JOURNAL CLUB PRESENTATION

SAMUEL KARIUKI

KRKSAM004

10/07/2015

IF – 8 (2013)

Background

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

Table 1. Background demographic and clinical characteristics of study participants at baseline.

Paired blood& CSF

SGA 54/144 Phylogenetic analysisComp: SM

Fst

Snn

Compartmentalization assessment

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.

Thank you

No contamination between subjects