HIV Associated Reservoirs and Comorbidities (HARC) Study:
The HARC Study establishes a biorepository that will allow for collaborative investigation of the neuropathogenic mechanisms of HIV and other infectious diseases. Peripheral blood, cerebrospinal fluid, and neuropsychological testing will be obtained from subjects of all profiles: people living with primary or chronic HIV who may be on or off treatment, those living with other infectious diseases of the central nervous system, and uninfected control participants.
In addition to being used for current research questions, HARC study samples will be stored for future use. Through the creation of this repository, we will undertake studies which we hope will provide better understanding of HIV and other infectious diseases, allowing us to better evaluate treatment responses, and to potentially identify markers of disease activity leading to more complete and effective treatments.
In addition to being used for current research questions, HARC study samples will be stored for future use. Through the creation of this repository, we will undertake studies which we hope will provide better understanding of HIV and other infectious diseases, allowing us to better evaluate treatment responses, and to potentially identify markers of disease activity leading to more complete and effective treatments.
Collaborators and Sub-Studies:
Shelli Farhadian, MD, PhD / Yale University / Single Cell CSF Sequencing
Dr. Farhadian uses advanced genomic tools to characterize immune activation in CSF during HIV infection at the single cell level.
Brinda Emu, MD / Yale University / Exosome Project
Lingeng Lu, MD, PhD / Yale University / Exosome Project
Exosomes are bilayer membranous nano-vesicles actively released into the circulation by living cells, and containing enriched bioactive molecules (proteins, DNA/RNA, lipids), mirroring the cells of origin and mediating cell-to-cell communications in a hormonal manner. We aim to investigate the associations of exosomal bioactive molecules in plasma (non-coding RNAs and proteins) and HIV-associated neurological disorders, and the diagnosis and prognosis of human cancer and other chronic diseases. We will further explore the role and molecular mechanisms of circulating exosomes in neurological impairment and HIV persistence during antiretroviral therapy (ART), non-AIDS-associated cancer, and other comorbidities in HIV patients.
Ya-Chi Ho, MD, PhD / Yale University / Mechanisms of HIV Latency
Dr. Ho’s lab seeks to understand how HIV persists in cells, particularly CD4 T lymphocytes, and whether epigenetic silencing can permanently and irreversibly silence HIV expression. Despite the presence of many classes of antiretroviral therapy, the HIV promoter LTR is left active and untreated. The lab uses a molecular virology approach to examine mechanisms of HIV persistence using blood samples from HIV-infected individuals. In addition, using a high-throughput drug screening, the lab is working on identification of HIV epigenetic silencing agents which can preferentially silence HIV expression without affecting host gene expression.
Kathryn Miller-Jensen, PhD / Yale University
Dr. Miller-Jensen's group applies quantitative, systems–level experimental and computational approaches to study how intercellular signaling heterogeneity regulates host–pathogen innate immune interactions in macrophages and HIV latency in T cells.
Richard Price, MD / University of California, San Francisco / CSF Escape
Using archived and prospectively collected samples obtained in three informative clinical settings, Dr. Price's lab will characterize viral populations in cerebrospinal fluid (CSF) and blood by deep sequencing or single genome amplification of envelope (env) and LTR regulatory genes. The resulting phylogenetic analysis, and the functional impact of these genes will be assessed with respect to macrophage and lymphocyte tropism and replication capacity in macrophages. These central biological features of HIV infection will define the origin and relationships of 'escaped' CSF HIV to the CNS reservoir and trace its release, expansion and intermingling with HIV derived from systemic infection.
John Mellors, MD / University of Pittsburgh
Dr. Mellors' lab focuses on resistance to antiretroviral drugs used for treatment and HIV prevention and on mechanisms of HIV persistence and strategies to deplete the reservoirs that are the barrier to curing HIV infection. The lab's work on HIV reservoirs showed that low-level viremia persists in most individuals on long-term suppressive ART, and that the level of residual viremia is predicted by the level of viremia before ART. Current work focuses on identifying agents to reverse HIV latency and to eliminate HIV infected cells. The impact of innovative therapies on HIV reservoirs is being studied in Phase I/II trials of histone deacetylase inhibitors, monoclonal antibodies to immune checkpoint ligands, monoclonal antibodies to HIV envelope glycoproteins, and TLR agonists.
Teresa Evering, MD, MS / The Aaron Diamond AIDS Research Center & The Rockefeller University
Dr. Evering employs a combination of phylogenetic, immunologic and systems biology approaches to explore the interplay between virus and host in HAND pathogenesis. The integrin α4β1 (VLA-4) is an integrin dimer. It is widely expressed on leukocyte plasma membranes and has a potentially important role in CNS homing. We seek to immunologically phenotype a cohort of virologically suppressed HIV-positive individuals with HAND and normal neurocognitive function. In doing so, we aim to determine the distribution of VLA-4 expression on leukocytes from paired cerebrospinal fluid and blood and identify potential relationships between VLA-4 expression and neurocognitive performance. Concurrent transcriptional profiling of these cells using RNA-sequencing (RNA-seq) is being performed in an effort to identify genes, signaling pathways and ultimately small molecule candidates for therapeutic development in HAND.
Ronald Swanstrom, PhD / University of North Carolina, Chapel Hill
Shelli Farhadian, MD, PhD / Yale University / Single Cell CSF Sequencing
Dr. Farhadian uses advanced genomic tools to characterize immune activation in CSF during HIV infection at the single cell level.
Brinda Emu, MD / Yale University / Exosome Project
Lingeng Lu, MD, PhD / Yale University / Exosome Project
Exosomes are bilayer membranous nano-vesicles actively released into the circulation by living cells, and containing enriched bioactive molecules (proteins, DNA/RNA, lipids), mirroring the cells of origin and mediating cell-to-cell communications in a hormonal manner. We aim to investigate the associations of exosomal bioactive molecules in plasma (non-coding RNAs and proteins) and HIV-associated neurological disorders, and the diagnosis and prognosis of human cancer and other chronic diseases. We will further explore the role and molecular mechanisms of circulating exosomes in neurological impairment and HIV persistence during antiretroviral therapy (ART), non-AIDS-associated cancer, and other comorbidities in HIV patients.
Ya-Chi Ho, MD, PhD / Yale University / Mechanisms of HIV Latency
Dr. Ho’s lab seeks to understand how HIV persists in cells, particularly CD4 T lymphocytes, and whether epigenetic silencing can permanently and irreversibly silence HIV expression. Despite the presence of many classes of antiretroviral therapy, the HIV promoter LTR is left active and untreated. The lab uses a molecular virology approach to examine mechanisms of HIV persistence using blood samples from HIV-infected individuals. In addition, using a high-throughput drug screening, the lab is working on identification of HIV epigenetic silencing agents which can preferentially silence HIV expression without affecting host gene expression.
Kathryn Miller-Jensen, PhD / Yale University
Dr. Miller-Jensen's group applies quantitative, systems–level experimental and computational approaches to study how intercellular signaling heterogeneity regulates host–pathogen innate immune interactions in macrophages and HIV latency in T cells.
Richard Price, MD / University of California, San Francisco / CSF Escape
Using archived and prospectively collected samples obtained in three informative clinical settings, Dr. Price's lab will characterize viral populations in cerebrospinal fluid (CSF) and blood by deep sequencing or single genome amplification of envelope (env) and LTR regulatory genes. The resulting phylogenetic analysis, and the functional impact of these genes will be assessed with respect to macrophage and lymphocyte tropism and replication capacity in macrophages. These central biological features of HIV infection will define the origin and relationships of 'escaped' CSF HIV to the CNS reservoir and trace its release, expansion and intermingling with HIV derived from systemic infection.
John Mellors, MD / University of Pittsburgh
Dr. Mellors' lab focuses on resistance to antiretroviral drugs used for treatment and HIV prevention and on mechanisms of HIV persistence and strategies to deplete the reservoirs that are the barrier to curing HIV infection. The lab's work on HIV reservoirs showed that low-level viremia persists in most individuals on long-term suppressive ART, and that the level of residual viremia is predicted by the level of viremia before ART. Current work focuses on identifying agents to reverse HIV latency and to eliminate HIV infected cells. The impact of innovative therapies on HIV reservoirs is being studied in Phase I/II trials of histone deacetylase inhibitors, monoclonal antibodies to immune checkpoint ligands, monoclonal antibodies to HIV envelope glycoproteins, and TLR agonists.
Teresa Evering, MD, MS / The Aaron Diamond AIDS Research Center & The Rockefeller University
Dr. Evering employs a combination of phylogenetic, immunologic and systems biology approaches to explore the interplay between virus and host in HAND pathogenesis. The integrin α4β1 (VLA-4) is an integrin dimer. It is widely expressed on leukocyte plasma membranes and has a potentially important role in CNS homing. We seek to immunologically phenotype a cohort of virologically suppressed HIV-positive individuals with HAND and normal neurocognitive function. In doing so, we aim to determine the distribution of VLA-4 expression on leukocytes from paired cerebrospinal fluid and blood and identify potential relationships between VLA-4 expression and neurocognitive performance. Concurrent transcriptional profiling of these cells using RNA-sequencing (RNA-seq) is being performed in an effort to identify genes, signaling pathways and ultimately small molecule candidates for therapeutic development in HAND.
Ronald Swanstrom, PhD / University of North Carolina, Chapel Hill
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Sponsors:
National Institute of Mental Health & National Institute of Neurologic Diseases and Stroke, National Institutes of Health
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Selected publications - see Publications:
Contact:
Jennifer Chiarella jennifer.chiarella@yale.edu Rachela Calvi rachela.calvi@yale.edu |