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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
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Early trafficking of HIV into the CNS
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Neuropathology of HIVE in the pre-HAART eraBrain viral load
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Synaptodendritic Injury in patients with HIV Encephalitis correlates with cognitive deficits
control HIV (+)
Human Frontalcortex
gp120 Transgenic Mice
Human Neuronal Cell Culture
MAP2
Synaptophysin
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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 NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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 NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
HIV Associated Leukoencephalopathy and IRIS in the HAART era
HIV load
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Neuroprotective effects of FGF1 on tg models of HIV gp120 toxicity
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Neuroprotective effects of lithium in models of HIV gp120 toxicity
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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)
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Dysregulation of the Cell Cycle kinase signaling pathways in HIV gp120 tg
models
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
HIVProteinsgp120
TatVpr
p35
CDK5Cytoskeletal (Tau, DCX)Synaptic (PSD95, synapsin)Transcriptional (MEF2)
Abnormalphosphorylation
Neurodegeneration
Calpain
Ca++p25
p10
CXCR4
NMDA-R
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Neuroprotective effects of Roscovitineform HIV-gp120 in neuronal cells
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
Neuroprotective effects of Roscovitine in HIV-gp120 tg mice
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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.
HIV NEUROBEHAVIORAL RESEARCH CENTERHIV NEUROBEHAVIORAL RESEARCH CENTER
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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