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GENETIC FACTORS LEADING TO LOSS OF VIRAL CONTROL IN HIV ELITE CONTROLLERS PATIENTS

GENETIC FACTORS LEADING TO LOSS OF VIRAL CONTROL IN HIV ELITE CONTROLLERS PATIENTS.

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GENETIC FACTORS LEADING TO LOSS OF VIRAL CONTROL IN HIV ELITE CONTROLLERS PATIENTS

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  1. GENETIC FACTORS LEADING TO LOSS OF VIRAL CONTROL IN HIV ELITE CONTROLLERS PATIENTS José M. Benito, Marcial García, Victoria de Santisteban, Ricardo Ramos, Clara Restrepo, María A. Navarrete-Muñoz, Agathe León, Ezequiel Ruiz-Mateos, Alfonso Cabello, José Alcamí, Miguel Górgolas, Norma Rallón; On behalf of ECRIS integrated in the Spanish AIDS Research Network Watson JD, Crick FH. Nature. 1953; 171(4356):737-8

  2. CONFLICT OF INTEREST • No conflicts of interest to declare

  3. ELITE CONTROLLERS (EC) • HIV patients capable of controlling viral replication to undetectable levels without the need of antiretroviral therapy. • They represent less 1% of all HIV infected population Elite Controllers Non Controllers CD4+ VL

  4. DIFFERENT FACTORS INVOLVED IN ELITE CONTROL OF HIV Factors associated to virological control Host factors Viral factors HLA-B*57 HLA-B*27 HLA-B*14 HLA-B*52 CCR5∆32 Defective viral strains

  5. Acute infection Chronic infection LOSS OF VIROLOGICAL CONTROL Loss of Virological control Virological control • Up to 30% of EC experience loss of virological control HIV-RNA plasma levels Leon et al. AIDS. 2016;30(8):1209-20 Years Weeks

  6. FACTORS INVOLVED IN LOSS OF ELITE CONTROL Factors associated to loss of virological control Viral factors Host factors • Clinical • Nadir CD4 • Coinfections (HCV, HBV) • Viral blips León et al. AIDS. 2016; Madec et al AIDS 2013 Yang et al. AIDS 2017 Chereau et. al Plos One 2017 • Epidemiological • Risk factor for HIV acquisition • Year of seroconversion • Superinfections León et al. AIDS. 2016; Madec et al AIDS 2013 Clerc et al. J Clin Virol. 2010 • Demographic • Gender • Age León et al. AIDS. 2016; Madec et al AIDS 2013

  7. FACTORS INVOLVED IN LOSS OF ELITE CONTROL Host-dependent biological mechanisms underlying this phenomenon • Clinical Other host genetic factors? Pro-inflammatory milieu HIV-specific T cells response Pernas et al. J Virol. 2017 Pernas et al. J Virol. 2017 • Epidemiological El-Far et al. Sci Rep. 2016 Pernas et al. J Virol. 2017 Pernas et al. J Virol. 2017 El-Far et al. Sci Rep. 2016

  8. HYPOTHESIS Expression levels of different genes involved in HIV pathogenesis could influence the ability of EC patients to maintain viral replication control . OBJECTIVE To investigate the association of several genes, previously related to pathogenesis of HIV infection, with the loss of spontaneous virological control in EC patients.

  9. PATIENTS Study population 7 PersistentControllers (PC) (Undetectable plasma HIV-RNA during follow-up) 13 EC patients (From the HIV controllers cohort of the Spanish AIDS Research Network (ECRIS) 6 TransientControllers (TC) (Plasma HIV-RNA > 50 copies/mL in two consecutive measurements during 1 year of follow-up)

  10. STUDY DESIGN 6 7

  11. STUDY DESIGN 6 7

  12. STUDY DESIGN 6 7

  13. METHODS PCA analysis Criopreserved PBMCs Analysis software RNA extraction Differential expression (FDR<0.05) PCA Component 1 Gene expression RT-PCR Group A Group B Component 2

  14. RESULTS

  15. RESULTS Genes expression profile was able to discriminate between TC and PC patients at T1 (PCA analysis) TC PC

  16. RESULTS Several genes were down-regulated at T1 in TC compared to PC FC = 0,78 FC = 0,68 PC p= 0.046 p= 0.006 2.5 25 TC FC = 0,59 p= 0.024 2.0 20 1.5 15 Relative mRNA gene expression Relative mRNA gene expression 1.0 10 5 0.5 0 0.0 IFI16 CDKN1A CTR9

  17. RESULTS Several genes were up-regulated at T2 compared to T1 in TC p= 0.047 p= 0.04 p= 0.03 0.15 5 0.20 2.0 10 p= 0.03 p= 0.012 4 8 0.15 1.5 0.10 3 6 Relative mRNA gene expression 0.10 1.0 2 4 0.05 0.05 0.5 2 1 0.00 0 0.00 0 0.0 ABCA1 [Fold change= 3,5] PAF1 [Fold change= 1,5] IL10 [Fold change= 2,2] IL21 [Fold change= 4,6] TRIM26 [Fold change= 1,32] T1 T2

  18. CONCLUSIONS • Our results demonstrate a down-modulation of different genes with anti-HIV activity in EC patients that precede the loss of spontaneous viral replication control in these patients. • These genes could be considered potential biomarkers of loss of spontaneous control and could provide new insights for the clinical management of these exceptional group of patients.

  19. ACKNOWLEDGEMENTS We would like to thank all patients and healthy donors who participated in the study. This study has been funded by: • Project CP14/00198 integrated in the State Plan for Scientific and Technical Research and Innovation. • ISCIII-Sub-Directorate General for Research Assessment and Promotion. • European Regional Development Fund (ERDF). • N Rallón is a Miguel Servet investigator from the ISCIII (CP14/00198). • M García is co-funded by CP14/00198 project and the Intramural Research Scholarship from IIS-FJD. • C Restrepo was funded by project RD12/0017/0031 and is currently funded by project RD16/0025/0013.

  20. RESEARCH TEAM Research laboratory in HIV and Viral Hepatitis,Instituto de Investigación Sanitaria-Fundación Jiménez Díaz UAM; Hospital Universitario Rey Juan Carlos

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