Compartmentalized HIV and SIV Populations in the Central Nervous System Are Associated with Neuropat

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Compartmentalized HIV and SIV Populations in the
Central Nervous System Are Associated with
Neuropathogenesis

• Gretja Schnell
• Graduate Student
• Laboratory of Ronald Swanstrom
• Department of Microbiology and Immunology
• University of North Carolina at Chapel Hill
• Chapel Hill, NC, USA

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The Heteroduplex Tracking Assay (HTA) is a tool
to describe HIV population dynamics and identify
compartmentalized variants in the population
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The Degree of Compartmentalization Correlates
with Neurological Disease State
(HAD)
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Compartmentalization Between Plasma and CSF is
Associated with Neurological Disease
n7
n19
n32
n9
CSF viral population switch from a purely blood,
or mixed blood and CNS source, to primarily a
local CNS source in HAD subjects
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Examination of the Origin of Compartmentalized
HIV-1

• Characterize the cellular origin of
  compartmentalized HIV-1
• Examine longitudinal plasma and cerebrospinal
  fluid (CSF) samples from human subjects with
  varying degrees of neurological disease during
  the initiation of HAART
• Analyze HIV-1 populations in blood and CSF using
  heteroduplex tracking assays, and calculate the
  viral decay rates
• Hypothesis HIV-1 in the CNS should be coming
  from long-lived cells.

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No Differential Decay of Compartmentalized Virus
in CSF when Starting HAART
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CSF-Compartmentalized Variants Decay Rapidly
after the Initiation of HAART
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Conclusions of Human Studies

• Subjects with more severe neurological disease,
  such as HAD subjects, have a greater percentage
  of virus in the CSF that is compartmentalized
  (unique or enriched in the CSF) compared to
  subjects with no neurological symptoms.
• Compartmentalized HIV-1 in the CSF of all
  subjects appears to be originating from
  short-lived cells of unknown origin, but
  producing virus distinct from the blood
  population.

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Development and Characterization of an
SIV/macaque Model

• SIVsm E660 macaque model (Phil Johnson, C.H.O.P.)
• Three phases of infection Primary/acute
  infection, asymptomatic, end-stage/AIDS
• Neurological impairment in 30 of infected
  macaques (qualitative)
• Examination of SIV population dynamics by HTA
  revealed either concordance or discordance
  between blood and CSF populations, similar to
  what is seen in human disease.

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Two Patterns of SIVsmE660 Population Dynamics are
Seen Between Blood and CSF
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CSF SIVsm Compartmentalization is Evident in
Macaque C002
CSF MCP-1 Levels are Elevated in Macaque C002
Plt0.01
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Perivascular Macrophages are Associated with
Compartmentalization and MCP-1 Levels
D110 PlasmaCSF concordant
D081 PlasmaCSF concordant
C002 PlasmaCSF discordant
plt0.05 plt0.01
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SIV/Macaque Model Summary

• Two patterns of SIVsmE660 infection of CSF
• Viral genetic populations in CSF concordant with
  those in the blood
• Viral genetic populations in CSF discordant from
  those in the blood
• Like HIV-1 infection in humans, CSF
  compartmentalization was associated with
  neurological disease (but n1).
• Compartmentalization is a measure of independent
  replication in the CNS that may lead to an
  inflammatory response and contribute to
  neuropathogenesis of HIV.

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Acknowledgements

• Ronald Swanstrom
• Patrick Harrington
• University of California at San Francisco
• Richard Price
• Serena Spudich
• University of California at San Diego
• Scott Letendre
• Kim Ritola

• University of North Carolina at Chapel Hill
• Kevin Robertson
• Colin Hall
• Rick Meeker
• Childrens Hospital of Philadelphia
• Phil Johnson
• Mary Connell
• Studies were funded by NIMH and UNC CFAR