Dynamics of Compartmentalized HIV-1 Populations in the Central Nervous System Patrick R. Harrington

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1 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). 1 Lineberger Comprehensive Cancer Center, Center for AIDS Research, Department of Biochemistry and Biophysics, and 2 Department of Neurology, University of North Carolina, Chapel Hill, North Carolina, USA 3 Departments 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

3 Detection of Viral Genetic Populations by HTA

4 Compartmentalization of HIV-1 Genetic Populations in Blood Plasma and CSF Revealed by V1/V2 (env) HTA Similar env populations BP CSF Unique env populations in plasma Unique env populations in CSF Unique env populations in plasma and CSF BP CSF BP CSF BP CSF *single-stranded probe band unique to compartment

Increased Compartmentalization Between Plasma and CSF HIV-1 env Populations is Associated with Neurological Status Patients with compartmentalized env sequences Relative Abundance of Unique env

5 Increased Compartmentalization Between Plasma and CSF HIV-1 env Populations is Associated with Neurological Status Patients with compartmentalized env sequences Relative Abundance of Unique env Variants in CSF 100% % of Patients 80% 60% 40% 20% Unique Variants in Plasma and CSF Unique Variants in CSF Unique Variants in Plasma All Variants Shared 0% Primary Infection No CNS Disease MCMD HAD HAD No HAD Neurological Status

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

7 At Least Two Phases of Viral Decline in the Periphery During Antiretroviral Therapy Sources of HIV-1 RNA free virus short-lived, productively infected cells (CD4+ T cells) long-lived infected cells (Macrophages, resting T cells) 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

8 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 Periphery CNS CD4 + T cells Macrophages CSF Macrophages Perivascular Microglia Astrocytes Neurons 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.

9 Haas Study-4 treatment-naïve, asymptomatic subjects CSF/Plasma Sampling Start CSF/Plasma Sampling End Three-drug therapy Start CSF/Plasma Sampling Start CSF/Plasma Sampling End Baseline hours postinitiation of therapy Time (Hours)

10 HIV-1 Compartmentalization in the CNS BP CSF BP CSF # # # Relative Variant Load (copies/ml) single-stranded probe *unique variant in CSF # enriched variant in CSF

Decline of HIV-1 Genetic Variants During Antiretroviral Therapy: Compartmentalized HIV-1 Variants in CSF Decline Rapidly Patient 2 V4/V5 Variants Decline of

11 Decline of HIV-1 Genetic Variants During Antiretroviral Therapy: Compartmentalized HIV-1 Variants in CSF Decline Rapidly 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

12 Decline of HIV-1 Variants in CSF During Antiretroviral Therapy CSF variants shared with blood Compartmentalized CSF variants Subject 1 2, % decrease t 1/2 max (h) % decrease t 1/2 max (h) t 1/2 p value 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.

13 Dynamics of HIV-1 Populations in the CNS

14 Dynamics of HIV-1 Populations in the CNS-HAD?

15 Dynamics of Compartmentalized HIV-1 Populations in the Central Nervous System Conclusions 1. The amount of CNS-specific production of HIV-1 in CSF is associated with neurological disease status. 2. 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)

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

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