1. 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, Malaysia Late Breaker Track A, Wednesday 3 July WELBA02

2. ANRS-EP38-IMMIP study  A physiopathological study focusing on patients with perinatal HIV infection born 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

3. ANRS-EP38-IMMIP : study design n=93 HIV in perinatal period >15 years > 15 ans Current immune and virological status 2007-2009 25 ml Since Birth In care before 1996 Lifetime HIV disease CD4/HIV-RNA/ Treatment 1 HIV disease correlates 2

4. Patients' characteristics median[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]

5. Patients’ HIV disease history median[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/ml5.6 [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

6. 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 Thymus Periphery 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 )

7. Current HIV RNA level CD4 N CD4 RTE Higher CD4 RTE % in viremic than in aviremic patients CD4 N Levels similar to those of uninfected patients CD4 RTE Aviremic Viremic Median(IQR): 56% (44-64)Median(IQR): 79% (74-83)

8. Current CD4 cell levels aviremic: r=0.431, P=0.001 viremic: r=0.387, P=0.04 aviremic: r=0.520, P=0.0007 viremic: r=0.022, P=0.93 CD4 N CD4 RTE Positively correlated to CD4 cell counts CD4 N

9. Cumulative viremiaCoreceptor Positive correlation with cumulative viremia over the past 10 yrs Higher in patients with X4R5 strains than in those with R5 strains CD4 RTE CD4 N R5 X4R5 Duration CD4%<15% CD4 RTE Negative 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)

10. No association with: Age CDC stage C Treatment history Ethnicity HIV subtype Other HIV disease parameters CD4 RTE % were higher in female than in male patients

11. Multivariate models : a summary aviremic patients Age (per year)0.620.26 Current CD4 cell count0.010.009 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 seropositivityNot included0.99 CD4 N CD4 RTE

12. Conclusions In patients included in the ANRS-EP38-IMMIP study:  CD4 N and CD4 RTE levels were in the range reported for healthy adolescents/young adults  CD4 N and CD4 RTE levels were directly correlated with CD4 cell count  Paradoxical associations between CD4 N and CD4 RTE percentages and current and/or past HIV replication levels  Enhanced thymopoiesis appears to compensate for high rates of HIV-driven T-cell depletion oObserved in several pediatric studies, and some adults studies (early asymptomatic phase) oIn most adults, thymopoeisis is reduced by viral replication  The thymus remains active but … is not without damage after periods of immunosuppression

13. 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 Blanche Methodology : Dr Josiane Warszawski Virology : Pr Christine Rouzioux Immunology : Dr Daniel Scott-Algara, Dr Florence Buseyne