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 /
Defects CD4+ Lymphopenia 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 /
Defects CD4+ Lymphopenia 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 /
Defects CD4+ Lymphopenia 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 /
Defects CD4+ Lymphopenia 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 /
Defects CD4+ Lymphopenia 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 /
Defects CD4+ Lymphopenia 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 /
Defects CD4+ Lymphopenia 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 • lean body mass at 96w9
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.
Ridker, Circulation 2012 IL-1β inhibition in HIV
• Study drug and placebo provided by Novartis • Pilot Study: N=10 individuals treated all with 150mg canakinumab once, with followup for 12 weeks • NHLBI funded: Hsue, Deeks, Ridker, Tawakol • Started in November 2015. • Main study: N=100 individuals randomized 2:1 treated with 150mg canakinumab at baseline and at 12 weeks, followed for 36 weeks
Slide from Priscilla Hsue, 2015 CIRT Cardiovascular Inflammation Reduction Trial
• N=7000 • F/U: 5 years Effects of Low Dose Methotrexate on Inflammation and Endothelial Function in Treated HIV
5314
• Randomized double blinded placebo controlled study in treated and suppressed HIV-infected individuals with CVD or 1 CV risk factor (N=200). • Occurring simultaneously as the trial in uninfected subjects with CVD • Primary endpoints are safety, impact on inflammatory markers/immune activation, and endothelial function • 75% enrolled at this time
Targeting the JAK-STAT Pathway with Ruxolitinib to Reduce Inflammation
5336
• Randomized pilot study in treated and suppressed HIV- infected individuals with CD4 >350/uL. • Participants will be randomly assigned (by chance) to eiher receive 5 weeks of treatment with ruxolitinib (taken by mouth twice a day) or no study treatment.
Buckland. Nat Rev Rheum 2009 Inhibition of the mTOR Pathway with Sirolimus for HIV Reservoir/Inflammation Reduction in Traeted HIV
mTOR Pathway 5337
• Randomized pilot study in treated and suppressed HIV-infected individuals with CD4 >400/uL. • Participants will receive sirolimus by mouth for 20 weeks. • Participants will be followed for 44 weeks, including a 12 week lead-in period before sirolimus initiation. Zoncu. Nature Rev Mole Cel Biol 2011
Sitagliptin for Reducing Inflammation and Immune Activation
Nutrient Sensing System and Aging 5346 • A Randomized, Blinded Placebo- Controlled Trial of a Dipeptidyl Peptidase-4 Inhibitor (Sitagliptin, Januvia) for Reducing Inflammation and Immune Activation in HIV Infected Men and Women • Treated and suppressed HIV-infected, non-diabetic individuals with CD4 >100/uL. • Participants will receive the intervention for 16 weeks, including a 12 week lead-in period before sirolimus initiation. Otin. Cell 2013
“The clinical consequences of manipulation of IFN signaling are difficult to predict in vivo and therapeutic interventions in human studies should be approached with caution”.
? Will Any Intervention Succeed? The Hallmarks of Aging
Adapted from Otin, Cell 2013 CONCLUSIONES
1. Algunas de las estrategias de inmunomodulación estudiadas ha demostrado mejoría de parámetros inmunológicos. 2. Ninguna de las estrategias empleadas de inmunomodulación ha demostrado mejoría de desenlaces clínicos. 3. Es posible que el origen multifactorial de la inflamación dificulte encontrar intervenciones que permitan restaurar totalmente el sistema inmune. 4. Existent otros mecanismos que conducen a envejecer más rápido además de la inflamación. 5. Nuestras principales herramientas siguen siendo el inicio de TAR precoz, el control de los factores de riesgo y la promoción de estilos de vida saludables. Fauja Singh, here aged 100, prepares • DOB: April 1, 1911. for Britain’s Edinburgh marathon in • Now aged 105. 2011 • UK records for the 200 m, 400 m, 800 m, mile and 3000 m for his age group, records all set within a single 94 minute period. • Marathon 90+: 5h 40’ (aged 92) • Marathon 100+: 8h 11’ • Height 172cm, weight 52kg • No smoke, no alcohol, vegetarian diet. • “I am very careful with different foods: phulka, dal, green vegetables, yogurt and milk, lots of water and tea with ginger”. • “I go to bed early”.