1 (HSV-1) are distantly related alphaherpesviruses whose natural hosts are pigs and humans, respectively. Adult infections of natural hosts are mild and rarely lethal. However, both viruses are also able to infect other hosts, often with lethal effects. In this report, we use the paradigm of infection of a common permissive cell type and microarray analysis to determine if these two diverse alphaherpesviruses engage similar or different cellular pathways to obtain a common outcome: productive infection. We compared cellular gene expression in growth-arrested, primary rat embryonic fibroblasts that were mock infected or infected with either purified PRV-Becker or HSV-1(F). Infections by either virus affect the transcription of more than 1,500 cellular genes by threefold or more. Few differences are detected early, and the majority of changes occur during the late stages of infection. Remarkably, the transcripts of about 500 genes are regulated in common, while the rest are regulated in a virus-specific manner. Genes whose expression is affected by infection fall into a diverse group of functional classes and cellular pathways. Furthermore, a comparison of the cellular response to HSV-1 infection of primary human and rat fibroblasts revealed unexpected diversity in the transcript profiles. [ABSTRACT FROM AUTHOR]
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- 2004
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9. Resistance profile of the HIV-1 maturation inhibitor GSK3532795 in vitro and in a clinical study.
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Dicker, Ira, Zhang, Sharon, Ray, Neelanjana, Beno, Brett R., Regueiro-Ren, Alicia, Joshi, Samit, Cockett, Mark, Krystal, Mark, and Lataillade, Max
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IN vitro studies , *VIRAL replication , *AMINO acids , *HIV - Abstract
GSK3532795 (formerly BMS955176) is a second-generation maturation inhibitor (MI) that progressed through a Phase 2b study for treatment of HIV-1 infection. Resistance development to GSK3532795 was evaluated through in vitro methods and was correlated with information obtained in a Phase 2a proof-of-concept study in HIV-1 infected participants. Both low and high concentrations of GSK3532795 were used for selections in vitro, and reduced susceptibility to GSK3532795 mapped specifically to amino acids near the capsid/ spacer peptide 1 (SP1) junction, the cleavage of which is blocked by MIs. Two key substitutions, A364V or V362I, were selected, the latter requiring secondary substitutions to reduce susceptibility to GSK3532795. Three main types of secondary substitutions were observed, none of which reduced GSK3532795 susceptibility in isolation. The first type was in the capsid C-terminal domain and downstream SP1 region (including (Gag numbering) R286K, A326T, T332S/N, I333V and V370A/M). The second, was an R41G substitution in viral protease that occurred with V362I. The third was seen in the capsid N-terminal domain, within the cyclophilin A binding domain (V218A/M, H219Q and G221E). H219Q increased viral replication capacity and reduced susceptibility of poorly growing viruses. In the Phase 2a study, a subset of these substitutions was also observed at baseline and some were selected following GSK35323795 treatment in HIV-1-infected participants. [ABSTRACT FROM AUTHOR]
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- 2019
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10. Clinical Resistance to Enfuvirtide Does Not Affect Susceptibility of Human Immunodeficiency Virus Type 1 to Other Classes of Entry Inhibitors.
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Ray, Neelanjana, Harrison, Jessamina E., Blackburn, Leslie A., Martin, Jeffrey N., Deeks, Steven G., and Doms, Robert W.
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HIV , *HTLV , *DRUG resistance , *PHARMACOLOGY , *PROTEINS - Abstract
The clinical use of the human immunodeficiency virus (HIV) fusion inhibitor enfuvirtide (ENF) can select for drug-resistant HIV-1 strains bearing mutations in the HR1 region of the viral envelope (Env) protein. We analyzed the properties of multiple Env proteins isolated from five patients who experienced an initial decline in viral load after ENF therapy followed by subsequent rebound due to emergence of ENF-resistant HIV-1. Prior to ENF therapy, each patient harbored genetically and phenotypically diverse Env proteins that used CCR5 and/or CXCR4 to elicit membrane fusion. Coreceptor usage patterns of the Envs isolated from two patients underwent homogenization following ENF therapy, whereas in the other three patients, recombination appeared to allow the introduction of a single HR1 sequence with ENF resistance mutations into phenotypically distinct Env proteins. Analysis of individual Env clones also revealed that prior to ENF therapy, there was sometimes marked heterogeneity in the susceptibility of individual Env proteins to coreceptor inhibitors. After virologic failure, all Envs acquired resistance to ENF but exhibited no consistent change in their sensitivity to the fusion inhibitor T-1249 or to coreceptor inhibitors. In summary, using patient-derived Env proteins, we found that ENF failure was associated with emergence of high-level resistance to ENF due largely to mutations in HR1 but that susceptibility to other entry inhibitors was unaffected, that in these late-stage patients there was greater clonal variability to coreceptor than to fusion inhibitors, and that recombination events in vivo could sometimes restore Env genotypic and phenotypic heterogeneity by introducing drug-resistant gp41 sequences into heterologous gp120 backgrounds. [ABSTRACT FROM AUTHOR]
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- 2007
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11. N-terminal substitutions in HIV-1 gp41 reduce the expression of non-trimeric envelope glycoproteins on the virus
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Dey, Antu K., David, Kathryn B., Ray, Neelanjana, Ketas, Thomas J., Klasse, Per J., Doms, Robert W., and Moore, John P.
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HIV , *HTLV , *HEALTH of gay men , *HIGHLY active antiretroviral therapy - Abstract
Abstract: The native, functional HIV-1 envelope glycoprotein (Env) complex is a trimer of two non-covalently associated subunits: the gp120 surface glycoprotein and the gp41 transmembrane glycoprotein. However, various non-functional forms of Env are present on virus particles and HIV-1-infected cells, some of which probably arise as the native complex decays. The aberrant forms include gp120–gp41 monomers and oligomers, as well as gp41 subunits from which gp120 has dissociated. The presence of non-functional Env creates binding sites for antibodies that do not recognize native Env complexes and that are, therefore, non-neutralizing. Non-native Env forms (monomers, dimers, tetramers and aggregates) can also arise when soluble gp140 proteins, lacking the cytoplasmic and transmembrane domains of gp41, are expressed for vaccine studies. We recently identified five amino acids in the gp41 N-terminal region (I535, Q543, S553, K567 and R588) that promote gp140 trimerization. We have now studied their influence on the function and antigenic properties of JR-FL Env expressed on the surfaces of pseudoviruses and Env-transfected cells. The 5 substitutions in gp41 reduce the expression of non-trimeric gp160s, without affecting trimer levels. Pseudovirions bearing the mutant Env are fully infectious with similar kinetics of Env-mediated fusion. Various non-neutralizing antibodies bind less strongly to the Env mutant, but neutralizing antibody binding is unaffected. Hence the gp41 substitutions do not adversely affect Env structure, supporting their use for making new Env-based vaccines. The mutant Env might also help in studies intended to correlate antibody binding to virus neutralization. Of note is that the 5 residues are much more frequent, individually or collectively, in viruses from subtypes other than B. [Copyright &y& Elsevier]
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- 2008
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12. Antiviral Activity, Safety, and Exposure–Response Relationships of GSK3532795, a Second-Generation Human Immunodeficiency Virus Type 1 Maturation Inhibitor, Administered as Monotherapy or in Combination With Atazanavir With or Without Ritonavir in a Phase 2a Randomized, Dose-Ranging, Controlled Trial (AI468002).
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Hwang, Carey, Schürmann, Dirk, Sobotha, Christian, Boffito, Marta, Sevinsky, Heather, Ray, Neelanjana, Ravindran, Palanikumar, Hong Xiao, Keicher, Christian, Hüser, Andreas, Krystal, Mark, Dicker, Ira B., Grasela, Dennis, and Lataillade, Max
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HIV-positive persons , *DIAGNOSIS of HIV infections , *ANTIVIRAL agents , *ATAZANAVIR , *MEDICAL care - Abstract
Background. GSK3532795 is a second-generation human immunodeficiency virus type 1 (HIV-1) maturation inhibitor that targets HIV-1 Gag, inhibiting the final protease cleavage between capsid protein p24 and spacer protein-1, producing immature, noninfectious virions. Methods. This was a phase 2a, randomized, dose-ranging multipart trial. In part A, subtype B-infected subjects received 5–120 mg GSK3532795 (or placebo) once daily for 10 days. In part B, subtype B-infected subjects received 40 mg or 80 mg GSK3532795 once daily with atazanavir (ATV) with or without (±) ritonavir (RTV) or standard of care (SOC) (tenofovir disoproxil fumarate 300 mg, emtricitabine 200 mg, and ATV/RTV 300 mg/100 mg) for 28 days. In part C, subtype C-infected subjects received 40 mg or 120 mg GSK3532795 once daily (or placebo) for 10 days. Endpoints included change in HIV-1 RNA from baseline on day 11 (parts A/C) or day 29 (part B). Results. A >1 log10 median decline in HIV-1 RNA was achieved by day 11 in parts A and C and day 29 in part B at GSK3532795 doses ≥40 mg; part B subjects receiving GSK3532795 and ATV ± RTV achieved similar declines to those receiving SOC. Median of the maximum declines in HIV-1 RNA were similar for the 40–120 mg once-daily dose groups regardless of baseline Gag polymorphisms. There were no deaths, adverse events leading to discontinuation, or serious adverse events. Conclusions. GSK3532795 demonstrated potent antiviral activity against subtype B (monotherapy or with ATV ± RTV) and subtype C, and was generally well tolerated, which supported continued development of GSK3532795 in subjects with HIV-1 subtype B or subtype C. [ABSTRACT FROM AUTHOR]
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- 2017
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13. Clinical Trial of the Anti-PD-L1 Antibody BMS-936559 in HIV-1 Infected Participants on Suppressive Antiretroviral Therapy.
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Gay, Cynthia L., Bosch, Ronald J., Ritz, Justin, Hataye, Jason M., Aga, Evgenia, Tressler, Randall L., Mason, Stephen W., Hwang, Carey K., Grasela, Dennis M., Ray, Neelanjana, Cyktor, Josh C., Coffin, John M., Acosta, Edward P., Koup, Richard A., Mellors, John W., Eron, Joseph J., and AIDS Clinical Trials 5326 Study Team
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MEDICAL research , *ANTIRETROVIRAL agents , *PLASMA gases , *RNA , *CLINICAL trials , *THERAPEUTIC use of monoclonal antibodies , *ANTIGENS , *COMPARATIVE studies , *HIV , *HIV infections , *RESEARCH methodology , *MEDICAL cooperation , *RESEARCH , *RESEARCH funding , *STATISTICAL sampling , *T cells , *EVALUATION research , *RANDOMIZED controlled trials , *ANTI-HIV agents - Abstract
Background: Reversing immune exhaustion with an anti-PD-L1 antibody may improve human immunodeficiency virus type 1 (HIV-1)-specific immunity and increase clearance of HIV-1-expressing cells.Methods: We conducted a phase I, randomized, double-blind, placebo-controlled, dose-escalating study of BMS-936559, including HIV-1-infected adults aged >18 to <70 years on suppressive antiretroviral therapy with CD4+ counts >350 cells/μL and detectable plasma HIV-1 RNA by single-copy assay. Data on single infusions of BMS-936559 (0.3 mg/kg) versus placebo are described. The primary outcomes were safety defined as any grade 3 or greater or immune-related adverse event (AE) and the change in HIV-1 Gag-specific CD8+ T cell responses from baseline to day 28 after infusion.Results: Eight men enrolled: 6 received 0.3 mg/kg of BMS-936559, and 2 received placebo infusions. There were no BMS-936559-related grade 3 or greater AEs. In 1 participant, asymptomatic hypophysitis (a protocol-defined immune-related AE) was identified 266 days after BMS-936559 infusion; it resolved over time. The mean percentage of HIV-1 Gag-specific CD8+ T cells expressing interferon γ increased from baseline (0.09%) through day 28 (0.20%; P = .14), driven by substantial increases in 2 participants who received BMS-936559.Conclusions: In this first evaluation of an immunologic checkpoint inhibitor in healthy HIV-1-infected persons, single low-dose BMS-936559 infusions appeared to enhance HIV-1-specific immunity in a subset of participants.Clinical Trials Registration: NCT02028403. [ABSTRACT FROM AUTHOR]- Published
- 2017
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14. Genotypic correlates of susceptibility to HIV-1 attachment inhibitor BMS-626529, the active agent of the prodrug BMS-663068.
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Zhou, Nannan, Nowicka-Sans, Beata, McAuliffe, Brian, Ray, Neelanjana, Eggers, Betsy, Fang, Hua, Fan, Li, Healy, Matthew, Langley, David R., Hwang, Carey, Lataillade, Max, Hanna, George J., and Krystal, Mark
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HIV infections , *THERAPEUTICS , *HIV-positive persons , *HIV-1 glycoprotein 120 , *DISEASE susceptibility , *PRODRUGS , *REVERSE genetics , *RNA - Abstract
Objectives In an 8 day monotherapy study of subjects infected with HIV-1 (subtype B) (NCT01009814), BMS-626529 (an attachment inhibitor that binds to HIV-1 envelope glycoprotein gp120), administered as the prodrug BMS-663068, produced substantial declines in plasma HIV-1 RNA. However, large variability in susceptibility to BMS-626529 was noted and virus with low susceptibility was less likely to be suppressed by BMS-663068 administration. The current analysis sought to investigate the genotypic correlates of susceptibility to BMS-626529. Methods In vitro selection experiments, evaluation of clinical samples of subtype B from the monotherapy study and evaluation of intrinsically resistant subtype AE viruses were conducted. Reverse genetics was used to identify key substitutions in envelope clones responsible for reduced susceptibility. Results An M426L or S375M change were the major substitutions associated with reductions in susceptibility to BMS-626529 in baseline samples of subtype B viruses from the monotherapy study, with M434I and M475I contributing to a lesser extent. Class resistance in subtype AE viruses was mapped to 375H and 475I substitutions, found in the vast majority of these viruses. Analysis of multiple envelope clones from infected subjects showed higher intrasubject variability in susceptibility to BMS-626529 compared with other classes of entry inhibitors. Conclusions These data define key genotypic substitutions in HIV-1 gp120 that could confer phenotypic resistance to BMS-626529. [ABSTRACT FROM PUBLISHER]
- Published
- 2014
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15. Pharmacodynamics, Safety, and Pharmacokinetics of BMS-663068, an Oral HIV-1 Attachment Inhibitor in HIV-1–Infected Subjects.
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Nettles, Richard E., Schürmann, Dirk, Zhu, Li, Stonier, Michele, Huang, Shu-Pang, Chang, Ih, Chien, Caly, Krystal, Mark, Wind-Rotolo, Megan, Ray, Neelanjana, Hanna, George J., Bertz, Richard, and Grasela, Dennis
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PHARMACODYNAMICS , *PHARMACOKINETICS , *HIV , *HTLV , *SMALL molecules - Abstract
Background. BMS-663068 is a prodrug of the small-molecule inhibitor BMS-626529, which inhibits human immunodeficiency virus type 1 (HIV-1) infection by binding to gp120 and interfering with the attachment of virus to CD4+ T-cells.Methods. Fifty HIV-1–infected subjects were randomized to 1 of 5 regimen groups (600 mg BMS-663068 plus 100 mg ritonavir every 12 hours [Q12H], 1200 mg BMS-663068 plus 100 mg ritonavir every bedtime, 1200 mg BMS-663068 plus 100 mg ritonavir Q12H, 1200 mg BMS-663068 Q12H plus 100 mg ritonavir every morning, or 1200 mg BMS-663068 Q12H) for 8 days in this open-label, multiple-dose, parallel study. The study assessed the pharmacodynamics, pharmacokinetics, and safety of BMS-663068.Results. The maximum median decrease in plasma HIV-1 RNA load from baseline ranged from 1.21 to 1.73 log10 copies/mL. Plasma concentrations of BMS-626529 were not associated with an antiviral response, while low baseline inhibitory concentrations and the minimum and average steady-state BMS-626529 plasma concentrations, when adjusted by the baseline protein binding–adjusted 90% inhibitory concentration (inhibitory quotient), were linked with antiviral response. BMS-663068 was generally well tolerated.Conclusions. Administration of BMS-663068 for 8 days with or without ritonavir resulted in substantial declines in plasma HIV-1 RNA levels and was generally well tolerated. Longer-term clinical trials of BMS-663068 as part of combination antiretroviral therapy are warranted.Clinical Trials Registration. NCT01009814. [ABSTRACT FROM PUBLISHER]
- Published
- 2012
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16. Enhanced Phosphatase Activity Attenuates α-Synucleinopathy in a Mouse Model.
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Kang-Woo Lee, Walter Chen, Eunsung Junn, Joo-Young Im, Grosso, Hilary, Sonsalla, Patricia K., Xuyan Feng, Ray, Neelanjana, Fernandez, Jose R., Yang Chao, Masliah, Eliezer, Voronkov, Michael, Braithwaite, Steven P., Stock, Jeffry B., and Mouradian, M. Maral
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PARKINSON'S disease , *PHOSPHOPROTEIN phosphatases , *PHOSPHATASES , *NEURODEGENERATION , *METHYLATION - Abstract
α-Synuclein (α-Syn) is a key protein that accumulates as hyperphosphorylated aggregates in pathologic hallmark features of Parkinson's disease (PD) and other neurodegenerative disorders. Phosphorylation of this protein at serine 129 is believed to promote its aggregation and neurotoxicity, suggesting that this post-translational modification could be a therapeutic target. Here, we demonstrate that phosphoprotein phosphatase 2A (PP2A) dephosphorylatesα-Syn at serine 129 and that this activity is greatly enhanced by carboxyl methylation of the catalytic C subunit of PP2A.α-Syn-transgenic mice raised on a diet supplemented with eicosanoyl-5-hydroxytryptamide, an agent that enhances PP2A methylation, dramatically reduced both α-Syn phosphorylation at Serine 129 and α-Syn aggregation in the brain. These biochemical changes were associated with enhanced neuronal activity, increased dendritic arborizations, and reduced astroglial and microglial activation, as well as improved motor performance. These findings support the notion that serine 129 phosphorylation ofα-Syn is of pathogenetic significance and that promoting PP2A activity is a viable disease-modifying therapeutic strategy for α-synucleinopathies such as PD. [ABSTRACT FROM AUTHOR]
- Published
- 2011
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