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?

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* ***** 10

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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