Nuevas Dianas Terapéuticas en el Tratamiento de la Inflamación en el VIH Sergio Serrano Villar Determinantes Genéticos y Ambientales Alteran el Proceso de Envejecimiento Mike Weyand. Age: 58 Isabel Preysler. Edad: 64 HIV: 20 years Estatus VIH desconocido Has suffered from: Cónyuges: Mario Vargas-Llosa, Miguel osteoporosis, lipodystrophy, Boyer, Carlos Falco, Julio Iglesias memory loss. Hijos:Chábeli Iglesias, Julio Iglesias Jr, Enrique Iglesias, Tamara Falcó, Ana Boyer, Identify and Target Novel Pathways HIV-1 Infection Th17 depletion Immunodeficiency TLR 7,8 Activation Microbi al Viral Reactivation Translocation (eg, CMV) Innate Immune Activation (MØ/DC) ? IDO - 1 -induced ? T Cell Turnover, Inflammatory Cytokine ?Tissue Factor, Tryptophan Activation, Lymphoid Secretion Clotting Catabolism Fibrosis (eg, IL - 6, TNF -α ) T Cell Proliferative Functional T Cell Defects / CD4+ Lymphopenia Defects Cardiovascular , Renal, and Liver Disease , Thrombosis, Osteo porosis , Frailty, Infections, Malignancy CAD/Stroke Cognitive Dysfunction Slide from Peter Hunt; 2014 Residual HIV Replication HIV-1 Infection Th17 depletion Immunodeficiency TLR 7,8 Activation Microbi al Viral Reactivation Translocation (eg, CMV) Innate Immune Activation (MØ/DC) ? IDO - 1 -induced ? T Cell Turnover, Inflammatory Cytokine ?Tissue Factor, Tryptophan Activation, Lymphoid Secretion Clotting Catabolism Fibrosis (eg, IL - 6, TNF -α ) T Cell Proliferative Functional T Cell Defects / CD4+ Lymphopenia Defects Cardiovascular , Renal, and Liver Disease , Thrombosis, Osteo porosis , Frailty, Infections, Malignancy CAD/Stroke Cognitive Dysfunction Slide from Peter Hunt; 2014 Variable penetration of ARV in tissue Ongoing viral replication and subtherapeutic ART Specialized T follicular helper cells are concentrations in lymph nodes inaccessible to CD8+ T cells Fletcher, PNAS 2014 (see also Lorenzo-Redondo, Nature 2016) Fukazawa, Nat Med 2015 ART intensification Añadir un cuarto fármaco antirretroviral con el objetivo de mejorar la disfunción inmunológica residual: -frenar la replicación viral persistente -mejorar la concentración de Hunt. Blood, 2013 fármacos en los reservorios virales Resultados poco consistentes para muchas variables evaluadas: recuento de CD4, inmunoactivación/inflamación, DNA proviral RNA intracelular, Serrano-Villar. Plos Pathogens 2016 Enhancing the GALT HIV-1 Infection Th17 depletion Immunodeficiency TLR 7,8 Activation Microbi al Viral Reactivation Translocation (eg, CMV) Innate Immune Activation (MØ/DC) ? IDO - 1 -induced ? T Cell Turnover, Inflammatory Cytokine ?Tissue Factor, Tryptophan Activation, Lymphoid Secretion Clotting Catabolism Fibrosis (eg, IL - 6, TNF -α ) T Cell Proliferative Functional T Cell Defects / CD4+ Lymphopenia Defects Cardiovascular , Renal, and Liver Disease , Thrombosis, Osteo porosis , Frailty, Infections, Malignancy CAD/Stroke Cognitive Dysfunction Slide from Peter Hunt; 2014 Decreases in Colonic and Systemic Inflammation in HIV after IL-7 12-week, single-arm, open-label study 23 ART suppressed HIV-infected patients with incomplete CD4(+) T-cell recovery One cycle (consisting of three subcutaneous injections of rIL-7 • CD4(+) and CD8(+) T-cells in peripheral blood • T-cells expressing the gut homing integrin α4β7 • T-cells in the gut mucosa • sCD14 and D-dimer, IL-1β production of peripheral blood monocytes. Sereti , Plos Pathogens 2014 Target Microbial Translocation Sevelamer Decreases Microbial Translocation and Immune Activation in Acute SIV LPS SCORE Kristoff, JCI 2014 Sevelamer Did Not Modified Bacterial Translocation/Inflammatory Markers in ART-naive Patients 40 HIV-infected subjects HIV RNA >50 copies/ml CD4>400 cells/mm3 Sandler, JID 2014 Mesalamine Did Not Modified Bacterial Translocation/Inflammatory Markers in ART-naive Patients 33 HIV-infected subjects HIV RNA <50 copies/ml CD4<350 cells/mm3 Ma. PLoS One 2014 Stubborn Failure To Succesfully Reduce Microbial Translocation Unsuccessful to Date • Sevelamer (Sandler, JID 2014) • Mesalamine (Somsouk, PLoS One 2014) • Rifaximine (Tenorio, JID 2015) • Chloroquine. (Routy, HIV Med 2015) • Probiotics (Stiksrud, JAIDS 2015) Modest Effects, Unclear Clinical Implications • Prebiotics (Gori, Mucosal Immunology 2011; d’Ettorre; PLOS One 2015; Serrano-Villar CROI 2015) • Probiotics (Villar, JAIDS 2014) • Synbiotics (Cahn, CID 2013) Does Any Aspect of Human Biology Scape from The Influence of the Microbiome? AUTOIMMUNE DISEASE MATING CNS Sharon.PNAS 2010 Kamada. Nat. Rev Immunol 2013 ATHEROSCLEROSIS CANCER Cryan. Nat. Rev 2012 Koeth. Nat Med 2012 Swchabe. Science 2012 A Peacekeeper Intestinal Bacteria Faecalibacterium prausnitzii Velasquez-Manoff. Nature 2015 Bacterial metabolism is associated with the extent of immune recovery during ART Serrano-Villar, et al. CROI 2015 H3-Acetylation levels Serrano-Villar, et al. EBioMedicine 2016 Effects of Visbiome Extra Strength on Gut Microbiome and Immune Activation Markers 5350 • Randomized pilot study in treated and suppressed HIV-infected, with CD4 >200/uL. • Treatment Group: Visbiome Extra Strength + stable antiretroviral therapy (ART) for 24 weeks • Control Group: Placebo for Visbiome Extra Strength + stable ART for 24 weeks • Participants will receive the intervention for 16 weeks, including a 12 week lead-in period before sirolimus initiation. • Participants will be followed off probiotic therapy/placebo for an additional 12 weeks (38 weeks total). Fecal Transplantation in HIV-infected Individuals Somsouk. CROI 2016 The REFRESH Study A Phase I/II randomized, double-blind, placebo controlled study of REpeated low-dose Fecal microbiota REstoration in Hiv. HIV-infected individuals On effective ART (>48w with HIV RNA<20 copies/mL) Persistent CD4/CD8 ratio <1 FMT N=15 10 5 5 5 5 5 5 5 capsules Placebo N=15 10 5 5 5 5 5 5 5 capsules Week -1 0 1 2 3 4 5 6 7 8 12 24 36 48 Stools Blood Immunosenescence HIV-1 Infection Th17 depletion Immunodeficiency TLR 7,8 Activation Microbi al Viral Reactivation Translocation (eg, CMV) Innate Immune Activation (MØ/DC) ? IDO - 1 -induced ? T Cell Turnover, Inflammatory Cytokine ?Tissue Factor, Tryptophan Activation, Lymphoid Secretion Clotting Catabolism Fibrosis (eg, IL - 6, TNF -α ) T Cell Proliferative Functional T Cell Defects / CD4+ Lymphopenia Defects Cardiovascular , Renal, and Liver Disease , Thrombosis, Osteo porosis , Frailty, Infections, Malignancy CAD/Stroke Cognitive Dysfunction Slide from Peter Hunt; 2014 PD-1 blockade enhances both T and B cell responses during chronic HIV/SIV infection Vijayakumar, Retrovirology 2015 PD-1 blockade enhances both T and B cell responses during chronic HIV/SIV infection Vijayakumar, Retrovirology 2015 Lymphoid Fibrosis HIV-1 Infection Th17 depletion Immunodeficiency TLR 7,8 Activation Microbi al Viral Reactivation Translocation (eg, CMV) Innate Immune Activation (MØ/DC) ? IDO - 1 -induced ? T Cell Turnover, Inflammatory Cytokine ?Tissue Factor, Tryptophan Activation, Lymphoid Secretion Clotting Catabolism Fibrosis (eg, IL - 6, TNF -α ) T Cell Proliferative Functional T Cell Defects / CD4+ Lymphopenia Defects Cardiovascular , Renal, and Liver Disease , Thrombosis, Osteo porosis , Frailty, Infections, Malignancy CAD/Stroke Cognitive Dysfunction Slide from Peter Hunt; 2014 Antifibrotic Therapy in SIV Infection Preserves CD4 T Cell Populations and Improves Immune Reconstitution Fibrosis of the paracortical T cell zone (TZ) in SIV infected rhesus macaques initiating ART Estes. JID 2014 Coagulation Pathways HIV-1 Infection Th17 depletion Immunodeficiency TLR 7,8 Activation Microbi al Viral Reactivation Translocation (eg, CMV) Innate Immune Activation (MØ/DC) ? IDO - 1 -induced ? T Cell Turnover, Inflammatory Cytokine ?Tissue Factor, Tryptophan Activation, Lymphoid Secretion Clotting Catabolism Fibrosis (eg, IL - 6, TNF -α ) T Cell Proliferative Functional T Cell Defects / CD4+ Lymphopenia Defects Cardiovascular , Renal, and Liver Disease , Thrombosis, Osteo porosis , Frailty, Infections, Malignancy CAD/Stroke Cognitive Dysfunction Slide from Peter Hunt; 2014 Aspirin fails to impact immune activation or endothelial function in treated HIV 5331 Inflammatory Pathways HIV-1 Infection Th17 depletion Immunodeficiency TLR 7,8 Activation Microbi al Viral Reactivation Translocation (eg, CMV) Innate Immune Activation (MØ/DC) ? IDO - 1 -induced ? T Cell Turnover, Inflammatory Cytokine ?Tissue Factor, Tryptophan Activation, Lymphoid Secretion Clotting Catabolism Fibrosis (eg, IL - 6, TNF -α ) T Cell Proliferative Functional T Cell Defects / CD4+ Lymphopenia Defects Cardiovascular , Renal, and Liver Disease , Thrombosis, Osteo porosis , Frailty, Infections, Malignancy CAD/Stroke Cognitive Dysfunction Slide from Peter Hunt; 2014 Saturn-HIV trial • eGFR decline and cystatin-C at 24w1 • LP-PLA22 and oxidative LDL at 24 weeks3 • Lp-PLA2, IP-10, tissue factor+ patrolling monocytes, T cell activation, but did not alter hsCRP, IL-6 or D-dimers at 48w4 • BMD at week 485 • NT-proBNP at 96 w6 • BMD and insulin resistance at 96w7 , oxLDL and • IMT at week 968 9 • lean body mass at 96w 1, Longenecker, CID 2014; 2, Ross Eckard, JID 2014; 3, Hileman, AIDS 2016, 4, Funderburg JAIDS 2015; 5, Erladson; AIDS 2015; 6, Dirajlal-Fargo, AIDS 2015; 7, McComsey CROI 2015 abstract#134; 8, McComsey CROI 2015 abstract#137; 9, Erlandson, AIDS Res Hum Retro 2015 CANTOS CANAKINUMAB ANTI-INFLAMMATORY THROMBOSIS OUTCOMES STUDY • IL-1B inhibition using canakinumab dramatically reduces inflammatory markers at 4 months. • CANTOS began enrollment in late 2011 and will include 17,200 subjects.