The SIV Macaque Model of

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The SIV Macaque Model of HIV CNS Disease Janice
E. Clements Retrovirus Lab
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Typical HIV/SIV Progression
Acute
Terminal
Asymptomatic
CD4 Cells
Plasma Viral Load
Weeks
Months to Years
Years
SIV-30 CNS disease
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Macaques Infected SIV/17E-Fr - treated HAART
CSF Viral load
Plasma Viral load
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Typical HIV/SIV Progression
Acute
Terminal
Asymptomatic
CD4 Cells
Plasma Viral Load
Weeks
Months to Years
Years
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Accelerated, Consistent SIV/Macaque Model

• Virus strains
• Species of macaque

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Pigtailed macaques
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Classical SIV Encephalitis
Perivascular Cuff
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Macrophage Activation
Macrophage expression of MHC II CD68

• Increases during acute infection, but decreases
• 21-42 days p.i.
• High level of expression correlates with
• CNS lesions, disease at 84 days p.i.

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Infection of Astrocytes by SIV
10 day p.i. Nef Ab
84 day p.i. Nef Ab
21 day p.i. Nef Ab
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Neurodegeneration/Apoptosis
MNGC
PV Macrophages
Neuron
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Plasma CSF Viral Load
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Chemokines in SIV Encephalitis
Quantitated in plasma CSF

• CCR5 ligands
• RANTES
• MIP-1a
• ??????
• CCR2 ligand CCL2 (MCP-1)

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CCL2 Expression CSFPlasma Ratio
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Viral RNA in the Brain
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Viral RNA DNA in the Brain
RNA
10000
10000
10000
1000
1000
1000
DNA
100
100
100
10
10
10
326
392
616
672
674
F4C
V698
V390
V313
V367
716
726
369
879
A42
D7A
364
382
10 Days p.i.
21 Days p.i.
56 Days p.i.
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Does CNS Virus Re-enter Blood

• SIV model examined virus genotypes throughout
  infection.
• Specific genotypes are found in brain during
  acute and asymptomatic stage of infection.
• Evidence in SIV model for seeding of peripheral
  blood with virus genotypes from brain.

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Correlates of Neurological Disease

• Viral entry to CNS during acute infection
• Infection and activation of macrophages
• Upregulation of CCL2 in CSF
• Infection and Activation of Astrocytes
• Viral load in CSF after acute infection
• Viral RNA in brain
• CNS Inflammation with immunosuppresion
• Neuronal degeneration and neuronal loss
• in CNS PNS

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Innate immune responses in the CNS
Rapid production of type I IFN is important for
host survival of viral infections IFN? is the
major type I IFN produced in CNS IFN? induces
the production of neurotrophic factors and
anti-inflammatory cytokines Slows virus spread
and constrains virus replication before the
induction of virus specific immune responses
IFN?
Neuron
Microglial cell
IFN?
Adapted from Griffin DE. Nat. Rev. Immunol. 3493
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IFN? Protein levels in Brain
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IFNb Inhibits SIV in Macrophages
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IFNb and Latency in Macrophages

• Macrophages and microglia are infected during
  acute infection.
• Rapid innate immune responses, elicit IFNb Mx
  (IFN-response gene).
• Latency in brain caused by immunological
  mechanism similar to latency in T lymphocytes.

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When to Treat in this Model

• Take advantage of this predictable model

• Initiate after innate immune response is
  effective
• Initiate prior to loss of innate immune control

• Prevent inflammatory events in the CNS other
• tissues.

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