Marco Salemi
University Of Florida
Project start date: 2009-02-15
Project end date: 2014-01-31
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VIRAL EVOLUTION IN PEROPHERAL MACROPHAGES AND BRAIN DURING PROGRESSION TO AIDS
Marco Salemi, Research Assistant Scientist
University Of Florida, 219 Grinter Hall, Gainesville, Fl 32611-5500
Grant 5R01NS063897-02 from National Institute Of Neurological Disorders And Stroke
Abstract: Despite the introduction of highly-active antiretroviral treatment (HAART), the proportion of newly HIV-1 infected patients developing HIV-associated dementia (HAD) is increasing. Currently, there is no effective therapy for HAD. Understanding the evolutionary factors driving the emergence of neurovirulent strains during disease progression is of pivotal importance to develop a realistic model of neuroAIDS. The objectives of the current proposal are to define viral evolutionary steps within the central nervous system (CNS) and select monocyte/macrophages from bone marrow, gut, lung and blood preceding and associated with the onset of neuropathogenesis. The Rhesus macaque model of neuroAIDS will be employed to study the evolution of the viral quasispecies during disease progression and to track SIV-infected macrophage subsets infiltrating the brain. 24 animals will be infected with a genetically-defined viral swarm. Peripheral blood and tissue samples will be collected over time and used for amplification of a 3.3kb fragment, including gp160, nef and 5´ LTR, of the viral genome, as well as some full-length genomes from selected tissues. We will use laser-captured microscopy to isolate viral variants from specific productively infected macrophage in the brain at early and end stage disease. High-resolution phylogenetic, population genetics, and molecular clock algorithms (phylodynamics) will reveal genetic aspects of viral reservoirs linked to the onset of a neuropathogenic infection that have not yet been characterized because of ethical problems associated with tissue sampling in humans. Specific Aim 1 will investigate the evolutionary dynamics of SIV in lymphoid and non- lymphoid tissues during the course of the infection via longitudinal PBMC/tissue macrophages sampling and brain biopsies of monkeys with and without CD8+ T-cell depletion; Specific Aim 2 will identify macrophage subsets involved in brain entry and acting as potential viral reservoirs for brain infection. We will be able to identify tempo and mode of brain infection and evolutionary signatures leading to the emergence of infectious macrophage-tropic quasispecies that could be used to predict and monitor the disease. Equally important is the possibility to use the findings into developing drugs that target macrophage and viral quasispecies associated to neuropathogenesis. Overall, we will compile the most comprehensive database of longitudinal SIV sequences from a variety of tissues to date. The PI, although a new investigator without previous R01 funding, has significant experience in cutting-edge analysis of genetic data, and has assembled a unique and qualified interdisciplinary team to assist in the study. This project on HIV-associated dementia examines the evolution of immunodeficiency viruses in various tissues involved in brain infection. A monkey model of neuroAIDS is used that mimics the course of HIV infection in humans. The result will be a of the genetic basis for the onset of dementia in patients with AIDS leading the way to the development of new diagnostic and therapeutic tools
Keywords: AIDS; AIDS Dementia; AIDS Dementia Complex; AIDS Virus; AIDS neuropathy; AIDS with dementia; AIDS-related dementia; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immune Deficiency Syndrome Virus; Acquired Immune Deficiency Syndrome related dementia; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Acquired Immunodeficiency Syndrome Virus; Algorithms; Amentia; Amino Acids; Animal Model; Animal Models and Related Studies; Animals; Anti-Retroviral Agents; Antiretroviral Agents; Arts; Automobile Driving; Autopsy; Biopsy; Blood; Blood monocyte; Body Tissues; Bone Marrow; Brain; Brain region; CD8; CD8B; CD8B1; CD8B1 gene; Cells; Central Nervous System; Cerebrospinal Fluid; DNA Recombination; DNA recombination (naturally occurring); Data; Data Banks; Data Bases; Databank, Electronic; Databanks; Database, Electronic; Databases; Dementia; Dementia Complex, AIDS-Related; Dementia Complex, Acquired Immune Deficiency Syndrome; Dementia Due to HIV Disease; Dementia associated with AIDS; Dementia in human immunodeficiency virus (HIV) disease; Developed Countries; Developed Nations; Developing Countries; Developing Nations; Development; Disease; Disease Progression; Disorder; Drivings, Automobile; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; Electromagnetic, Laser; Encephalon; Encephalons; Epidemic; Ethics; Event; Evolution; Funding; Genes; Genes, Viral; Genetic; Genetic Algorithm; Genetic Programming; Genetic Recombination; Genetic analyses; Genetics, Population; Genome; Goals; HIV; HIV Dementia; HIV Infections; HIV associated dementia; HIV-1; HIV-1 associated dementia; HIV-1 dementia; HIV-Associated Cognitive Motor Complex; HIV-I; HIV-related dementia; HIV1; HTLV-III; HTLV-III Infections; HTLV-III-LAV Infections; Host resistance; 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; INFLM; Immune; Immunodeficiency Disorder; Immunodeficiency Syndrome; Immunodeficiency Virus Type 1, Human; Immunologic Deficiency Syndrome, Acquired; Immunologic Deficiency Syndromes; Immunological Deficiency Syndromes; Individual; Industrialized Countries; Industrialized Nations; Infection; Inflammation; Investigators; LAV-HTLV-III; LYT3; Lasers; Length; Less-Developed Countries; Less-Developed Nations; Link; Lung; Lymphadenopathy-Associated Virus; Lymphatic Tissue; Lymphoid; Lymphoid Tissue; Macaca mulatta; Maintenance; Maintenances; Man (Taxonomy); Man, Modern; Marrow monocyte; Mediating; Meninges; Methods and Techniques; Methods, Other; Microscopy; Mining; Minings; Modeling; Molecular; Monitor; Monkeys; Mononuclear; Nervous System, Brain; Nervous System, CNS; Neuraxis; Neuropathogenesis; Onset of illness; PBMC; Pathogenesis; Patients; Pattern; Peripheral Blood Mononuclear Cell; Phagocytes; Phagocytic Cell; Phylogenetic Analysis; Phylogenetics; Population; Population Dynamics; Population Genetics; Population Sizes; Pressure; Pressure- physical agent; Process; Qualifying; R01 Mechanism; R01 Program; RPG; Radiation, Laser; Recombination; Recombination, Genetic; Research Grants; Research Personnel; Research Project Grants; Research Projects; Research Projects, R-Series; Researchers; Resolution; Respiratory System, Lung; Reticuloendothelial System, Blood; Reticuloendothelial System, Bone Marrow; Rhesus; Rhesus Macaque; Rhesus Monkey; SIV; Sampling; Science of Statistics; Series; Simian Immunodeficiency Viruses; Staging; Statistics; T-Cell Depletion; T-Lymphotropic Virus Type III Infections, Human; Techniques; Testing; Therapeutic; Third-World Countries; Third-World Nations; Time; Tissue Sample; Tissues; Under-Developed Countries; Under-Developed Nations; Variant; Variation; Viral; Viral Genes; Viral Genome; Virulence; Virus; Virus-HIV; Viruses, General; amebocyte; aminoacid; anti-retroviral; antiretroviral; base; brain tissue; cell type; clinical data repository; clinical data warehouse; data repository; design; designing; disease onset; disease/disorder; disorder onset; driving; effective therapy; end stage disease; experience; experiment; experimental research; experimental study; genetic analysis; gp160; human T cell leukemia virus III; human T lymphotropic virus III; hypoimmunity; immune deficiency disorder; immunodeficiency; innovate; innovation; innovative; knowledge base; longitudinal database; macrophage; migration; model organism; monocyte; necropsy; neuroAIDS; neurotropic; new diagnostics; next generation diagnostics; novel diagnostics; pandemic; pandemic disease; peripheral blood; postmortem; pressure; public health relevance; pulmonary; relational database; research study; spinal fluid; statistics; time use; tool; treatment strategy
Relevance: This project on HIV-associated dementia examines the evolution of immunodeficiency viruses in various tissues involved in brain infection. A monkey model of neuroAIDS is used that mimics the course of HIV infection in humans. The result will be a of the genetic basis for the onset of dementia in patients with AIDS leading the way to the development of new diagnostic and therapeutic tools
Project start date: 2009-02-15
Project end date: 2014-01-31
Budget start date: 1-FEB-2010
Budget end date: 31-JAN-2011
PFA/PA: PA-07-070
5R01NS063897-02 (2010): $711142
Grants awarded to Marco Salemi
Viral Evolution In Peropheral Macrophages And Brain During Progression To AIDS
Marco Salemi
Pathology, Immunol & Lab Meduniversity Of Florida
Grant 1R01NS063897-01A2 from National Institute Of Neurological Disorders And Stroke IRG: NAED
Abstract: Despite the introduction of highly-active antiretroviral treatment (HAART), the proportion of newly HIV-1 infected patients developing HIV-associated dementia (HAD) is increasing. Currently, there is no effective therapy for HAD. Understanding the evolutionary factors driving the emergence of neurovirulent strains during disease progression is of pivotal importance to develop a realistic model of neuroAIDS. The objectives of the current proposal are to define viral evolutionary steps within the central nervous system (CNS) and select monocyte/macrophages from bone marrow, gut, lung and blood preceding and associated with the onset of neuropathogenesis. The Rhesus macaque model of neuroAIDS will be employed to study the evolution of the viral quasispecies during disease progression and to track SIV-infected macrophage subsets infiltrating the brain. 24 animals will be infected with a genetically-defined viral swarm. Peripheral blood and tissue samples will be collected over time and used for amplification of a 3.3kb fragment, including gp160, nef and 5´ LTR, of the viral genome, as well as some full-length genomes from selected tissues. We will use laser-captured microscopy to isolate viral variants from specific productively infected macrophage in the brain at early and end stage disease. High-resolution phylogenetic, population genetics, and molecular clock algorithms (phylodynamics) will reveal genetic aspects of viral reservoirs linked to the onset of a neuropathogenic infection that have not yet been characterized because of ethical problems associated with tissue sampling in humans. Specific Aim 1 will investigate the evolutionary dynamics of SIV in lymphoid and non- lymphoid tissues during the course of the infection via longitudinal PBMC/tissue macrophages sampling and brain biopsies of monkeys with and without CD8+ T-cell depletion; Specific Aim 2 will identify macrophage subsets involved in brain entry and acting as potential viral reservoirs for brain infection. We will be able to identify tempo and mode of brain infection and evolutionary signatures leading to the emergence of infectious macrophage-tropic quasispecies that could be used to predict and monitor the disease. Equally important is the possibility to use the findings into developing drugs that target macrophage and viral quasispecies associated to neuropathogenesis. Overall, we will compile the most comprehensive database of longitudinal SIV sequences from a variety of tissues to date. The PI, although a new investigator without previous R01 funding, has significant experience in cutting-edge analysis of genetic data, and has assembled a unique and qualified interdisciplinary team to assist in the study. This project on HIV-associated dementia examines the evolution of immunodeficiency viruses in various tissues involved in brain infection. A monkey model of neuroAIDS is used that mimics the course of HIV infection in humans. The result will be a of the genetic basis for the onset of dementia in patients with AIDS leading the way to the development of new diagnostic and therapeutic tools
Project start date: 2009-02-15
Project end date: 2014-01-31