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. 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
  2. ncbi 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
  3. ncbi 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
  4. ncbi 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
  5. ncbi 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

Scientific Experts

  • J L Mankowski
  • M Christine Zink
  • Janice E Clements
  • Lucio Gama
  • Jason B Dinoso
  • Kenneth W Witwer
  • Susan C Follstaedt
  • S Alireza Rabi
  • Angela K Brice
  • Joel N Blankson
  • Robert F Siliciano
  • John J Varrone
  • Suzanne E Queen
  • Ming Li
  • Patrick M Tarwater
  • Christopher M Bartizal
  • David R Graham
  • Sheila A Barber

Detail Information

Publications5

  1. 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
    ....
  2. ncbi 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...
  3. ncbi 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
    ....
  4. ncbi 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
    ....
  5. ncbi 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...