journal club presentation 10 07 2015
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HIV in the CNS
HAD
• Psychomotor slowing• Mood changes• Anxiety• Memory deficits• Abstraction • Information processing• Decision making• Verbal fluency• Attention
Microglia
Perivascular mΦ
CD8
CD4 Th
monocytes
HIV
AcuteNeuron
Cel
lula
r fa
ctor
sV
iral p
rote
ins
Infla
mm
ator
y re
spon
ses
Astrocyte
Blood Brain
BBB
Diapedesis
• Cognitive impairment• Motor disorders• Behavioral changes
HAND
CD4Pleocytosis
Background
• Virologic characteristics associated with early CNS infection.
• Cross-sectional and longitudinal study• Cohort of 72 ART naïve infected for <2 yrs• Paired CSF and Plasma samples collected at enrollment,
6 wks and every 6 months thereafter– Timing of compartmentalization establishment– Relationship between cellular inflammation, viral loads and
phylogenetic state– Longitudinal maintenance and evolution of compartmentalization
Temporal patterns of CNS viral replication and inflammation
Treated the 144 samples as independent observations
• Acute 0-4 months• Early 5-12 months• Established 13-24 months
Conclusion: Detectable CNS compartmentalized populations are present at greater frequency With longer time since HIV-1 exposure
Factors associated with CSF viral loads
Inflammation: WBC>10cell/ulNo Inflammation: WBC<10cell/ul
Conc: increased viral burden in the CNS can result from two factors, independent CNS replication or influx of infected cells
Persistence of viral replication in the CNS
Evaluation of the persistence of viral replication in the CNS
20/37CSF viral loads of > 1000cp/ml
2 yrs follow up
9/20- eq(-) with min pleocytosis in all time points
11/20 – pleocytosis and/or comp
6/20 - states in 2 or more time points
Concl: Local replication and/or inflammation can persist or reoccur over time
Viral evolution in the CNS over timePaired bloodand CSF SGA Seq and align Neighbor joining trees and
Bayesian analysis - BEAST
Equilibrated< 4 months
Compart.> 4 months
Viral entry phenotype
Paired bloodand CSF SGA Pseudotyped viruses
Affinofile cells: CD4 and CCR5 differentially induced
Infected affinofile cells with either high or low CD4
lysis
Luciferase Assay
Concl: CNS is initially exposed to R5- tropic variants and the viruses remain R5 T cell tropic for the first 2 years but evolutionto macrophage tropism also begins during this period
InterCompNo Low CD4 and MDM
Equi populations with low CD4infectivity had also low MDMinfectivity
Growth of pseudoviruses in MDM from 3 donorsPseudoviruses were first grown in high CD4 affinofile cells
DiscussionFour states can define the relationship between virus in the CSF/CNS and blood early during
infection.
Conclusions
• Local HIV replication and robust CNS inflammatory response in the CNS begins early
• In a subset of the subjects CNS involvement can persist over time
• Viral population in CSF is dynamic as a result of local replication and influx of infected CD4 T cells.
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