Neuroprotective and anti-human immunodeficiency virus activity of minocycline.
BACKGROUND
The prevalence of human immunodeficiency virus (HIV) central nervous system (CNS) disease has not decreased despite highly active antiretroviral therapy. Current antiretroviral drugs are expensive, have significant adverse effects including neurotoxicity, and few cross the blood-brain barrier.


OBJECTIVE
To examine the ability of minocycline, an antibiotic with potent anti-inflammatory and neuroprotective properties, to protect against encephalitis and neurodegeneration using a rapid, high viral load simian immunodeficiency virus (SIV) model of HIV-associated CNS disease that constitutes a rigorous in vivo test for potential therapeutics.


METHODS
Five SIV-infected pigtailed macaques were treated with 4 mg/kg per day of minocycline beginning at early asymptomatic infection (21 days after inoculation). Another 6 macaques were inoculated with SIV but remained untreated. Blood and cerebrospinal fluid (CSF) samples were taken on days 7, 10, 14, 21, 28, 35, 43, 56, 70, 77, and 84, and all macaques were humanely killed at 84 days after inoculation, a time that corresponds to late-stage infection in HIV-infected individuals.


METHODS
Blood and CSF samples were tested for viral load by real-time reverse transcription-polymerase chain reaction and levels of monocyte chemoattractant protein 1 were quantitated by enzyme-linked immunosorbent assay. The presence and severity of encephalitis was determined by microscopic examination of tissues. Central nervous system inflammation was further assessed by measuring infiltration and activation of macrophages, activation of p38 mitogen-activated protein kinase and expression of amyloid precursor protein by quantitative immunohistochemistry.


RESULTS
Minocycline-treated macaques had less severe encephalitis (P = .02), reduced CNS expression of neuroinflammatory markers (major histocompatibility complex class II, P = .03; macrophage marker CD68 , P = .07; T-cell intracytoplasmic antigen 1, P = .03; CSF monocyte chemoattractant protein 1, P = .001), reduced activation of p38 mitogen-activated protein kinase (P<.001), less axonal degeneration (beta-amyloid precursor protein, P = .03), and lower CNS virus replication (viral RNA, P = .04; viral antigen, P = .04). In in vitro analysis, minocycline suppression of HIV and SIV replication in cultured primary macrophages did not correlate with suppression of activation of p38-mitogen-activated protein kinase pathways, whereas suppression in primary lymphocytes correlated with suppression of p38 activation.


CONCLUSIONS
In this experimental SIV model of HIV CNS disease, minocycline reduced the severity of encephalitis, suppressed viral load in the brain, and decreased the expression of CNS inflammatory markers. In vitro, minocycline inhibited SIV and HIV replication. These findings suggest that minocycline, a safe, inexpensive, and readily available antibiotic should be investigated as an anti-HIV therapeutic.
Zink
M Christine
MC
Department of Comparative Medicine, Johns Hopkins University School of Medicine, Baltimore, Md 21205, USA. mczink@jhmi.edu
Uhrlaub
Jennifer
J
DeWitt
Jesse
J
Voelker
Tauni
T
Bullock
Brandon
B
Mankowski
Joseph
J
Tarwater
Patrick
P
Clements
Janice
J
Barber
Sheila
S
D015526:AIDS Dementia Complex / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D002490:Central Nervous System / Q000378:metabolism / Q000473:pathology / Q000821:virology; D018932:Chemokine CCL2 / Q000378:metabolism; D004195:Disease Models, Animal; D018792:Encephalitis, Viral / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006678:HIV / Q000187:drug effects*; D008214:Lymphocytes / Q000378:metabolism / Q000821:virology; D008254:Macaca nemestrina; D008264:Macrophages / Q000378:metabolism / Q000821:virology; D008911:Minocycline / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects*; D019562:Viral Load; D014779:Virus Replication / Q000187:drug effects*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000900:Anti-Bacterial Agents; D000893:Anti-Inflammatory Agents; D015415:Biomarkers; D018932:Chemokine CCL2; D018696:Neuroprotective Agents; D048051:p38 Mitogen-Activated Protein Kinases; D008911:Minocycline