View
220
Download
4
Category
Preview:
Citation preview
Impact of Minocycline onSIV CNS and PNS Disease
M. Christine Zink
DementiaNeuropathy
Current anti-HIV therapeutics: toxicity, complex dosing, resistance mutations
No effective neuroprotective drugs
HIV-Associated Neurological Disease
Encephalitis & Neurodegeneration
Virus replication in macrophages
Neuronal apoptosis Activated caspase -APP
Minocycline:Old Drug with a New Function?
Effective against osteoarthritis in human clinical trialsNeuroprotective in animal models of
Multiple sclerosisStrokebrain traumaParkinson’s diseaseALSHuntington’s disease
Why Minocycline?
10
100
1000
10000
100000
10
100
1000
10000
100000
* ***** 10
100
1000
10000
100000
^
* ***
100,000
1,000,000
10,000,000
100.000.000
10 Days 21 Days 56 Days 84 Days
Initiate Minocycline Treatment
Suppresses microglial activation Inhibits several apoptotic factors
On market for 30 years
Off patent Good CNS penetrance
Safe when used daily for years
Minocycline Reduces Severity of SIVE
Minocycline-treated
Untreated macaques
Severity of EncephalitisNone MildMild Moderate Severe
31 11 1
22 030
(p = 0.032)
Untreated Minocycline-treated
Minocycline Reduced Macrophage Activation
CD68 MHC Class II
(p = 0.028)(p = 0.066)
Minocycline Suppressed MCP-1 Expression
Minocycline
2.65
Minocycline CSF:Plasma MCP-1
3 7 10 14 28 42 56 70 840
5
10
15
20
25
30
2.65
Days Postinoculation
(p < 0.001)
Untreated
2.65
Chemokine CSF:Plasma MCP-1
3 7 10 14 28 42 56 70 840
10
20
30
2.65
Days Postinoculation
Anti-inflammatory effects
Minocycline Reduces CSF Viral Load
Minocycline-TreatedUntreated
(p = 0.039)
(p = 0.04)
• Antibacterial• Anti-inflammatory• Antiviral?
Does Minocycline Suppress Virus Replication?
Monkeys Cell culture
Minocycline Suppresses SIV/HIV Replication in Lymphocytes and Macrophages
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
HIV Peripheral Neuropathy: The SIV Model
Sensory pain, most severe in distal extremities
30-50% of untreated individuals Toxicity of some antiretroviral drugs
Somatosensory Pathway
DRGPeripheral Nerve
EpidermalNerve Fibers
DRG
0
5
10
15
20
25
30
0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1 1.1 1.2 1.3Conduction Velocity (m/s)
controlSIV-infectedcontrol
Slower Conduction Velocity
Peripheral Nerve
Epidermal Nerve Fibers
Uninfected Control SIV-infected
Minocycline Prevents DRG Neuronal Loss
p < 0.001
Control SIV-infected SIV+Mino0.000.050.100.150.200.250.300.350.400.45 p = 0.03
Uninfected SIV Infected Teno/Mino Tenofovir0.000
0.025
0.050
0.075
0.100
0.125
0.150
0.175
0.200
p = 0.0025
p = 0.32
p = 0.0001
Minocycline/Tenofovir Prevents ENF Loss
Minocycline in Human Clinical Trials
BeforeTreatment
AfterTreatment
84 % reductionin MS lesions
Johns Hopkins: Multicenter clinical trial in HIV-infected patients with neurological disease - PI: Ned Sacktor
Clinical trials in Uganda
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)
Funding:NINDS NIMH
Technical Assistance:John AndersonChris Bartizal
Suzanne QueenBruce Baldwin
Brandon BullockMing Li
Chante AustinTauni Voelker
Jami Young
Retrovirus Faculty:M. Christine ZinkJoe Mankowski
Bob AdamsTahar Babas
Craig FletcherLucio Gama
Collaborators:Patrick Tarwater
Justin McArthur & LabAvi Nath & Lab
Carlos Pardo & LabBob Siliciano & Lab
Mathias Ringkamp & Lab
Graduate Students:Angela BriceKris Helke
Victoria Laast Susan Follstaedt
Emily McVeyGreg Szeto
Acknowledgements
Recommended