HIV in the CNS

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Dynamics of Compartmentalized HIV-1 Populations
in the Central Nervous System
Patrick R. Harrington Postdoctoral
Fellow Laboratory of Ronald Swanstrom Lineberger
Comprehensive Cancer Center University of North
Carolina at Chapel Hill Chapel Hill, NC, USA
2
Dynamics of Compartmentalized HIV-1 Populations
in the Central Nervous System
Kimberly Ritola,1 Kevin Robertson,2 Susan A.
Fiscus,1 Colin Hall,2 and Ronald Swanstrom.1
Increased HIV-1 env compartmentalization in the
presence of HIV-associated dementia. Journal of
Virology. In press (Aug. 2005). Patrick R.
Harrington,1 David W. Haas,3 Kimberly Ritola,1
and Ronald Swanstrom.1 Compartmentalized HIV-1
present in cerebrospinal fluid is produced by
short-lived cells. Journal of Virology. In
press (July 2005). 1Lineberger Comprehensive
Cancer Center, Center for AIDS Research,
Department of Biochemistry and Biophysics, and
2Department of Neurology, University of North
Carolina, Chapel Hill, North Carolina,
USA 3Departments of Medicine, Microbiology and
Immunology, and Vanderbilt Meharry Center for
AIDS Research, Vanderbilt University School of
Medicine, Nashville, Tennessee, USA
Funding Lineberger Cancer Center, UNC-Chapel
Hill NIMH, NINDS, NIH UNC Center for AIDS
Research Vanderbilt Meharry Center for AIDS
Research
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Detection of Viral Genetic Populations by HTA
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Compartmentalization of HIV-1 Genetic Populations
in Blood Plasma and CSF Revealed by V1/V2 (env)
HTA
single-stranded probe band ? unique to
compartment
5
Increased Compartmentalization Between Plasma and
CSF HIV-1 env Populations is Associated with
Neurological Status
Patients with compartmentalized env sequences
of Patients
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Dynamics of HIV-1 Populations in Blood and CSF of
Asymptomatic Subjects During the Initiation of
Antiretroviral Therapy
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At Least Two Phases of Viral Decline in the
Periphery During Antiretroviral Therapy
Change in log plasma HIV RNA
Limit of detection
Time after initiation of antiretroviral therapy
(Perelson, et al., Shaw, et al. 1995) Adapted
from HIVpositive.com
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Antiretroviral Therapy and HIV-1 in cerebrospinal
fluid

• Studies of Bulk HIV-1 RNA in CSF
• Usually a rapid decline in CSF viral load during
  therapy
• Slower decline?Neurological disease (Ellis, et.
  al. 2000 Eggers, et. al. 2003)
• Kinetics of CSF viral decay do not correlate with
  blood
• Not known which source is being treated when bulk
  viral loads decline in CSF
• Experimental Design use HTA to measure the
  decline of individual HIV-1 genetic variants in
  blood and CSF

Hypothesis CSF HIV-1 variants produced by cells
within the CNS will decline more slowly in
response to antiretroviral therapy compared with
CSF HIV-1 coming from peripheral sources.
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Haas Study-4 treatment-naïve, asymptomatic
subjects
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HIV-1 Compartmentalization in the CNS
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Decline of HIV-1 Genetic Variants During
Antiretroviral Therapy Compartmentalized HIV-1
Variants in CSF Decline Rapidly
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Decline of HIV-1 Variants in CSF During
Antiretroviral Therapy
Conclusion A short-lived, HIV-productively
infected cell population exists in the central
nervous system and contributes to the HIV-1
population in cerebrospinal fluid.
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Dynamics of HIV-1 Populations in the CNS
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Dynamics of HIV-1 Populations in the CNS-HAD?
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Dynamics of Compartmentalized HIV-1 Populations
in the Central Nervous System

• Conclusions
• The amount of CNS-specific production of HIV-1 in
  CSF is associated with neurological disease
  status.
• In asymptomatic subjects, short-lived cells
  (perhaps trafficking CD4 T cells) play an
  important role in the production and maintenance
  of locally produced HIV-1 populations in CSF.

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