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

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1 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

2 The Heteroduplex Tracking Assay (HTA) is a tool to describe HIV population dynamics and identify compartmentalized variants in the population

3 The Degree of Compartmentalization Correlates with Neurological Disease State (HAD)

4 Compartmentalization Between Plasma and CSF is Associated with Neurological Disease P<0.01 P<0.01 P=NS n=7 n=19 n=32 n=9 *CSF viral population switch from a purely blood, or mixed blood and CNS source, to primarily a local CNS source in HAD subjects

5 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.

6 No Differential Decay of Compartmentalized Virus in CSF when Starting HAART Plasma vs. CSF % Difference (T 0 ) CSF % Difference (T n vs. T n+1 ) Pt V4/V5 % Difference CSF Viral Load 100 % Difference Pt V4/V5 %Difference Pt V4/V5 % Difference Pt V4/V CSF Viral Load CSF Viral Load CSF Viral Load 100

7 CSF-Compartmentalized Variants Decay Rapidly after the Initiation of HAART Pt V4/V5 Variant Decay Rates Viral Rates of Decay Variant Load Half-life (days) % Difference Days on HAART CSF Decay: CSF-compartmentalized variants Shared variants Plasma Decay: Total viral load 0 0 Plasma CSF CSF % Difference compartmentalized BP vs. CSF Pt ADC=1 variants Pt ADC=2 Pt ADC=3 Pt ADC=3 Asymptomatic* *Harrington, P.R., et al. (2005). J Virol. 79(13):

8 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.

9 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.

10 Two Patterns of SIVsmE660 Population Dynamics are Seen Between Blood and CSF

11 CSF SIVsm MCP-1 Compartmentalization Levels are Elevated in is Evident Macaque in C002 Macaque C002 *P<0.01

12 Perivascular Macrophages are Associated with Compartmentalization and MCP-1 Levels D110 Plasma:CSF concordant D081 Plasma:CSF concordant C002 Plasma:CSF discordant *p<0.05 **p<0.01

13 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 n=1). Compartmentalization is a measure of independent replication in the CNS that may lead to an inflammatory response and contribute to neuropathogenesis of HIV.

14 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 Children s Hospital of Philadelphia Phil Johnson Mary Connell Studies were funded by NIMH and UNC CFAR