Naive CD4 T lymphocytes and recent thymic emigrants, 15 or more years after perinatal HIV infection
The ANRS-EP38-IMMIP study
Stéphane Blanche, Daniel Scott-Algara, Jérôme Le Chenadec, Céline Didier, Thomas Montange, Véronique Avettand-Fenoel, Christine Rouzioux, Jean-Paul Viard, Catherine Dollfus, Naima Bouallag, Josiane Warszawski, Florence Buseyne
IAS 2013, Kuala Lumpur, MalaysiaLate Breaker Track A, Wednesday 3 July
WELBA02
ANRS-EP38-IMMIP study
A physiopathological study focusing on patients with perinatal HIV infectionborn at the start of the epidemic (before 12/1993)
Did not have early access to HAART 60% are alive and in regular follow-up (French birth cohort, 2010)
Now: young adults and older patients with a pediatric history of HIV disease
Aim: to improve our knowledge of the virological and immunological status of adolescents and young adults infected during the perinatal period
ANRS-EP38-IMMIP : study designn=93HIV in perinatal period>15 years
> 15 ans
Current immune
and virological status
2007-2009
25 ml
Since BirthIn care before 1996
Lifetime HIV diseaseCD4/HIV-RNA/ Treatment
1
HIV disease correlates2
Patients' characteristicsmedian[range]
%
Age (yrs) 17 [15-24]Sex Male Female
43 %57 %
Current HAART Yes aviremic
85 %75 %
Current CD4 cell counts aviremic viremic
642 [522-939]423 [274-521]
Patients’ HIV disease historymedian[IQR] %
CDC Stage C No Yes
76 24
CD4 cell percentage <15% At least once Lifetime duration of CD4%<15% (yrs)
80 1.9 [0.5;4.1]
Cumulative duration of plasma HIV-RNA<500 copies/ml 5.6 [2.6;7.2]
Cumulative duration of HAART (yrs) 9 [7;11]
over life time, except for plasma HIV-RNA (available since 1996)over the last 10 years
Naive T lymphocytes and thymic activity
Naive T cell production - De novo in the thymus = recent thymic emigrants (RTE, CD31+) - homeostatic proliferation in the periphery (CD31-) reduced T-cell repertoire diversity
→ % of CD31+ RTE among naive CD4 T-lymphocytes : a marker of
thymic activity
Adapted from Kohler, Blood 2009
ThymusPeriphery
The size of the naive T-cell compartment determines the diversity of the T-cell repertoire and is thus critical to provide immunity to foreign antigens → % naive CD4 T lymphocytes (among total peripheral blood CD4 T cells )
Current HIV RNA level
plasma HIV RNA
CD
4 N (%
)
< 80 copies/ml >= 80 copies/ml0
20
40
60
80
100 P=0.10
plasma HIV RNA
%C
D4 R
TE
< 80 copies/ml >= 80 copies/ml0
20
40
60
80
100P=0.003
CD4N
CD4RTE
CD4RTE Higher CD4RTE % in viremic than in aviremic patients
CD4N Levels similar to those of uninfected patients
CD4RTE
Aviremic Viremic Aviremic Viremic
Median(IQR): 56% (44-64) Median(IQR): 79% (74-83)
Current CD4 cell levels
CD4/µl
CD
4 RTE
(%)
0 500 1000 150050
60
70
80
90
100
110 <80 copies/ml >= 80 copies/ml
CD4/µl
CD
4 N (%
)
0 500 1000 15000
20
40
60
80
100 <80 copies/ml >= 80 copies/ml
aviremic: r=0.431, P=0.001viremic: r=0.387, P=0.04
aviremic: r=0.520, P=0.0007 viremic: r=0.022, P=0.93
CD4N CD4RTE
CD4RTE Positively correlated to CD4 cell counts CD4N
Cumulative viremia over the last 10 years(log HIV RNA copies x days)
CD
4 N (%
)
0 5000 10000 15000 200000
20
40
60
80
100
Tropisme
CD
4 N (%
)
R5 X4R50
20
40
60
80
100 P=0.001
Tropisme
CD
4 RTE
(%)
R5 X4R550
60
70
80
90
100P=0.50
Cumulative viremia over the last 10 years(log HIV RNA copies x days)
CD
4 RTE
(%)
0 5000 10000 150000
20
40
60
80
100
CD4N
Cumulative viremia Coreceptor
Positive correlation with cumulative viremia over the past 10 yrsHigher in patients with X4R5 strains than in those with R5 strains
CD4RTE
CD4N
R5 X4R5
R5 X4R5
Cumulative lifetime durationof CD4%<15 (months)
CD
4 N (%
)
0 50 100 1500
20
40
60
80
100
Cumulative lifetime durationof CD4%<15 (months)
CD
4 RTE
(%)
0 50 100 1500
20
40
60
80
100
Duration CD4%<15%
CD4RTENegative correlation with lifetime duration of CD4% < 15%Cumulative viremia : time updated Area Under the Curve of viral load (Zoufaly et al., 2009)Coreceptor usage : sequence analysis of HIV DNA env, using SVMGeno2pheno algorithm
Past HIV disease (aviremic patients)
No association with:Age CDC stage CTreatment historyEthnicityHIV subtype
Other HIV disease parameters
CD4RTE % were higher in female than in male patients
Multivariate models : a summary aviremic patients
Age (per year) 0.62 0.26
Current CD4 cell count 0.01 0.009
Coreceptor usage (X4R5>R5) 0.003 Not included
Cumulative viremia over the last 10 years
0.05 Not included
Duration of CD4 cell percentage < 15%
Not included 0.02
Sex (Female>Male) Not included 0.01
CMV seropositivity Not included 0.99
CD4N CD4RTE
Conclusions In patients included in the ANRS-EP38-IMMIP study:
CD4N and CD4RTE levels were in the range reported for healthy adolescents/young adults
CD4N and CD4RTE levels were directly correlated with CD4 cell count
Paradoxical associations between CD4N and CD4RTE percentages and current and/or past HIV replication levels
Enhanced thymopoiesis appears to compensate for high rates of HIV-driven T-cell depletion
o Observed in several pediatric studies, and some adults studies (early asymptomatic phase)
o In most adults, thymopoeisis is reduced by viral replication
The thymus remains active but … is not without damage after periods of immunosuppression
Acknowledgments
To all patients who agreed to participate in this study.
To the investigators of the ANRS-EP38-IMMIP and staff members
Principal Investigator : Pr Stéphane BlancheMethodology : Dr Josiane WarszawskiVirology : Pr Christine RouziouxImmunology : Dr Daniel Scott-Algara, Dr Florence Buseyne
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