Inves&gación básica y curación del VIH-1

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1 Inves&gación básica y curación del VIH-1 Javier Mar&nez-Picado 24 th Conference on Retroviruses and Opportunis6c Infec6ons UNIVERSITAT DE VIC

2 Empezamos bien

3 cart: How Early is Early Enough? Sáez-Cirion et al PLoS Pathog; Whitney et al 2014, Nature

4 Significant Decline in HIV Reservoir Size with Jintanat Early Ananworanich ART ALer treatment ini&a&on, in all Fiebig stages there is a rapid decrease in the frequency of cells harboring total HIV DNA, but it remains stable in chronic infec&on. Leyre, Chomont, CROI 2017 (948) RV254 and RV304 Thai studies

5 cart: How Early is Early Enough? Dura&on from infec&on to ART ini&a&on > 6 months 4 weeks 2 weeks 1 week Chronic Infec&on 14 days (n=14) Fiebig III 22 days (n=14) Fiebig I 26 days (n=8) Fiebig days (n=1) Days ALer Treatment Interrup&on Median days shown Rothenberger, PNAS 2015; Kroon, IAS 2016; Colby, CROI 2017 (852), Timothy Henrich and Steven Deeks (UCSF)

6 Strategy for HIV Cure Maintain viral suppression Reduce HIV reservoirs Reduce immune ac&va&on Reverse immune exhaus&on Improve HIV-specific immune responses Beber ART Combina6on therapies! LRA/immune adjuvant! bnab! Vaccine! Immune checkpoint blockers! An6-inflammatory agents! Engineered T cells and an6bodies! Gene edi6ng therapies

7 Whole body mapping of HIV DNA 29 HIV infected decedents followed clinically ( ) 1/3 virally suppressed, 1/3 with intermibent suppression; 1/3 without any suppression Viral suppression confirmed with HIV RNA of spleen (log 10 spleen RNA: 1.64 vs 2.67 vs 3.83 Tissue and PBMC HIV gag pol DNA assay using PCR Correc&on for HIV DNA due to blood pooling in organ applied (based on &ssue hemaglobin, blood hematocrit and cell counts) BB Gelman, Abstract #68

8 Whole body mapping of HIV DNA BB Gelman, Abstract #68

9 Residual disease in ART-treated HIV-infect. Curing HIV infec&on is a virological AND immunological problem It is possible that elimina&ng the last copy of HIV in the body will not cure the immune dysfunc&on (inflamma&on, loss of mucosal integrity, immune senescence, fibrosis, etc.) M Paiardini, Abstract #48

10 PD-1 and CTLA-4-expressing cells are major contributors to the SIV DNA pool within memory CD4+ T cells M Paiardini, Abstract #48

11 Innate immune detection of microbial nucleic acids Gürtler & Bowie Trends Microbiol. 2013

12 TLR7 Agonists Induce Transient Plasma Viremia durant cart " Viral reac&va&on only when using the TLR7 agonists " No peripheral produc&on of IFNα with GS-9620 (both doses), and minimal produc&on with GS-986 (0.1mg/Kg) Whitney et al, #95LB, CROI 2016

13 SIV pvl Rebound after Stopping ART 2 of 9 animals treated with TLR7 agonists have undetectable plasma virus up to 3-4 months off ART, both predicted by ex vivo reac&va&on cultures of PBMCs and inguinal LN

14 TLR7 Agonist treatment of SIV+ monkeys on ART can lead to complete viral remission VOA/VCC T-cell IR n=2 n=2 n=1 n=1 2 RM with viral remission J Whitney Abstract #338LB

15 TLR7 Agonist treatment of SIV+ monkeys on ART can lead to complete viral remission Viral Cocultures NEG SIV-specific T-cell Immune responses NEG In vivo CD8 deple&on NEG Adop&ve transfer of PBMC/LNMC NEG J Whitney Abstract #338LB

16 Genome-wide Methylation

17 Genome-wide methylation in HIV-infection May host DNA methyla&on be associated with HIV-1 disease progression phenotypes? HIV infection DNA methylation HIV disease progression Morón-López et al. Abstract #228

18 HIV infection affects host DNA methylation Morón-López et al. Abstract #228

19 cart partially reverts DNA methylation Morón-López et al. Abstract #228

20 Empezamos bien

21 Gene Editing Therapies CCR5 32 Gene disruption CCR5 ZFN modification Holt, Nat Biotechnol 2010; Naldini, Nat Gen 2011; Tebas et al N Eng J Med

22 Adoptive Cell Transfer NCT & NCT ; Tebas et al N Eng J Med

23 Chimeric Ag Receptors (CARs) Engineered hybrid proteins consisting of an extracellular scfv fused to co-stimulatory signaling domains CD28 or 4-1BB (CD137), coupled with CD3ζ to mediate T-cell activation ITAM ITAM: immunoreceptor tyrosine-based ac6va6on mo6f

24 Adoptive CAR Therapy

25 Adoptive CAR Therapy Demin Li

26 Chimeric Ag Receptors (CARs) CAR T cells targeting CD19 resulted in sustained complete responses within a population of refractory patients with B-cell malignancies Complete response rates of 90% in patients with relapsed or refractory acute lymphoblastic leukemia 161 clinical trials in oncology 0 clinical trials in HIV CD4ζ o >17 years persistence (safety) o No CAR-dependent decreases in pvl or viral reservoir Mitsuyasu et al. Blood 2000

27 Immuno-oncology drugs Hoos, 2016 Nature Review Drug Discovery

28 IciStem systema&cally monitors the pa&ents included for extensive periods of &me to beber understand the biological clues leading to viral reservoirs reduc5on and poten5al cases of HIV-1 eradica5on/remission among these pa&ents

29 Mouse Viral Outgrowth Assay (mvoa) Ra5onal to stop an5retroviral therapy in these pa5ents! NOD-Scid IL2gR / million CD4+ T cells Virus Reac&va&on 2 Control no-sct patients 4 SCT CCR5wt-patients Viral reactivation in plasma Patient s Cell engraftment Patient s Cell activation Viral reservoir in blood and spleenocytes Salgado et al. Abstract #306

30 Mouse Viral Outgrowth Assay (mvoa) Salgado et al. Abstract #306

31 Mouse Viral Outgrowth Assay (mvoa) IUPM = 1.6 per 10 6 CD4+T cells IUPM <0.004 per 10 6 CD4+T cells Pre-SCT Post- SCT (+34 months) *Input: 10M FROZEN CD4+T cells/mouse *Input: 50M CD4+T cells/mouse Engraftment (% Human CD45) VL (HIV-RNA copies/ml plasma) Time % VL(HIV-RNA copies/ml plasma) Time Human CD45 % Activation Time Time Salgado et al. Abstract #306

32 Thanks Sara Morón-López & María Salgado Fundació Lluita contra la SIDA Gilead

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