The Disproportionate Effect of Antiretroviral Therapy on CSF HIV

1
The Disproportionate Effect of Antiretroviral
Therapy on CSF HIV
Determinants of the CSF HIV-1 RNA Concentration
2
ART and CNS HIV-1Anticipated Problems and
Continuing Dogma

• Compartmentalized infection
• Restricted drug penetration across blood-brain
  barrier (BBB) and blood-CSF barrier (BCB)
• Possible consequences
• Site of persistence
• Site of mutation/selection
• Immune escape
• Pathogenicity
• Resistance
• Site of continued injury
• Need to target CNS with ART?

Harrington et al, UNC
3
Simple Model of CSF Infection and Treatment
Compartments
HIV Infection
Systemic (Blood)
HIV Replication
(1)
Leptomeninges (CSF)
HIV Replication
(2)
Brain
HIV Replication
CSF Infection types (1) transitory (2)
autonomous
4
ART and CNS HIV-1Accumulating Reality Experience

• Incidence of ADC is markedly reduced in developed
  world
• Unusual in those on ART
• Particularly with plasma viral suppression
• Treatment is usually effective in suppressing CSF
  HIV-1
• Even in face of drug resistance
• Acute decay kinetics may equal blood decay
• Why the disconnect?
• What are the factors determining CSF (CNS)
  responses?

5
Relationship of CSF to Plasma HIV-1 RNA
Paradigm of Treatment Failures

• Offs 57 off ART for gt 3 months
• Failures 35 on ART, plasma VL gt 500 cpm
• Successes 47 on ART, plasma VL lt 500

6
CSF to Plasma Responses to ART Paradigm of
Failures
7
Background of ART Effect in SNC Resistance
Treatments
8
CSF Responses to ART

• CSF HIV baseline below plasma
• CSF decay in some equal to plasma decay
• All CSF HIV approached or reached detection limit
• Even in 5 failures
• Pleocytosis resolved
• Even in 5 failures

9
STI in FailuresDisproportionate Increase in CSF
HIV-1 RNA

• CSF HIV RNA lower at baseline
• CSF HIV RNA increased more than plasma
• CSF WBCs also rose

10
Rapid CSF Response to ART in ADC Patient
Baseline ADC Stage 2 CD4 133 per µL CSF WBC 12
cells/ µL CSF protein 198 mg/dL Treated
with ABV, 3TC, NVP, IDV/r
11
T Cell Activation in Blood and CSF
HLA-DR/CD38 CD8 CD4 T Cells (CD3)
12
T Cell Activation in Blood and CSF
HLA-DR/CD38 CD8 CD4 T Cells (CD3)
13
CD8 T Cell Activation in Blood and
CSFReduction in Failures across Plasma but not
CSF HIV Levels

• Results
• Reduced CD8 activation in relation to plasma HIV
  in Failures compared to Offs
• Equal CD8 activation in relation to CSF HIV in
  Failures Offs
• Interpretation
• The level of immune activation drives CSF VL in
  relation to plasma HIV
• Effect of ART on activation explains lower CSF
  HIV in Failures than Offs at a given plasma VL

14
Immune Activation and CSF HIV-1Hypotheses from
Treatment Activation Data

• CD8 activation is a marker for generalized
  immunoactivation
• Blood CD8 activation is driven by systemic
  infection
• Failed treatment reduces activation in relation
  to plasma VL.
• CSF CD8 activation is determined by blood
  activation
• High correlation of blood and CSF CD8 activation
• CSF HIV infection is driven by level of systemic
  immune activation
• Failures and Offs show same relationship of CD8
  activation and CSF VL

15
Model of CSF Infection and Treatment
ART
Compartments
HIV Infection
(a1)
Systemic (Blood)
HIV Replication
(1)
(a2)
Leptomeninges (CSF)
HIV Replication
(a3)
(2)
Brain
HIV Replication
CSF Infection components (1) transitory (2)
autonomous (3) amplified
16
Plasma CSF HIV RNA CSF WBCs in Untreated HIV
Subjects Effect of CD4 Depletion

• 113 Untreated HIV
• (8 ADC)
• CD4 lt50 cells/µL
• High plasma VL
• Relatively low CSF HIV
• High plasma-CSF difference (?P-C HIV)
• Reduced CSF pleocytosis
• Association of very low CD4 with high ?P-C HIV
• ADC cluster with non-ADC

17
Model of CSF Infection and Treatment
Compartments
HIV Infection
Systemic (Blood)
HIV Replication
(1)
Leptomeninges (CSF)
HIV Replication
(2)
Brain
HIV Replication
CSF Infection components (1) transitory (2)
autonomous (3) amplified
18
Factors Determining CSF HIV-1 RNA Levels

• Transitory Component
• Plasma HIV-1 RNA concentration
• CD4 T cell activation ? CD4 T cell
  translocation
• Autonomous Component
• HIV-1 encephalitis
• MF activation translocation
• Amplified Component
• CD4 T cell availability
• CD4 T cell activation
• Treatment
• Effectively reduces plasma viremia
• Less potent direct effect on autonomous and
  amplified components protected by BBB BCB
• Indirect effect on all components of infection by
  reducing immune activation

19
Some Implications of Predominance of Amplified
CSF Infection

• Compatible with genetic compartmentalization of
  CSF infection throughout course (after PHI)
• Intrathecal selection expansion of contributing
  genomes
• Explains disproportionate effect of ART
• Through reduction of immune activation
• Contribution to CNS disease
• May enhance evolution to neuropathic variants
  passed to perivascular MFs by direct extension
• Amplified CSF HIV may derive from brain virus
• And thus provide magnified window into HIV
  encephalitis
• But may also obscure brain infection
• Level of encephalitis activity
• Treatment responses when/if MF infection
  dissociated

20
Acknowledgements

• SFGH/UCSF Neurology
• S Spudich
• E Lee
• CSF Consortium
• M Gisslen, L Hagberg L Rosengren, K Blennow
  (Goteborg)
• P Cinque (Milan)
• B Brew (Sydney)
• SFGH/ UCSF Core Immunology
• E Sinclair
• R Ronquillo

• SFGH/UCSF Core Virology
• T Liegler
• UNC Virology
• P Harrington
• R Swanstrom
• G Schnell
• SFGH/UCSF/PHP
• S Deeks
• R Hoh
• Grant Support
• R01 MH62701
• R01 NS37660
• R01 NS43103
• UL1 RR024131