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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

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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

slide2

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

compartmentalization of hiv 1 genetic populations in blood plasma and csf revealed by v1 v2 env hta

Unique env populations in

plasma and CSF

Similar env populations

Unique env populations in plasma

Unique env populations in CSF

BP CSF

BP CSF

BP CSF

BP CSF

Compartmentalization of HIV-1 Genetic Populations in Blood Plasma and CSF Revealed by V1/V2 (env) HTA

*single-stranded probe band

 unique to compartment

slide5

Relative Abundance of Unique env Variants in CSF

HAD

No HAD

Increased Compartmentalization Between Plasma and CSF HIV-1 env Populations is Associated with Neurological Status

Patients with compartmentalized env sequences

% of Patients

slide6
Dynamics of HIV-1 Populations in Blood and CSF of Asymptomatic Subjects During the Initiation of Antiretroviral Therapy
slide7

free virus

short-lived, productively infected cells (CD4+ T cells)

Sources of HIV-1 RNA

long-lived infected cells

(Macrophages, resting T cells)

0

-0.5

-1

-1.5

-2

-2.5

-3

0

2

4

6

8

10

12

14

16

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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CD4+ T cells

Macrophages

Periphery

CSF

CNS

Macrophages

Perivascular Microglia

Astrocytes

Neurons

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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CSF/Plasma Sampling Start

CSF/Plasma Sampling End

Three-drug therapy Start

CSF/Plasma Sampling Start

CSF/Plasma Sampling End

-120

-96

-72

-48

-24

0

24

48

72

96

120

Baseline

Time (Hours)

72-120 hours post-initiation of therapy

Haas Study-4 treatment-naïve, asymptomatic subjects

slide10

BP CSF BP CSF

#

Relative Variant Load (copies/ml)

#

#

single-stranded probe

*unique variant in CSF

#enriched variant in CSF

HIV-1 Compartmentalization in the CNS

slide11

Patient 2 V4/V5 Variants

Decline of CSF HIV-1 Variants

(h)

Relative Variant Load (copies/ml)

#

Time on therapy (h)

CSF HIV-1 variants shared with the periphery

Compartmentalized HIV-1 Variants in CSF

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 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.

  • Grazie molto per la vostra attenzione!
  • (Thank you very much for your attention)