Melanie Maria Ott
J. David Gladstone Institutes
Project start date: 2009-07-15
Project end date: 2014-06-30
Sponsored Links Excellgen http://Excellgen.com
ROLE OF FACTOR ACETYLATION IN THE REGULATION OF HIV TRANSCRIPTION
Melanie Maria Ott, Associate Investigator
J. David Gladstone Institutes, San Francisco, Ca 94158
Grant 5R01AI083139-02 from National Institute Of Allergy And Infectious Diseases
Abstract: Transcription is a key regulatory step in the HIV-1 life cycle that remains largely unexplored as therapeutic target. We have identified factor acetylation as a critical step in the regulation of HIV-1 transcription. Acetylation is the reversible transfer of an acetyl group (14 Da) to the -amino group of lysines. It is mediated by acetyl transferases (HAT) and reversed by the activity of deacetylases (HDACs). Inhibitors of HDACs are currently being explored as potential therapeutics to flush the latent reservoir in HIV-infected patients. Three factors stand out in the regulation of HIV transcription Tat, NF-B and cyclin T1/P-TEFb. Notably, the functions of Tat and NF-B are importantly regulated by reversible acetylation of these proteins. We now report that cyclin T1 in P-TEFb is also acetylated at four defined acetyl acceptor sites. Cyclin T1 acetylation activates P-TEFb by promoting its dissociation from ribonucleoprotein complexes containing 7SK RNA and Hexim1 and importantly regulates the activity of the HIV LTR. In addition, we have identified a novel posttranslational modification in Tat, monomethylation of lysine 51 by Set9 that regulates Tat acetylation and activates Tat transcriptional activity. We propose to examine the impact of these two new findings on the HIV transcriptional process. We hypothesize that reversible cyclin T1 acetylation is an important regulatory mechanism that controls the activity of the HIV promoter during active and latent HIV infection. In addition, we speculate that Tat monomethylation is a critical step to promote Tat acetylation thereby activating Tat transcriptional activity. Our specific aims are designed to test these hypotheses and to define the mechanisms associated with cyclin T1 acetylation and Tat methylation/acetylation in actively or latently HIV-infected T cells. Our focus lies on 1. Assessing the role of cyclinT1 acetylation in HIV replication. We propose to examine whether acetylation- deficient mutants of cyclinT1 can support HIV replication in CD4+ T cells and whether cyclin T1 acetylation regulates the establishment and maintenance of post-integration latency. Our preliminary results show that cyclin T1 acetylation is an important regulatory mechanism for the activity of the HIV LTR while it may not affect Tat transactivation. Since the basal activity of the HIV LTR is critical at the beginning of the infectious process or during reactivation from latency when the Tat protein is not yet produced, we speculate that cyclin T1 acetylation might be a critical determinant of HIV transcription at these times. 2. Characterizing how cyclin T1 acetylation regulates P-TEFb function at the HIV promoter. We propose to test the hypothesis that acetylated lysines in cyclin T1 interact with bromodomains in Brd4. Brd4 is a factor that can recruit P-TEFb to the HIV promoter in the absence of Tat and contains two bromodomains, which are bona fide binding domains for acetyl lysines. We speculate that cyclin T1 acetylation activates HIV LTR activity by recruiting Brd4 into the active P-TEF complex. Similarly, we will examine how acetylated cyclin T1 interacts with Tat and TAR RNA. 3. Studying how lysine methylation cooperates with Tat acetylation to regulate HIV transcription. We propose to study the potential crosstalk between Tat monomethylation by Set9 and Tat acetylation by p300. Our preliminary data show that Tat monomethylation is an early step in the Tat transactivation cycle and precedes Tat acetylation. We will test whether monomethylated Tat or Set9 recruits p300 to Tat. We will also examine how differently modified Tat species accumulate in HIV-1-infected T cells using modification-specific Tat antibodies generated in my laboratory. We anticipate that these studies will increase our molecular understanding of the biology of HIV transcription and provide novel insight into the therapeutic potential of HDAC inhibitors in HIV infection. We seek to identify and characterize novel regulatory mechanisms controlling HIV-1 transcription that might be exploited as new therapeutic targets. Our proposed studies characterize the role of reversible factor acetylation (cyclin T1 and Tat) in the control of active and latent HIV infection. These studies are directly relevant to HIV/AIDS and may contribute to the development of novel antiviral drugs that will address public need
Keywords: AIDS Virus; AIDS/HIV; AIDS/HIV problem; Acetylation; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Address; Affect; Alleles; Allelomorphs; Antibodies; Antiviral Agents; Antiviral Drugs; Antivirals; Arginine; Arginine, L-Isomer; Assay; Award; Binding; Binding (Molecular Function); Bioassay; Biologic Assays; Biological Assay; Biology; Bromodomain; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CHIP assay; CREBBP-Associated Factor; Cell Line; Cell Lines, Strains; CellLine; Cells; Cells, CD4; ChIP (chromatin immunoprecipitation); Charge; Complex; Cytofluorometry, Flow; Data; Deacetylase; Deacetylation; Development; Dissociation; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; EC 2; EC 2.1.1; EC 2.3.1.-; EP300; EP300 gene; Elongation Factor; Flow Cytofluorometries; Flow Cytometry; Flow Microfluorimetry; Flushing; Flushings; Funding; Gene Expression; Gene Products, RNA; Gene Transcription; Genes; Genes, p53; Genetic Alteration; Genetic Change; Genetic Transcription; Genetic defect; Gln; Glutamine; Grant; HDAC Agent; HIV; HIV Infections; HIV-1; HIV-I; HIV/AIDS; HIV/AIDS problem; HIV1; HTLV-III; HTLV-III Infections; HTLV-III-LAV Infections; Histone Acetylase PCAF; Histone Acetylation; Histone Deacetylase Inhibitor; Histones; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human immunodeficiency virus 1; Immunodeficiency Virus Type 1, Human; In Vitro; Infection; L-Arginine; L-Glutamine; L-Lysine; LAV-HTLV-III; Laboratories; Lentiviral Vector; Lentivirus Vector; Life Cycle; Life Cycle Stages; Lymphadenopathy-Associated Virus; Lysine; Maintenance; Maintenances; Mass Spectrum; Mass Spectrum Analysis; Mediating; Methylation; Methyltransferase; Microfluorometry, Flow; Modeling; Modification; Molecular; Molecular Interaction; Monitor; Mutation; P-CAF protein; P/CAF; P53; PCAF; Patients; Photometry/Spectrum Analysis, Mass; Physiologic; Physiological; Play; Post-Translational Modifications; Post-Translational Protein Processing; Posttranslational Modifications; Process; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Protein Acetylation; Protein Methylation; Protein Modification; Protein Modification, Post-Translational; Protein Processing, Post-Translational; Protein Processing, Posttranslational; Protein/Amino Acid Biochemistry, Post-Translational Modification; Proteins; Proviruses; Q. Levoglutamide; RNA; RNA Expression; RNA, Non-Polyadenylated; RNP; Recombinants; Recruitment Activity; Regulation; Reporting; Research; Ribonucleic Acid; Ribonucleoproteins; Role; Shapes; Site; Spectrometry, Mass; Spectroscopy, Mass; Spectrum Analyses, Mass; Spectrum Analysis, Mass; T-Cells; T-Lymphocyte; T-Lymphotropic Virus Type III Infections, Human; T4 Cells; T4 Lymphocytes; TAT; TP53; TP53 gene; TRP53; Tars; Testing; Therapeutic; Thymus-Dependent Lymphocytes; Time; Trans-Acting Factors; Trans-Activation (Genetics); Trans-Activation of Transcription Protein; Trans-Activator of Transcription of HIV; Trans-Activators; Transactivating Regulatory Protein; Transactivation; Transactivators; Transcription; Transcription Elongation; Transcription Process; Transcription Regulation; Transcription, Genetic; Transcriptional Control; Transcriptional Regulation; Transferase; Tumor Protein p53 Gene; Viral; Viral Genome; Virus-HIV; active control; amino group; base; chromatin immunoprecipitation; cofactor; combinatorial; cultured cell line; cyclin T; cyclin T1; design; designing; experiment; experimental research; experimental study; flow cytophotometry; gene product; genome mutation; helper T cell; histone modification; human T cell leukemia virus III; human T lymphotropic virus III; in vivo; inhibitor; inhibitor/antagonist; insight; life course; methylase; mutant; new therapeutic target; novel; p300; p300 acetyltransferase; p300-CREB-binding protein-associated factor; p300/CBP-Associated Factor; pCAF protein; public health relevance; reactivation from latency; recruit; research study; social role; tat Protein; therapeutic target; thymus derived lymphocyte; trans acting factor (genetic); transcription factor; transmethylase
Relevance: NARRATIVE We seek to identify and characterize novel regulatory mechanisms controlling HIV-1 transcription that might be exploited as new therapeutic targets. Our proposed studies characterize the role of reversible factor acetylation (cyclin T1 and Tat) in the control of active and latent HIV infection. These studies are directly relevant to HIV/AIDS and may contribute to the development of novel antiviral drugs that will address public need
Project start date: 2009-07-15
Project end date: 2014-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: PA-07-070
5R01AI083139-02 (2010): $378180
Grants awarded to Melanie Maria Ott
ROLE OF FACTOR ACETYLATION IN THE REGULATION OF HIV TRANSCRIPTION
Melanie Maria Ott, Associate Investigator
J. David Gladstone Institutes, San Francisco, Ca 94158
Grant 1R01AI083139-01A1 from National Institute Of Allergy And Infectious Diseases
Abstract: Transcription is a key regulatory step in the HIV-1 life cycle that remains largely unexplored as therapeutic target. We have identified factor acetylation as a critical step in the regulation of HIV-1 transcription. Acetylation is the reversible transfer of an acetyl group (14 Da) to the -amino group of lysines. It is mediated by acetyl transferases (HAT) and reversed by the activity of deacetylases (HDACs). Inhibitors of HDACs are currently being explored as potential therapeutics to flush the latent reservoir in HIV-infected patients. Three factors stand out in the regulation of HIV transcription Tat, NF-B and cyclin T1/P-TEFb. Notably, the functions of Tat and NF-B are importantly regulated by reversible acetylation of these proteins. We now report that cyclin T1 in P-TEFb is also acetylated at four defined acetyl acceptor sites. Cyclin T1 acetylation activates P-TEFb by promoting its dissociation from ribonucleoprotein complexes containing 7SK RNA and Hexim1 and importantly regulates the activity of the HIV LTR. In addition, we have identified a novel posttranslational modification in Tat, monomethylation of lysine 51 by Set9 that regulates Tat acetylation and activates Tat transcriptional activity. We propose to examine the impact of these two new findings on the HIV transcriptional process. We hypothesize that reversible cyclin T1 acetylation is an important regulatory mechanism that controls the activity of the HIV promoter during active and latent HIV infection. In addition, we speculate that Tat monomethylation is a critical step to promote Tat acetylation thereby activating Tat transcriptional activity. Our specific aims are designed to test these hypotheses and to define the mechanisms associated with cyclin T1 acetylation and Tat methylation/acetylation in actively or latently HIV-infected T cells. Our focus lies on 1. Assessing the role of cyclinT1 acetylation in HIV replication. We propose to examine whether acetylation- deficient mutants of cyclinT1 can support HIV replication in CD4+ T cells and whether cyclin T1 acetylation regulates the establishment and maintenance of post-integration latency. Our preliminary results show that cyclin T1 acetylation is an important regulatory mechanism for the activity of the HIV LTR while it may not affect Tat transactivation. Since the basal activity of the HIV LTR is critical at the beginning of the infectious process or during reactivation from latency when the Tat protein is not yet produced, we speculate that cyclin T1 acetylation might be a critical determinant of HIV transcription at these times. 2. Characterizing how cyclin T1 acetylation regulates P-TEFb function at the HIV promoter. We propose to test the hypothesis that acetylated lysines in cyclin T1 interact with bromodomains in Brd4. Brd4 is a factor that can recruit P-TEFb to the HIV promoter in the absence of Tat and contains two bromodomains, which are bona fide binding domains for acetyl lysines. We speculate that cyclin T1 acetylation activates HIV LTR activity by recruiting Brd4 into the active P-TEF complex. Similarly, we will examine how acetylated cyclin T1 interacts with Tat and TAR RNA. 3. Studying how lysine methylation cooperates with Tat acetylation to regulate HIV transcription. We propose to study the potential crosstalk between Tat monomethylation by Set9 and Tat acetylation by p300. Our preliminary data show that Tat monomethylation is an early step in the Tat transactivation cycle and precedes Tat acetylation. We will test whether monomethylated Tat or Set9 recruits p300 to Tat. We will also examine how differently modified Tat species accumulate in HIV-1-infected T cells using modification-specific Tat antibodies generated in my laboratory. We anticipate that these studies will increase our molecular understanding of the biology of HIV transcription and provide novel insight into the therapeutic potential of HDAC inhibitors in HIV infection. We seek to identify and characterize novel regulatory mechanisms controlling HIV-1 transcription that might be exploited as new therapeutic targets. Our proposed studies characterize the role of reversible factor acetylation (cyclin T1 and Tat) in the control of active and latent HIV infection. These studies are directly relevant to HIV/AIDS and may contribute to the development of novel antiviral drugs that will address public need
Keywords: AIDS Virus; AIDS/HIV; AIDS/HIV problem; Acetylation; Acquired Immune Deficiency Syndrome Virus; Acquired Immunodeficiency Syndrome Virus; Address; Affect; Alleles; Allelomorphs; Antibodies; Antiviral Agents; Antiviral Drugs; Antivirals; Arginine; Arginine, L-Isomer; Assay; Award; Binding; Binding (Molecular Function); Bioassay; Biologic Assays; Biological Assay; Biology; Bromodomain; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CHIP assay; CREBBP-Associated Factor; Cell Line; Cell Lines, Strains; CellLine; Cells; Cells, CD4; ChIP (chromatin immunoprecipitation); Charge; Complex; Cytofluorometry, Flow; Data; Deacetylase; Deacetylation; Development; Dissociation; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; EC 2; EC 2.1.1; EC 2.3.1.-; EP300; EP300 gene; Elongation Factor; Factor, Elongation; Flow Cytofluorometries; Flow Cytometry; Flow Microfluorimetry; Flushing; Flushings; Funding; Gene Expression; Gene Products, RNA; Gene Transcription; Genes; Genes, p53; Genetic Alteration; Genetic Change; Genetic Transcription; Genetic defect; Gln; Glutamine; Grant; HDAC Agent; HIV; HIV Infections; HIV-1; HIV-I; HIV/AIDS; HIV/AIDS problem; HIV1; HTLV-III; HTLV-III Infections; HTLV-III-LAV Infections; Histone Acetylase PCAF; Histone Acetylation; Histone Deacetylase Inhibitor; Histones; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human immunodeficiency virus 1; Immunodeficiency Virus Type 1, Human; In Vitro; Infection; L-Arginine; L-Glutamine; L-Lysine; LAV-HTLV-III; Laboratories; Lentiviral Vector; Lentivirus Vector; Life Cycle; Life Cycle Stages; Lymphadenopathy-Associated Virus; Lysine; Maintenance; Maintenances; Mass Spectrum; Mass Spectrum Analysis; Mediating; Methylation; Methyltransferase; Microfluorometry, Flow; Modeling; Modification; Molecular; Molecular Interaction; Monitor; Mutation; P-CAF protein; P/CAF; P53; PCAF; Patients; Photometry/Spectrum Analysis, Mass; Physiologic; Physiological; Play; Post-Translational Modifications; Post-Translational Protein Processing; Posttranslational Modifications; Process; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Protein Acetylation; Protein Methylation; Protein Modification; Protein Modification, Post-Translational; Protein Processing, Post-Translational; Protein Processing, Posttranslational; Protein/Amino Acid Biochemistry, Post-Translational Modification; Proteins; Proviruses; Q. Levoglutamide; RNA; RNA Expression; RNA, Non-Polyadenylated; RNP; Recombinants; Recruitment Activity; Regulation; Reporting; Research; Ribonucleic Acid; Ribonucleoproteins; Role; Shapes; Site; Spectrometry, Mass; Spectroscopy, Mass; Spectrum Analyses, Mass; Spectrum Analysis, Mass; T-Cells; T-Lymphocyte; T-Lymphotropic Virus Type III Infections, Human; T4 Cells; T4 Lymphocytes; TAT; TP53; TP53 gene; TRP53; Tars; Testing; Therapeutic; Thymus-Dependent Lymphocytes; Time; Trans-Acting Factors; Trans-Activation (Genetics); Trans-Activation of Transcription Protein; Trans-Activator of Transcription of HIV; Trans-Activators; Transactivating Regulatory Protein; Transactivation; Transactivators; Transcription; Transcription Elongation; Transcription Process; Transcription Regulation; Transcription, Genetic; Transcriptional Control; Transcriptional Regulation; Transferase; Tumor Protein p53 Gene; Viral; Viral Genome; Virus-HIV; active control; amino group; base; chromatin immunoprecipitation; cofactor; combinatorial; cultured cell line; cyclin T; cyclin T1; design; designing; experiment; experimental research; experimental study; flow cytophotometry; gene product; genome mutation; helper T cell; histone modification; human T cell leukemia virus III; human T lymphotropic virus III; in vivo; inhibitor; inhibitor/antagonist; insight; life course; methylase; mutant; new therapeutic target; novel; p300; p300 acetyltransferase; p300-CREB-binding protein-associated factor; p300/CBP-Associated Factor; pCAF protein; public health relevance; reactivation from latency; recruit; research study; social role; tat Protein; therapeutic target; thymus derived lymphocyte; trans acting factor (genetic); transcription factor; transmethylase
Relevance: NARRATIVE We seek to identify and characterize novel regulatory mechanisms controlling HIV-1 transcription that might be exploited as new therapeutic targets. Our proposed studies characterize the role of reversible factor acetylation (cyclin T1 and Tat) in the control of active and latent HIV infection. These studies are directly relevant to HIV/AIDS and may contribute to the development of novel antiviral drugs that will address public need
Project start date: 2009-07-15
Project end date: 2014-06-30
Budget start date: 15-JUL-2009
Budget end date: 30-JUN-2010
PFA/PA: PA-07-070
1R01AI083139-01A1 (2009): $382000
ROLE OF TAT AND SIRT1 IN THE T-CELL HYPERACTIVATION SYNDROME INDUCED BY HIV-1
Melanie Maria Ott, Associate Investigator
J. David Gladstone Institutes, San Francisco, Ca 94158
Grant 1R01AI081651-01A1 from National Institute Of Allergy And Infectious Diseases
Abstract: Symptoms of T-cell hyperactivation shape the course and outcome of HIV-1 infection, but the molecular mechanism(s) underlying this chronic immune activation are not well understood. We have identified a novel mechanism by which the HIV-1 Tat protein leads to chronic immune activation. We find that Tat hyperactivates T cells by blocking the deacetylase activity of SIRT1 (Kwon et al, Cell Host Microbe, 2008). SIRT1 is a nicotinamide adenine dinucleotide (NAD+)-dependent histone deacetylase and an important regulator of the transcription factor NF-B. Tat directly interacts with the deacetylase domain of SIRT1 and blocks the ability of SIRT1 to deacetylate the RelA/p65 subunit of NF-B. Because acetylated p65 is more active as a transcription factor, Tat hyperactivates the expression of NF-B-responsive genes, such as interleukin-2 (IL-2). These results support a model where the normal function of SIRT1 as a negative regulator of T-cell activation is suppressed by Tat during HIV infection. We propose to define the novel role of SIRT1 as a regulator of immune activation in HIV-infected T cells. We have new and unpublished findings that link the SIRT1 deacetylase activity with immune-suppressive functions of regulatory T cells (Tregs). Special focus of this proposal lies therefore on the characterization of the function of Tat and SIRT1 in Tregs and on the identification of novel SIRT1 substrates in effector and regulatory T cells populations. The importance of these studies is highlighted by their possible impact on the development of novel therapeutic interventions. Potent small molecule activators of SIRT1 have recently become available with great promise in diseases associated with aging (Milne et al, Nature, 2007). We will use these activators to test the hypothesis that activating the suppressor function of SIRT1 will counterbalance the immune stimulatory function of Tat and may represent a novel strategy to treat chronic immune activation in HIV-infected patients. Our specific aims are 1) we will study the role of SIRT1 in HIV-infected T cells. We will infect Jurkat T cell lines in which SIRT1 expression is down regulated via shRNAs with a GFP-tagged infectious clone of HIV-1 and study intracellular IL-2 production in infected (GFP+) and uninfected (GFP-) cells in response to activation with anti-CD3 and CD28 antibodies. We will also infect primary CD4+ T cell cultures with HIV-1 and test whether treatment with SIRT1 activators can reverse hyperstimulation of IL-2 production. 2) We will identify novel targets of the SIRT1 deacetylase activity in infected T cells. We have preliminary evidence that Tat by inhibiting SIRT1 induces hyperacetylation of several SIRT1 targets including proapoptotic factors p53 and Foxo3A. Since both factors are important regulators of T-cell death during HIV infection, we will study how Tat manipulates the transcriptional activities and proapoptotic functions of both factors. We will also perform genome-wide expression profiling and identify gene programs that are modulated by Tat expression or SIRT1 knockdown. 3) We will examine how the SIRT1/Tat interaction influences the development and function of Tregs. We have preliminary results showing that SIRT1 promotes TGF--induced Treg development and is involved in deacetylation of the transcription factor FoxP3. We propose to study how SIRT1 regulates expression and function of FoxP3 in Tregs and will characterize how Tat expression during HIV infection can interfere with this process. These studies will bring novel insight into the molecular biology of HIV-induced immune activation and identify yet undefined mechanisms of HDAC-mediated control of the immune response. We seek to identify and characterize novel regulatory mechanisms controlling T cell hyperactivation during HIV-1 infection. T cell hyperactivation is a hallmark of pathogenic HIV-1 infection and the strongest predictor of the progression to AIDS in infected individuals. Our proposed studies characterize novel mechanisms by which the HIV-1 Tat protein hyperactivates T cells. These studies are directly relevant to HIV/AIDS and may contribute to the development of novel antiviral drugs that will address public need
Keywords: AIDS; AIDS Virus; AIDS/HIV; AIDS/HIV problem; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immune Deficiency Syndrome Virus; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Acquired Immunodeficiency Syndrome Virus; Address; Adenosine 5`-(trihydrogen diphosphate), P`-5`-ester with 3-(aminocarbonyl)-1-beta-D-ribofuranosylpyridinium, inner salt; Age; Aging; Antibodies; Antiretroviral Therapy, Highly Active; Antiviral Agents; Antiviral Drugs; Antivirals; Apoptotic; Attenuated; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BRM; BSF-2; BSF2; BSF2 (B cell stimulating factor 2); Binding; Binding (Molecular Function); Biological Response Modifiers; Biomodulators; Blood Circulation; Blood Plasma; Bloodstream; CD28; CD28 gene; CD3; CD3 Antigens; CD3 Complex; CD3 molecule; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CD8; CD8B; CD8B1; CD8B1 gene; CMV; CREBBP-Associated Factor; Cell Communication and Signaling; Cell Culture Techniques; Cell Death; Cell Line; Cell Lines, Strains; Cell Signaling; CellLine; Cells; Cells, CD4; Chronic; Circulation; Co-Stimulator; Coenzyme I; Consensus; Costimulator; Coupled; Cytofluorometry, Flow; Cytomegalovirus; DIF; DNA Molecular Biology; DPN; Data; Deacetylase; Deacetylation; Development; Differentiation Factor, B-Cell; Dihydronicotinamide Adenine Dinucleotide; Diphosphopyridine Nucleotide; Disease; Disease Progression; Disorder; EC 2.3.1.-; Engineering; Engineerings; Epidermal Thymocyte Activating Factor; Equilibrium; Expression Profiling; Expression Signature; Flow Cytofluorometries; Flow Cytometry; Flow Microfluorimetry; GFP; Gene Expression; Generations; Genes; Genes, p53; Green Fluorescent Proteins; HAART; HCMV; HDAC; HDAC Proteins; HIV; HIV Infections; HIV-1; HIV-I; HIV/AIDS; HIV/AIDS problem; HIV1; HLA-BR; HLA-BR Antigens; HLA-D-Related Antigens; HLA-DR; HLA-DR Antigens; HLA-MT; HLA-MT Antigens; HPGF; HTLV-III; HTLV-III Infections; HTLV-III-LAV Infections; Helper Cells; Helper T-Cells; Helper-Inducer T-Lymphocyte; Hepatocyte-Stimulating Factor; Highly Active Antiretroviral Therapy; Histone Acetylase PCAF; Histone Deacetylase; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human immunodeficiency virus 1; Human, General; Hybridoma Growth Factor; IFN-beta 2; IFNB2; IL-1; IL-2; IL-6; IL1; IL2; IL2 Protein; IL6 Protein; INFLM; Immune; Immune Function, Cellular; Immune Markers; Immune Mediators; Immune Mediators/Modulators; Immune Regulators; Immune response; Immune system; Immunodeficiency Virus Type 1, Human; Immunologic Deficiency Syndrome, Acquired; Immunologic Markers; Individual; Inducer Cells; Infection; Infectious Agent; Inflammation; Inflammatory; Interleukin 2; Interleukin 2 Precursor; Interleukin 6 (Interferon, Beta 2); Interleukin I; Interleukin II; Interleukin-1; Interleukin-2; Interleukin-6; Interleukine 2; Interleukine 2 Precursor; Interleukine II; Interphase Cell; Intracellular Communication and Signaling; Investigation; LAV-HTLV-III; LYT3; Laboratories; Length of Life; Lentiviral Vector; Lentivirinae; Lentivirus; Lentivirus Vector; Link; Longevity; Lymph node proper; Lymphadenopathy-Associated Virus; Lymphocyte Mitogenic Factor; Lymphocyte-Stimulating Hormone; MGI-2; Macrophage Cell Factor; Man (Taxonomy); Man, Modern; Measures; Mediating; Microbe; Microfluorometry, Flow; Mitogenic Factor; Modeling; Molecular; Molecular Biology; Molecular Fingerprinting; Molecular Interaction; Molecular Profiling; Myeloid Differentiation-Inducing Protein; NAD; Nadide; Nature; Nicotinamide adenine dinucleotide; Nicotinamide-Adenine Dinucleotide; Non-dividing Cell; OKT3 antigen; Outcome; P-CAF protein; P/CAF; P53; PCAF; Participant; Patients; Peripheral; Phenotype; Plasma; Plasmacytoma Growth Factor; Play; Population; Process; Production; Programs (PT); Programs [Publication Type]; Proteins; Regulation; Regulatory Protein; Reporting; Research; Resting Cell; Reticuloendothelial System, Lymph Node; Reticuloendothelial System, Serum, Plasma; Role; SIV; Salivary Gland Viruses; Senescence; Serum, Plasma; Shapes; Signal Transduction; Signal Transduction Systems; Signaling; Simian Immunodeficiency Viruses; Subfamily lentivirinae; Surface; Symptoms; Syndrome; T Helper Factor; T cell growth factor; T-Cell Activation; T-Cell Growth Factor; T-Cell Stimulating Factor; T-Cells; T-Cells, Helper-Inducer; T-Lymphocyte; T-Lymphocytes, Helper; T-Lymphocytes, Inducer; T-Lymphotropic Virus Type III Infections, Human; T3 Antigens; T3 Complex; T3 molecule; T4 Cells; T4 Lymphocytes; T44; TAT; TNF; TNF A; TNF gene; TNFSF2; TP53; TP53 gene; TRP53; Testing; Therapeutic; Thymocyte Stimulating Factor; Thymus-Dependent Lymphocytes; Trans-Acting Factors; Trans-Activation of Transcription Protein; Trans-Activator of Transcription of HIV; Trans-Activators; Transactivating Regulatory Protein; Transactivators; Tumor Necrosis Factor Gene; Tumor Protein p53 Gene; Viral; Viral Diseases; Virus Diseases; Virus-HIV; Virus-Lenti; anti-retroviral therapy, highly active; balance; balance function; biological signal transduction; body system, allergic/immunologic; cultured cell line; cytokine; cytomegalovirus group; design; designing; disease/disorder; experiment; experimental research; experimental study; flow cytophotometry; gene product; genetic regulatory protein; genome-wide; helper T cell; host response; human T cell leukemia virus III; human T lymphotropic virus III; human cytomegalovirus; immune function; immunoresponse; infectious organism; insight; interest; interferon beta 2; life span; lifespan; lymph gland; lymph nodes; lymphocyte activating factor; microbial; molecuar profile; molecular signature; necrocytosis; new approaches; novel; novel approaches; novel strategies; novel strategy; novel therapeutic intervention; organ system, allergic/immunologic; p300 acetyltransferase; p300-CREB-binding protein-associated factor; p300/CBP-Associated Factor; p65; pCAF protein; programs; public health relevance; receptor expression; regulatory gene product; research study; response; senescent; shRNA; short hairpin RNA; small hairpin RNA; small molecule; social role; tat Protein; thymus derived lymphocyte; trans acting factor (genetic); transcription factor; viral infection; virus infection
Relevance: Narrative We seek to identify and characterize novel regulatory mechanisms controlling T cell hyperactivation during HIV-1 infection. T cell hyperactivation is a hallmark of pathogenic HIV-1 infection and the strongest predictor of the progression to AIDS in infected individuals. Our proposed studies characterize novel mechanisms by which the HIV-1 Tat protein hyperactivates T cells. These studies are directly relevant to HIV/AIDS and may contribute to the development of novel antiviral drugs that will address public need
Project start date: 2010-01-01
Project end date: 2014-12-31
Budget start date: 1-JAN-2010
Budget end date: 31-DEC-2010
PFA/PA: PA-07-070
1R01AI081651-01A1 (2010): $477500
Melanie Maria Ott
J. David Gladstone Institutes
Project start date: 2010-01-01
Project end date: 2014-12-31
MECHANISMS AND FUNCTIONS OF CORE-INDUCED LIPID DROPLET ACCUMULATION IN HEPATITIS
Melanie Maria Ott
J. David Gladstone Institutes, San Francisco, Ca 94158
Grant 1R56AI085056-01 from National Institute Of Allergy And Infectious Diseases
Project start date: 2010-09-01
Project end date: 2011-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
PFA/PA: PA-07-070
1R56AI085056-01 (2010): $482500