“The Shifting Patterns of HIV Encephalitis Neuropathology” · “The Shifting Patterns of HIV...

HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER

“The Shifting Patterns of HIV Encephalitis Neuropathology”

Eliezer Masliah

National Institutes of Mental HealthEvolving Mechanisms of HIV

Neuropathogenesis in the HAART era: Domestic and Global Issues

Venice, Italy

April 16, 2007

Departments of Neurosciences and PathologyUniversity of California, San Diego


Points that will be covered1. HIV-mediated neurodegeneration and

cognition2. Shifting patterns of HIV neuropathology in

the HAARTsub-acute to chronicfrom opportunistic infections to co-morbid

3. Emerging co-morbidity factors in the HAART Drug abuse, HCV, aging, ART, psychiatric

4. Pathogenesis of the DENDRITIC pathology in the HAART era and NEUROPROTECTIO N


Early trafficking of HIV into the CNS


Neuropathology of HIVE in the pre-HAART eraBrain viral load


Synaptodendritic Injury in patients with HIV Encephalitis correlates with cognitive deficits

control HIV (+)

Human Frontalcortex

gp120 Transgenic Mice

Human Neuronal Cell Culture

MAP2

Synaptophysin


I. No cognitive impairment - No HIVE

II. Cognitive impairment - No HIVERole of systemic disease in microglial activation

III. No cognitive impairment with HIVERole of neuroprotective factors

IV. Cognitive impairment with HIVE

Group I Group III

Group II Group IV

FGF1-expression

HIV, cognitive impairment and neurodegeneration Role of trophic factors


HIV in the Brain

Pre-HAART

HIV replication in the CNS

During HAARTDuring HAART

Selective pressures:resistance mutations

CD4 response/longevitycompartmentalizationSub-acute HIVE

Neuroinflammatory Response

Progression to AIDSand death 1-3 yrs

after HIV dx

Death in 10-15 yrs

Chronic HIVE

In plasma viral load and OILatent HIV in the CNS


Chronic HIV Encephalitis in the HAART eraGroups

HIV load pre-HAART vs HAART

White matterastrogliosis

Peri-vascularinflammation

Burned-out A protein deposition

1. aggressive forms with severe HIVE and white matter injury (IRIS?)

2. extensive perivascular lymphocytic infiltration (IRIS?)

3. ‘burn-out’ forms of HIVE and

4. aging-associated amyloid accumulation with Alzheimer’s-like neuropathology

HAARTpre-HAART


HIV Associated Leukoencephalopathy and IRIS in the HAART era

HIV load


Co-morbid factors affecting the CNS of HIV in the HAART era1. Aging 2. Psychiatric complications (MDD)3. Drug Abuse (METH, Cocaine,

heroine)4. HCV5. IRIS, Toxicity associated with ART


Aging associated Neuropathology in the NNTC cohort

Total of 75 HIV+ 50 years or older cases from NNTC

17% of HIV+ had -synuclein + intracellular aggregates andneurites compared to 8% in the HIV- group.

Higher frequency of diffuse amyloid plaques in >50 year

Intracellular A deposits in pyramidal neurons in >50 year

Neurite Intracellular Lewy body Plaques Intracellular

A immunoreactivity synuclein immunoreactivity


Dysregulation of genes encoding for synaptic proteins in HIV patients with MDD

0.007-40%61.4 (16.5)

36.7 (8.3)

Tetraspan 5

0.008-74%37.7 (23.4)

9.6 (10.1)

Somatostatin

0.003-34%82.4 (12.55)

54.1 (13.1)

MAPKK1

0.025-41%31.5(8.5)

18.7 (5.4)

MAP1B

0.001-59%34.4(6.7)

14.0 (7.7)

Synapsin II

p % Change

No MDDMDDGene ng (SD)

qRT-PCR Genes down regulated MAP’s Somatostatin

HIV- HIV+

Total of 20 cases with HIVE (n=12 no MDD and 8 MDD) Affymetrix U133 plus 2 gene chip and qRT-PCR Major Depression Disorder


Dysregulation of IFN stimulated genes in METH users with HIVE

Greater loss of CALBINDIN inter-neurons in HIV+METH+

Genes Up regulated (3-5 fold) by Affym and q-PCR- ISG15, 27, 35, STAT-1

No HIVE, No METH Yes HIVE, No METH Yes HIVE, Yes METH

ISG-15 immunoreactivity


Role of HCV co-infection in the pathogenesis of HIV encephalitis

Detection of HCV mRNA in the brains of HIV HCV+ by nested PCR

Detection of HCV in astrocytes of HIV+ HCV+ cases

Detection of HCV antigens in heparin columns by WB

GFAP HCV


The changing neuropathologic profile of HIVE in the HAART era

In the era of highly active antiretroviral agents, HIVE has changed from a subacute neuro-inflammatory disorder to a more chronic and protracted neurodegenerative condition with more diffuse dendritic pathology.

Control HIVE

Pre-HAART HAART era


Mechanisms of neurodegeneration in HIV patients in the HAART era

1. Chronic HIVE -- Neurodegeneration2. Need for developing adjuvant

therapies with NEUROPROTECTIVE AGENTS

3. Dysregulation of signaling pathways such as MAPK’s, GSK3and CDK5


Neuroprotective effects of FGF1 on tg models of HIV gp120 toxicity


Neuroprotective effects of lithium in models of HIV gp120 toxicity


Design • Open-label, 12-week, single center, pilot trial of lithium

for HIV-associated neurocognitive impairment• No randomization or blinding• Lithium dosing begins at 300 mg qD and is adjusted to

maintain 12-hour trough between 0.4-0.8 mEq/L• Methods: phlebotomy, LP, NP testing, MRS

Objectives• To determine the effect of 12 weeks of lithium on

neuropsychological performance in HIV-infected individuals with symptomatic cognitive impairment

• To determine the effect of 12 weeks of lithium therapy on brain metabolites measured by MRS

Lithium clinical trial for the treatment of Cognitive Impairment in AIDS (Letendre

et al)


0

0.5

1

1.5

2

2.5

12 WeeksBaseline

P = .008*G

loba

l Def

icit

Scor

e .73

.44

* Paired t-test

Neuropsychological performance improved in all participants at week 12


GF

Ras

Raf-1

MEK

MEKK

ERK

CREB

P

PI3K

ErbB2-3

FAKGFR

SchGrb2SOS

IntegrinReceptor

PDK1

AktCdk5/p35

Pak1

Cytoskeleton

Neuronalsurvival

Neuriteoutgrowth

NMDA-R

GSK3


Dysregulation of the Cell Cycle kinase signaling pathways in HIVE

Total of 10 HIVE and 10 HIVE- cases. Of 12,625 different mRNA transcripts analyzed, approximately 49 were Down regulated and 72 were Up regulated by 2 fold in the frontal cortex.

Down-regulated genes- MAP2, GABA-R, Na and K Channels

Cell cycle associated genes: CDK5, p35, p39, CDC2 and PAK1


Dysregulation of the Cell Cycle kinase signaling pathways in HIV gp120 tg

models


HIVProteinsgp120

TatVpr

p35

CDK5Cytoskeletal (Tau, DCX)Synaptic (PSD95, synapsin)Transcriptional (MEF2)

Abnormalphosphorylation

Neurodegeneration

Calpain

Ca++p25

p10

CXCR4

NMDA-R


N-CH3OH

OH-

Cl-

O OHO=

Flavopiridol

HNN

NN

NNH

CH3OH Roscovitine

CDK’s inhibitors pharmacologyCDK’s are required for replication of HIV, HSV and other virusesthat can replicate in non-dividing cells.

There are purine and flavinoid types of pharmacological Cdk inhibitors (PCI).

PCI’s have been proposed as a new group of anti-HIV and anti-cancer drugs

Purine PCI’s target Cdk1,5,7 and flavinoid PCI’s targets 1,2,4,7,9


Neuroprotective effects of Roscovitineform HIV-gp120 in neuronal cells


Neuroprotective effects of Roscovitine in HIV-gp120 tg mice


Conclusions1. From subacute to Chronic HIVE

2. From opportunistic infections to co-morbidconditions

3. Proportion of HIVE up, but with lower CNS viralburden

4. Increasing aging and dendritic pathology

5. Need to develop adjuvant neuroprotectivetreatments to block GSK3, CDK5 and otherpathways.


AcknowledgmentsExperimental NeuropathologyLaboratoryL. HansenA. PaulinoM. ManteA. AdameE. RockensteinC. GibsonL. Crews

UCSD PsychiatryI. EverallR. Kuczinsky

HNRC / UCSDI. Grant-DIRECTORR. EllisT. JerniganR. HeatonS. LetendreA. McCutchanT. MarcotteJ. H AtkinsonM. WallaceS. ArchibaldM. ChernerD. MooreM. Frybarger

OthersC. Wiley (Pittsburgh)C. Achim (Pittsburgh)H. Gendelman (Omaha)H. Fox (Scripps)S. Lipton (Scripps)G. Gonzales (MGH)L. Mucke (UCSF/Gladstone)T. Wyss-Coray(UCSF)F.Gage (Salk)

SUPPORTED BY GRANTS FROM NIMH and NIDANNTC- Gelman, Morgello, Singer, UCSD-CNTN,

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