Impact of Minocycline on

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Impact of Minocycline on SIV CNS and PNS
Disease M. Christine Zink
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HIV-Associated Neurological Disease

• Current anti-HIV therapeutics
• toxicity, complex dosing, resistance mutations

• No effective neuroprotective drugs

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Encephalitis Neurodegeneration
Virus replication in macrophages
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MinocyclineOld Drug with a New Function?

• Effective against osteoarthritis in human
  clinical trials
• Neuroprotective in animal models of
• Multiple sclerosis
• Stroke
• brain trauma
• Parkinsons disease
• ALS
• Huntingtons disease

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Why Minocycline?
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Minocycline Reduces Severity of SIVE
(p 0.032)
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Minocycline Reduced Macrophage Activation
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Minocycline Suppressed MCP-1 Expression
Minocycline
(p lt 0.001)

• Anti-inflammatory effects

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Minocycline Reduces CSF Viral Load
Minocycline-Treated
Untreated
(p 0.039)
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Does Minocycline Suppress Virus Replication?

• Antibacterial
• Anti-inflammatory
• Antiviral?

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Minocycline Suppresses SIV/HIV Replication in
Lymphocytes and Macrophages
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Resistance?

• virus cultured in presence of minocycline did
  not develop resistance
• plasma virus from SIV-infected, minocycline
  macaques was not resistant to later
  suppression by minocycline

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HIV Peripheral Neuropathy The SIV Model

• Sensory pain, most severe in distal extremities
• 30-50 of untreated individuals
• Toxicity of some antiretroviral drugs

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Somatosensory Pathway
Epidermal Nerve Fibers
Peripheral Nerve
DRG
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DRG
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Peripheral Nerve
Slower Conduction Velocity
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Epidermal Nerve Fibers
Uninfected Control
SIV-infected
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Minocycline Prevents DRG Neuronal Loss
p lt 0.001
p 0.03
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Minocycline/Tenofovir Prevents ENF Loss
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Minocycline in Human Clinical Trials
Before Treatment
After Treatment
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Minocycline Potential Clinical Impact

• Suppression of HIV-induced neurodegeneration
  (CNS PNS)
• Potential improvement in individuals with toxic
  neuropathy associated with ART
• Reduction of CNS PNS inflammation (macrophage
  activation, CCL2 expression)
• Reduction of CNS CSF viral load
• Some activity against secondary opportunistic
  infections (malaria, TB, Chlamydia)

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