Minocycline Inhibits Immune Reactivation of CNS SIV

Summary

Principal Investigator: JANICE ELLEN CLEMENTS
Affiliation: Johns Hopkins University
Country: USA
Abstract: Highly active antiretroviral therapy (HAART) has dramatically extended the life expectancy and improved the quality of life for HIV-infected individuals by suppressing virus replication and reconstituting immune function. However, HAART alone cannot eradicate HIV infection due to the presence of persistent viral reservoirs in latently infected cells and/or anatomical sanctuaries such as the CNS. Currently, the best prospect for life-long control of HIV infection is continuous effective treatment. Unfortunately, cost, accessibility and toxicity issues associated with antiretroviral drugs, compromise this approach. Furthermore, evidence for ongoing virus replication and reactivation of latent reservoirs during long-term effective HAART is amassing. These events not only lead to the emergence of drug-resistant HIV, but also continuously renew the half-life of latent virus reservoirs. Thus, recent efforts have focused on identifying new antiretroviral agents that intensify HAART. Ideal candidates would penetrate the CNS and other anatomical sanctuaries, exhibit efficacy in lymphocytes and macrophages, and lack toxicity long-term. Using a rigorous SIV/macaque model of HIV AIDS & CNS disease, we have identified the antibiotic minocycline as an excellent candidate to augment HAART. Studies in our model demonstrated that SIV-infected macaques treated with minocycline (without HAART) had less severe encephalitis, reduced expression of neuroinflammatory markers, less axonal degeneration and lower virus replication in CSF and brain. We further demonstrated that minocycline inhibits HIV/SIV replication in primary PBMC and macrophage cultures. Herein, we provide evidence that minocycline also inhibits reactivation of latent SIV and HIV from primary resting CD4+ lymphocytes isolated from SFV-infected macaques and HIV-infected individuals. Thus, minocycline, which exhibits exceptional CNS penetration, also possesses antiretroviral activity and suppresses reactivation of latent virus. These data provide compelling evidence for the immediate testing of minocycline as adjunctive therapy in an SIV/CART (combined antiretroviral therapy) model. We hypothesize that minocycline, through its ability to suppress both de novo replication of HIV/SIV and reactivation of latent HIV/SIV, will further suppress both 1) ongoing replication in peripheral CD4+ lymphocytes and monocytes as well as CNS cells in infected macaques treated with CART, and 2) reactivation of peripheral and CNS reservoirs of latent SIV, during intensification therapy with CART and upon cessation of CART treatment. We further hypothesize that the mechanism(s) by which minocycline suppresses reactivation of latently-infected lymphocytes and monocytes involves impaired recruitment of transcriptional activators to the LTR, which is mediated through its ability to suppress intracellular levels of Ca2+ and ROS (reactive oxygen species) both early and essential intermediates of diverse signal transduction pathways that induce reactivation of these quiescent cells.
Funding Period: 2007-01-03 - 2011-12-31
more information: NIH RePORT

Top Publications

  1. pmc SIV replication is directly downregulated by four antiviral miRNAs
    Jeanne M Sisk
    Department of Molecular and Comparative Pathobiology, Edward D, Miller Research Building, The Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205, USA
    Retrovirology 10:95. 2013
  2. pmc Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-infected macaques that increases virus infectivity
    Shruthi Ravimohan
    Division of Infectious Diseases, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 7:e42801. 2012
  3. pmc Canonical type I IFN signaling in simian immunodeficiency virus-infected macrophages is disrupted by astrocyte-secreted CCL2
    Luna Alammar Zaritsky
    Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
    J Immunol 188:3876-85. 2012
  4. pmc Induction of innate immune responses by SIV in vivo and in vitro: differential expression and function of RIG-I and MDA5
    Juliene G Co
    Johns Hopkins School of Medicine, Department of Molecular and Comparative Pathobiology, Baltimore, MD 21205, USA
    J Infect Dis 204:1104-14. 2011
  5. pmc Human immunodeficiency virus infection of human astrocytes disrupts blood-brain barrier integrity by a gap junction-dependent mechanism
    Eliseo A Eugenin
    Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    J Neurosci 31:9456-65. 2011
  6. pmc Simian immunodeficiency virus infection in the brain and lung leads to differential type I IFN signaling during acute infection
    Luna Alammar
    Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, MD 21201, USA
    J Immunol 186:4008-18. 2011
  7. pmc Minocycline suppresses activation of nuclear factor of activated T cells 1 (NFAT1) in human CD4+ T cells
    Gregory L Szeto
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    J Biol Chem 286:11275-82. 2011
  8. pmc A simian immunodeficiency virus macaque model of highly active antiretroviral treatment: viral latency in the periphery and the central nervous system
    Janice E Clements
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Curr Opin HIV AIDS 6:37-42. 2011
  9. pmc Initiation of HAART during acute simian immunodeficiency virus infection rapidly controls virus replication in the CNS by enhancing immune activity and preserving protective immune responses
    David R Graham
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, 733 N Broadway, BRB 831, Baltimore, MD 21205, USA
    J Neurovirol 17:120-30. 2011
  10. pmc PrPC, the cellular isoform of the human prion protein, is a novel biomarker of HIV-associated neurocognitive impairment and mediates neuroinflammation
    Toni K Roberts
    Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Am J Pathol 177:1848-60. 2010

Scientific Experts

  • Janice E Clements
  • M CHRISTINE contact ZINK
  • J L Mankowski
  • Eliseo A Eugenin
  • Lucio Gama
  • Kenneth W Witwer
  • Gregory L Szeto
  • David R Graham
  • Angela K Brice
  • Jeanne M Sisk
  • Luna Alammar Zaritsky
  • Shruthi Ravimohan
  • Juliene G Co
  • Luna Alammar
  • Patrick M Tarwater
  • Toni K Roberts
  • Lisa Nowoslawski Akhtar
  • Suzanne E Queen
  • Ming Li
  • Robert F Siliciano
  • Jason B Dinoso
  • Sheila A Barber
  • Susan C Follstaedt
  • Elizabeth L Engle
  • Joel L Pomerantz
  • David R M Graham
  • Kathleen M Kelly
  • Hongwei Qin
  • Michelle T Muldowney
  • Etty N Benveniste
  • Susan Morgello
  • Lora L Yanagisawa
  • Joan W Berman
  • Hung Chih Yang
  • Olaf Kutsch
  • S Alireza Rabi
  • Joel N Blankson
  • John J Varrone
  • Christopher M Bartizal

Detail Information

Publications18

  1. pmc SIV replication is directly downregulated by four antiviral miRNAs
    Jeanne M Sisk
    Department of Molecular and Comparative Pathobiology, Edward D, Miller Research Building, The Johns Hopkins University School of Medicine, 733 N Broadway, Baltimore, MD 21205, USA
    Retrovirology 10:95. 2013
    ..We examined whether specific host miRNAs directly target SIV RNA early in infection and might be induced via type I interferon pathways...
  2. pmc Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-infected macaques that increases virus infectivity
    Shruthi Ravimohan
    Division of Infectious Diseases, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, United States of America
    PLoS ONE 7:e42801. 2012
    ....
  3. pmc Canonical type I IFN signaling in simian immunodeficiency virus-infected macrophages is disrupted by astrocyte-secreted CCL2
    Luna Alammar Zaritsky
    Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA
    J Immunol 188:3876-85. 2012
    ..The interactions between chemokine and cytokine pathways are a novel finding that may specifically occur in the CNS...
  4. pmc Induction of innate immune responses by SIV in vivo and in vitro: differential expression and function of RIG-I and MDA5
    Juliene G Co
    Johns Hopkins School of Medicine, Department of Molecular and Comparative Pathobiology, Baltimore, MD 21205, USA
    J Infect Dis 204:1104-14. 2011
    ..We have shown for the first time to our knowledge the functional role of MDA5 in the innate immune response to SIV infection...
  5. pmc Human immunodeficiency virus infection of human astrocytes disrupts blood-brain barrier integrity by a gap junction-dependent mechanism
    Eliseo A Eugenin
    Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    J Neurosci 31:9456-65. 2011
    ..This mechanism of toxicity contributes to understanding how CNS damage is spread even in the current ART era and how minimal or controlled HIV infection still results in cognitive impairment in a large population of infected individuals...
  6. pmc Simian immunodeficiency virus infection in the brain and lung leads to differential type I IFN signaling during acute infection
    Luna Alammar
    Department of Molecular and Comparative Pathobiology, The Johns Hopkins School of Medicine, Baltimore, MD 21201, USA
    J Immunol 186:4008-18. 2011
    ..These data provide a novel observation that during acute SIV infection in the brain, there is differential signaling through the IFN-α/β receptor that fails to activate expression of IFN-α in the brain...
  7. pmc Minocycline suppresses activation of nuclear factor of activated T cells 1 (NFAT1) in human CD4+ T cells
    Gregory L Szeto
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    J Biol Chem 286:11275-82. 2011
    ..These findings provide a novel mechanism for minocycline induced suppression of CD4(+) T cell activation and may better inform the application of minocycline as an immunomodulatory agent...
  8. pmc A simian immunodeficiency virus macaque model of highly active antiretroviral treatment: viral latency in the periphery and the central nervous system
    Janice E Clements
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    Curr Opin HIV AIDS 6:37-42. 2011
    ....
  9. pmc Initiation of HAART during acute simian immunodeficiency virus infection rapidly controls virus replication in the CNS by enhancing immune activity and preserving protective immune responses
    David R Graham
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, 733 N Broadway, BRB 831, Baltimore, MD 21205, USA
    J Neurovirol 17:120-30. 2011
    ..Collectively, these data indicate preserved innate and adaptive immune activity in the brain following HAART initiation during acute SIV infection in this macaque model, suggesting profound benefits following acute treatment of SIV...
  10. pmc PrPC, the cellular isoform of the human prion protein, is a novel biomarker of HIV-associated neurocognitive impairment and mediates neuroinflammation
    Toni K Roberts
    Department of Pathology, Albert Einstein College of Medicine, Bronx, New York 10461, USA
    Am J Pathol 177:1848-60. 2010
    ..This report presents the first evidence that PrP(C) dysregulation occurs in cognitively impaired HIV-1-infected individuals and that PrP(C) participates in the pathogenesis of HIV-1-associated CNS disease...
  11. pmc Suppressor of cytokine signaling 3 inhibits antiviral IFN-beta signaling to enhance HIV-1 replication in macrophages
    Lisa Nowoslawski Akhtar
    Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL 35294, USA
    J Immunol 185:2393-404. 2010
    ....
  12. pmc Simian immunodeficiency virus-infected macaques treated with highly active antiretroviral therapy have reduced central nervous system viral replication and inflammation but persistence of viral DNA
    M Christine Zink
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    J Infect Dis 202:161-70. 2010
    ..During the era of highly active antiretroviral therapy (HAART), the prevalence of HIV-associated central nervous system (CNS) disease has increased despite suppression of plasma viremia...
  13. pmc Minocycline attenuates HIV infection and reactivation by suppressing cellular activation in human CD4+ T cells
    Gregory L Szeto
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    J Infect Dis 201:1132-40. 2010
    ..The anti-HIV effects of minocycline are mediated by altering the cellular environment rather than directly targeting virus, placing minocycline in the class of anticellular anti-HIV drugs...
  14. pmc Coordinated regulation of SIV replication and immune responses in the CNS
    Kenneth W Witwer
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
    PLoS ONE 4:e8129. 2009
    ..These studies further suggest that interventions should target HIV-infected individuals with increased CCL2 levels or HIV RNA in the CNS...
  15. pmc A simian immunodeficiency virus-infected macaque model to study viral reservoirs that persist during highly active antiretroviral therapy
    Jason B Dinoso
    Department of Pharmacology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    J Virol 83:9247-57. 2009
    ....
  16. pmc Mechanisms of minocycline-induced suppression of simian immunodeficiency virus encephalitis: inhibition of apoptosis signal-regulating kinase 1
    Susan C Follstaedt
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    J Neurovirol 14:376-88. 2008
    ....
  17. pmc Natural host genetic resistance to lentiviral CNS disease: a neuroprotective MHC class I allele in SIV-infected macaques
    Joseph L Mankowski
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
    PLoS ONE 3:e3603. 2008
    ..These concordant findings demonstrate that particular MHC class I alleles play major neuroprotective roles in lentiviral-induced CNS disease...
  18. ncbi The accelerated simian immunodeficiency virus macaque model of human immunodeficiency virus-associated neurological disease: from mechanism to treatment
    Janice E Clements
    Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA
    J Neurovirol 14:309-17. 2008
    ....