High Specificity HIV-1 Markers Predictive of Neuro-AIDS

Summary

Principal Investigator: Brian Wigdahl
Affiliation: Drexel University College of Medicine
Country: USA
Abstract: The progression of human immunodeficiency virus type 1 (HIV-1 )-associated disease in the immune and central nervous systems is associated with the ability of the virus to localize and replicate in specific cell populations within these compartments. Recent studies have suggested the possibility that genetic alterations within the HIV-1 genome introduced during viral replication may be correlated with either the stage of HIV-1 disease and/or neurologic status. We have recently demonstrated that a viral transactivator protein, Vpr, exhibits enhanced affinity for specific HIV-1 LTR C/EBP binding site configurations that can result in enhanced long terminal repeat (LTR) activation and correlate with end stage disease and HIVD. Additional studies have led to the identification of a number of HIV-1 LTR sequence signatures that increase in frequency within the peripheral blood compartment during progressive disease and track with the development of HIVD. These observations form the basis for the proposed investigations. The working hypothesis of these studies is that C/EBP and Sp binding site signatures within the LTR, which are selected for during viral replication over the course of HIV-1 disease, can be used as molecular markers to identify HIV-1-infected individuals that may be more prone to develop HIVD. The specific aims of this application are to (1) establish an HIV-1 LTR clone bank and sequence database derived from HIV-1-infected immune cell populations in the peripheral blood collected longitudinally from patients with defined clinical histories with respect to anti-retroviral therapy, drugs of abuse, and neurologic status, and from CNS-resident cells (microglial cells, perivascular macrophages, and astrocytes) at the time of autopsy; (2) analyze the LTR sequence database for the presence of the 3T C/EBP site I and 5TSp site III markers (and potential markers in other LTR regions), and establish correlations between marker prevalence and disease progression and severity, neurologic status, anti-retroviral therapy, and use of drugs of abuse; (3) develop a single nucleotide polymorphism (SNP) genotype assay for the detection of the 3T C/EBP site I and 5T Sp site III marker (and potential markers in other regions of the LTR) for use as a diagnostic assay indicative and/or predictive of peripheral disease progression and neurologic status; and (4) determine the ability of LTR clones containing the viral marker(s) to support transient expression in cell types of immune, neuroglial and bone marrow origin, and establish correlations between LTR function and clinical parameters established in previous aims. These studies may lead to the identification of additional tools to predict the development of HIVD and, in turn, provide more information to guide the therapeutic management of the HIV-1-infected patient.
Funding Period: 2004-09-30 - 2009-07-31
more information: NIH RePORT

Top Publications

  1. pmc Extracellular human immunodeficiency virus type 1 viral protein R causes reductions in astrocytic ATP and glutathione levels compromising the antioxidant reservoir
    Adriano Ferrucci
    School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA
    Virus Res 167:358-69. 2012
  2. pmc Impact of Tat Genetic Variation on HIV-1 Disease
    Luna Li
    Department of Microbiology and Immunology, Drexel University College of Medicine, 245 N 15th Street, MS no 1013A, Philadelphia, PA 19102, USA
    Adv Virol 2012:123605. 2012
  3. pmc Substance abuse, HIV-1 and hepatitis
    Nirzari Parikh
    Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
    Curr HIV Res 10:557-71. 2012
  4. pmc Extracellular HIV-1 viral protein R affects astrocytic glyceraldehyde 3-phosphate dehydrogenase activity and neuronal survival
    Adriano Ferrucci
    School of Biomedical Engineering, Science and Health Systems, Drexel University College of Medicine, Philadelphia, PA 19102, USA
    J Neurovirol 19:239-53. 2013
  5. pmc Genetic variation and HIV-associated neurologic disease
    Satinder Dahiya
    Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
    Adv Virus Res 87:183-240. 2013
  6. pmc Immunological control of herpes simplex virus infections
    Kevin P Egan
    Department of Microbiology and Immunology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA
    J Neurovirol 19:328-45. 2013
  7. pmc CCAAT enhancer binding protein and nuclear factor of activated T cells regulate HIV-1 LTR via a novel conserved downstream site in cells of the monocyte-macrophage lineage
    Satinder Dahiya
    Department of Microbiology and Immunology, and Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 9:e88116. 2014
  8. pmc Deployment of the human immunodeficiency virus type 1 protein arsenal: combating the host to enhance viral transcription and providing targets for therapeutic development
    Satinder Dahiya
    Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129, USA
    J Gen Virol 93:1151-72. 2012
  9. pmc Human immunodeficiency virus viral protein R as an extracellular protein in neuropathogenesis
    Adriano Ferrucci
    School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania, USA
    Adv Virus Res 81:165-99. 2011
  10. pmc Macrophage colony stimulating factor regulation by nuclear factor kappa B: a relevant pathway in human immunodeficiency virus type 1 infected macrophages
    Michael Kogan
    Department of Neuroscience, Center for Neurovirology, School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, USA
    DNA Cell Biol 31:280-9. 2012

Scientific Experts

  • Brian Wigdahl
  • Evelyn M Kilareski
  • Adriano Ferrucci
  • Michael R Nonnemacher
  • Satinder Dahiya
  • Vanessa Pirrone
  • Yujie Liu
  • Aikaterini Alexaki
  • Luna Li
  • Anupam Banerjee
  • Nirzari Parikh
  • Marianne Strazza
  • Kevin P Egan
  • Michael Kogan
  • Benjamas Aiamkitsumrit
  • Sonia Shah
  • Bryan Irish
  • Edward Acheampong
  • Will Dampier
  • Bryan P Irish
  • Stephen R Jennings
  • Sharon Wu
  • Anand Mehta
  • Tracy Fischer-Smith
  • David Cunningham
  • Yuxong Ke
  • Timothy Block
  • Jay Rappaport
  • Valerie Haine
  • Sandhya Kortagere
  • Jeffrey M Jacobson
  • JULIO MARTIN-GARCIA
  • Adam Wojno
  • Dennis Kolson
  • David Downie
  • Olimpia Meucci
  • Jade Ku
  • Brian Moldover
  • Laila Servance
  • Rushabh Shah
  • Sharon Lewis
  • Brandon Blakey
  • Katherine Flaig
  • Shendra Passic
  • Joyce B Suchitra
  • Udaykumar Ranga
  • Zafar K Khan
  • Nirmala Rajagopalan
  • Devin L Stauff
  • Albert S Lossinsky
  • Aschalew Mengistu
  • Shane J Quiterio
  • Zahida Parveen
  • Noel Ngoubilly
  • Muhammad Mukhtar
  • Roger J Pomerantz

Detail Information

Publications25

  1. pmc Extracellular human immunodeficiency virus type 1 viral protein R causes reductions in astrocytic ATP and glutathione levels compromising the antioxidant reservoir
    Adriano Ferrucci
    School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, USA
    Virus Res 167:358-69. 2012
    ..Studies are underway to better understand the intricate correlation between reductions in ATP and GSH metabolites and how they affect neuronal survival in end-stage disease...
  2. pmc Impact of Tat Genetic Variation on HIV-1 Disease
    Luna Li
    Department of Microbiology and Immunology, Drexel University College of Medicine, 245 N 15th Street, MS no 1013A, Philadelphia, PA 19102, USA
    Adv Virol 2012:123605. 2012
    ..Tat as a therapeutic target for anti-HIV drugs has also been discussed...
  3. pmc Substance abuse, HIV-1 and hepatitis
    Nirzari Parikh
    Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
    Curr HIV Res 10:557-71. 2012
    ..The impact of HIV-1 and substance abuse on hepatitis virus-induced disease is also a focal point...
  4. pmc Extracellular HIV-1 viral protein R affects astrocytic glyceraldehyde 3-phosphate dehydrogenase activity and neuronal survival
    Adriano Ferrucci
    School of Biomedical Engineering, Science and Health Systems, Drexel University College of Medicine, Philadelphia, PA 19102, USA
    J Neurovirol 19:239-53. 2013
    ..We propose a model that may explain some of the neurological damage and therefore neurocognitive impairment observed during the course of HIV-1 disease. ..
  5. pmc Genetic variation and HIV-associated neurologic disease
    Satinder Dahiya
    Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, USA
    Adv Virus Res 87:183-240. 2013
    ....
  6. pmc Immunological control of herpes simplex virus infections
    Kevin P Egan
    Department of Microbiology and Immunology, Drexel University College of Medicine, 245 North 15th Street, Philadelphia, PA 19102, USA
    J Neurovirol 19:328-45. 2013
    ..Particular emphasis is placed on the evidence pointing to the HSV-1-specific CD8(+) T cells in the trigeminal belonging to the TRM class of memory T cells and the role of TRM cells in virus infection, pathogenesis, latency, and disease. ..
  7. pmc CCAAT enhancer binding protein and nuclear factor of activated T cells regulate HIV-1 LTR via a novel conserved downstream site in cells of the monocyte-macrophage lineage
    Satinder Dahiya
    Department of Microbiology and Immunology, and Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 9:e88116. 2014
    ..Thus, the events at DS3 positively regulate the HIV-1 promoter in cells of the monocyte-macrophage lineage. ..
  8. pmc Deployment of the human immunodeficiency virus type 1 protein arsenal: combating the host to enhance viral transcription and providing targets for therapeutic development
    Satinder Dahiya
    Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19129, USA
    J Gen Virol 93:1151-72. 2012
    ....
  9. pmc Human immunodeficiency virus viral protein R as an extracellular protein in neuropathogenesis
    Adriano Ferrucci
    School of Biomedical Engineering, Science, and Health Systems, Drexel University, Philadelphia, Pennsylvania, USA
    Adv Virus Res 81:165-99. 2011
    ....
  10. pmc Macrophage colony stimulating factor regulation by nuclear factor kappa B: a relevant pathway in human immunodeficiency virus type 1 infected macrophages
    Michael Kogan
    Department of Neuroscience, Center for Neurovirology, School of Medicine, Temple University, Philadelphia, Pennsylvania 19140, USA
    DNA Cell Biol 31:280-9. 2012
    ..In conclusion, our findings demonstrate that NF-κB induces M-CSF expression on a promoter level via multiple functional NF-κB binding sites and that this pathway is likely relevant in HIV-1 infection of macrophages...
  11. pmc Cellular phenotype impacts human immunodeficiency virus type 1 viral protein R subcellular localization
    Adriano Ferrucci
    Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19129, USA
    Virol J 8:397. 2011
    ....
  12. pmc Role of mu-opioids as cofactors in human immunodeficiency virus type 1 disease progression and neuropathogenesis
    Anupam Banerjee
    Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA 19102, USA
    J Neurovirol 17:291-302. 2011
    ..Understanding the opioid-HIV-1 interface at the molecular level is vitally important in designing better treatment strategies for HIV-1-infected patients who abuse opioids...
  13. pmc Transcriptional regulation of the chemokine co-receptor CCR5 by the cAMP/PKA/CREB pathway
    Anupam Banerjee
    Department of Microbiology and Immunology, Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 245 N 15th Street, MS 1013A, Philadelphia, Pennsylvania 19102, USA
    Biomed Pharmacother 65:293-7. 2011
    ..Our results lend critical insight into the precise mechanism governing the cAMP-CCR5 axis in progenitor cells and pose interesting questions regarding its functional role in HIV-1 infection...
  14. pmc Breaking down the barrier: the effects of HIV-1 on the blood-brain barrier
    Marianne Strazza
    Department of Microbiology and Immunology, and Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, PA 19102, USA
    Brain Res 1399:96-115. 2011
    ....
  15. pmc Development of co-selected single nucleotide polymorphisms in the viral promoter precedes the onset of human immunodeficiency virus type 1-associated neurocognitive impairment
    Luna Li
    Department of Microbiology and Immunology, Drexel University College of Medicine, 245 N 15th Street, MS 1013A, Philadelphia, PA 19102, USA
    J Neurovirol 17:92-109. 2011
    ....
  16. pmc Structural and functional studies of CCAAT/enhancer binding sites within the human immunodeficiency virus type 1 subtype C LTR
    Yujie Liu
    Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, Pennsylvania 19129, USA
    Biomed Pharmacother 64:672-80. 2010
    ..Furthermore, the synergistic interaction between C/EBPβ-2 and Tat with the subtype C LTR was also observed in U-937 cells as previously demonstrated with the subtype B LTR...
  17. pmc Innate and adaptive factors regulating human immunodeficiency virus type 1 genomic activation
    Sonia Shah
    Department of Microbiology and Immunology, Drexel University College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA
    J Neuroimmune Pharmacol 5:278-93. 2010
    ..Finally, this review is discussed from the viewpoint of how an understanding of the interplay of all of these factors will help guide the next generation of therapies...
  18. ncbi PMA-induced differentiation of a bone marrow progenitor cell line activates HIV-1 LTR-driven transcription
    Aikaterini Alexaki
    Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, USA
    DNA Cell Biol 26:387-94. 2007
    ..These studies elucidate the impact of infected bone marrow monocytic cell differentiation on LTR activity and its potential impact on HIV-1-associated disease...
  19. pmc Cellular reservoirs of HIV-1 and their role in viral persistence
    Aikaterini Alexaki
    Department of Microbiology and Immunology, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, USA
    Curr HIV Res 6:388-400. 2008
    ..The contribution of these and other cell populations in HIV-1 persistence, as well as the possible strategies to eliminate latently infected cells are critically examined in this review...
  20. pmc HIV-1 infection of bone marrow hematopoietic progenitor cells and their role in trafficking and viral dissemination
    Aikaterini Alexaki
    Department of Microbiology and Immunology, Drexel University College of Medicine, Philadelphia, PA, USA
    PLoS Pathog 4:e1000215. 2008
    ..A monocyte subpopulation with these features has been shown to expand during the course of HIV-1 disease, particularly in HAD patients, and is characterized by low CD14 expression and the presence of cell surface CD16...
  21. pmc CCAAT/enhancer-binding proteins and the pathogenesis of retrovirus infection
    Yujie Liu
    Department of Microbiology and Immunology, Center for Molecular Virology and Neuroimmunology, Center for Cancer Biology, Philadelphia, PA 19129, USA
    Future Microbiol 4:299-321. 2009
    ..The structure and function of the C/EBPbeta gene and the related protein isoforms are discussed along with the transcription factors, coactivators, viral proteins, cytokines and chemokines that affect C/EBP function...
  22. pmc Regulation of HIV-1 transcription in cells of the monocyte-macrophage lineage
    Evelyn M Kilareski
    Center for Molecular Virology and Translational Neuroscience, Institute for Molecular Medicine and Infectious Disease, Drexel University College of Medicine, 245 N 15th St, Philadelphia, Pennsylvania 19102, USA
    Retrovirology 6:118. 2009
    ..The impact of genetic variation on LTR-directed transcription during the course of retrovirus disease is also reviewed...
  23. pmc Cholesterol-depleting statin drugs protect postmitotically differentiated human neurons against ethanol- and human immunodeficiency virus type 1-induced oxidative stress in vitro
    Edward Acheampong
    Dorrance H Hamilton Laboratories, Division of Infectious Diseases, Department of Medicine, Thomas Jefferson University, 1020 Locust Street, Suite 329, Philadelphia, Pennsylvania 19107, USA
    J Virol 81:1492-501. 2007
    ..The results of this study provide new insights into HIV-1 neuropathogenesis aimed at the development of future HIV-1 therapeutics to eradicate viral reservoirs from the brain...