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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS055648-05
Application #
8008753
Study Section
Special Emphasis Panel (ZRG1-AARR-C (02))
Program Officer
Wong, May
Project Start
2007-01-03
Project End
2012-12-31
Budget Start
2011-01-01
Budget End
2012-12-31
Support Year
5
Fiscal Year
2011
Total Cost
$657,516
Indirect Cost
Name
Johns Hopkins University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Drewes, Julia L; Szeto, Gregory L; Engle, Elizabeth L et al. (2014) Attenuation of pathogenic immune responses during infection with human and simian immunodeficiency virus (HIV/SIV) by the tetracycline derivative minocycline. PLoS One 9:e94375
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Ravimohan, Shruthi; Gama, Lucio; Engle, Elizabeth L et al. (2012) Early emergence and selection of a SIV-LTR C/EBP site variant in SIV-infected macaques that increases virus infectivity. PLoS One 7:e42801
Zaritsky, Luna Alammar; Gama, Lucio; Clements, Janice E (2012) Canonical type I IFN signaling in simian immunodeficiency virus-infected macrophages is disrupted by astrocyte-secreted CCL2. J Immunol 188:3876-85
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Alammar, Luna; Gama, Lucio; Clements, Janice E (2011) Simian immunodeficiency virus infection in the brain and lung leads to differential type I IFN signaling during acute infection. J Immunol 186:4008-18
Eugenin, Eliseo A; Clements, Janice E; Zink, M Christine et al. (2011) Human immunodeficiency virus infection of human astrocytes disrupts blood-brain barrier integrity by a gap junction-dependent mechanism. J Neurosci 31:9456-65
Co, Juliene G; Witwer, Kenneth W; Gama, Lucio et al. (2011) Induction of innate immune responses by SIV in vivo and in vitro: differential expression and function of RIG-I and MDA5. J Infect Dis 204:1104-14
Graham, David R; Gama, Lucio; Queen, Suzanne E et al. (2011) 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. J Neurovirol 17:120-30
Szeto, Gregory L; Pomerantz, Joel L; Graham, David R M et al. (2011) Minocycline suppresses activation of nuclear factor of activated T cells 1 (NFAT1) in human CD4+ T cells. J Biol Chem 286:11275-82

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