HIV infection and CD4 recovery
Transcript of HIV infection and CD4 recovery
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ImpactImpact
ofof
RaltegravirRaltegravir
onon
ImmuneImmune ReconstitutionReconstitution
andand
ThymopoiesisThymopoiesis
in in
HIVHIV--1 1 InfectedInfected
PatientsPatients
withwith UndetectableUndetectable
ViremiaViremia
Carolina Garrido, N Rallón, N Zahonero, M López, V Soriano, C de Mendoza, and JM Benito
Hospital Carlos III, Madrid
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HIV HIV infectioninfection
andand
CD4 CD4 recoveryrecovery
HIV-infection CD4+T-cells Immune deficiency
Opportunistic infections
HAART HIV Viral Load CD4+T-cells
Raltegravir First-in-class integrase inhibitor Has proven potent antiviral activity but also showed good immunologic recovery
Background
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RaltegravirRaltegravir
immunologicimmunologic
outcomesoutcomesBackground
THPE0132
700
600
500
400
300
CD
4 co
unt(
cell/
mm
3 )
ATV DRV RALn
baseline+ 6 monthsΔ
CD4
p
CD4+T cells
(cell/mm3)
52524 [344,703]444 [354,606]-22 [-127,55]
0.173
25231 [157-493]291 [176,492]
28 [-36,80]
0.104
86555 [429-776]630 [472,812]40 [-31,136]
0.012
Switching experiences in HCIII:
- ATV
- DRV
- RAL
Switch one drug for another in a context
of undetectable viremia
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ImmunologicImmunologic
recoveryrecoveryBackground
The CD4+T-cellrecovery after HAART can be due to:
Recent thymicemigrants (RTEs)
The expansion ofperipheral T cells
Thymus Supply of new lymphocytes to the periphery. Impaired during HIV-infection
Kohler and Thiel, Blood, 2009
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ThymicThymic
functionfunction
Thymic function T-cell receptor excision circles (TRECs) Stable DNA episomes
formed during T-cell receptor gene rearrangement within the thymus↑
% cells TREC+ = RTEs
↓
% cells TREC+ = cells after several divisionsTRECs
are lost
upon
cell
division
Background
CD31
Surface marker
Present in TREC-rich T-cells
Indicator of recent thymic emigrants
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ObjectiveObjective
The aim of the study was
to characterize the immunologic recovery of
HIV-infected patients under suppressed viremia
after switching to a RAL containig regimen
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PatientsPatients
andand
samplessamples
Viral load < 50 RNA cop/mL
Baseline +6 months
Switch to a RAL-containig regimenMantain the same regimen
Control group Raltegravir
group
For each patient, two blood samples were collected: one at baseline
one 6 months later
PBMCs were obtained from peripheral blood by density gradient centrifugation
Cells were criopreserved until use
Methods
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ImmunologicImmunologic
characterizationcharacterization
CD4+T-Lymphocyte
effector naiveeffector memory
central memory
- CD4-PC7
- CD45RA-ECD
- CD27-PE
- CD38-PC5
- CD31-FITC
PBMCs were stained with fluorescent-conjugated monoclonal antibodies specificfor cell surface markers:
Expression of these surface markers was analyzed by flow cytometry using a 5-color-flow-cytometer FC500 (Coulter, Miami, FL)
Activation markerRecent thymic emigrants (RTE) marker
Maturation markers
Methods
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StudyStudy
populationpopulation
Baseline characteristics of the study population did not differ among groups
Control group: 84% PI (67% ATV, 17% LPV); 11% NNRTIs; 5% NRTIs
RAL group: 53% PI; 47% 2NRTIs
Results
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CD4CD4++TT--cellcell
countcount
After the 6-month period, only the group whoswitched to RAL experienced a significantchange in CD4 count
Control
800
600
400
200
0
Raltegravir
CD
4+ T-c
ell(
cell/
mm
3 )
*
Results
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CD4CD4++TT--cellcell
maturationmaturation
Effector
Naive
Effector
memory
Central memory
Effector
Naive
Effector
memory
Central memory
0.421
0.014
0.005
0.421
0.117
0.199
0.723
0.133
*
*
Wilcoxon Signed Ranks Testp
After the 6-months period, significant changes in the population subsets distribution only occurred in the RAL group, where the subset of naive cells increased its proportion
+6 monthsBaseline
Con
trol
Ral
tegr
avir
Results
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CD31 CD31 expressionexpression
CD31 expression did not vary significantly in any of the study groups neither in the whole population or in particular cellular subsets
Results
Baseline
+ 6 months
p=0.811
p=0.306 p=0.191
p=0.420
p=0.679 p=0.277p=0.306
p=0.872
p=0.314
p=0.117
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CD38 CD38 expressionexpression
In the control group there was a slightlysignificant decrease in the CD38 expressionlevel of both naive and effector subsets
In the RAL group, we observed a significantdecrease in the effector population but a significantincrease in the level of CD38 expression of naive cells
Results
* * * *
p=0.036
+ 6 monthsBaseline
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AssociationAssociation
betweenbetween
CD38 CD38 andand
CD31CD31Results
100806040200
% naïve cells expressing CD31
100
80
60
40
20
0
% n
aïve
cel
ls e
xpre
ssin
g C
D38
R Sq Linear = 0,51
Control-RAL + 6 months
Pearson correlation sig (2-tailed) < 0.001
100806040200
100
80
60
40
20
0
R Sq Linear = 0,262
% naïve cells expressing CD31
% n
aïve
cel
ls e
xpre
ssin
g C
D38
Control-RAL baseline
Pearson correlation sig (2-tailed) = 0.001
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ConclusionsConclusions
Switching to a RAL-containing regimen in a context of suppressed viremia induced a significant gain in CD4+T-cell count.
This improvement was mainly due to an increase in the subset of CD4+Naive cells.
The increase in CD4+naive cells could not be clearly associated to recent thymicemigrants, as there was no significant rise in the expression of CD31.
However, the increase of CD38 expression on naive CD4+T-cells and thesignificant association between CD38 and CD31 markers on this subset of CD4+ cells, suggest that the immune recovery observed in patients switching to RAL may be due, at least in part, to newly produced cells in the thymus.
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AcknowledgmentsAcknowledgmentsInfectious
Diseases
Department
of
Hospital Carlos III
(Molecular Biology Lab. + Clinical Section)
Norma Rallón
Mariola López
Jose Miguel Benito
Natalia Zahonero
Carmen de Mendoza
Vicente Soriano