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