1 / 29

Objectives

Objectives. To review current concepts on the mechanisms and pathogenic consequences of uncontrolled inflammation and immune activation in HIV-related immune deficiencyTo describe the role of bystander and microbial-driven immune activation in the natural history of progressive HIV infectionTo survey current knowledge of the physiological and clinical implication of incomplete immune reconstitution in effectively treated HIV infection .

lotus
Download Presentation

Objectives

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

    1. HIV Pathogenesis: Activation and Inflammation Benigno Rodriguez, MD Assistant Professor of Medicine Clinical Director Center for AIDS Research Case Western Reserve University Cleveland, Ohio

    2. Objectives To review current concepts on the mechanisms and pathogenic consequences of uncontrolled inflammation and immune activation in HIV-related immune deficiency To describe the role of bystander and microbial-driven immune activation in the natural history of progressive HIV infection To survey current knowledge of the physiological and clinical implication of incomplete immune reconstitution in effectively treated HIV infection 2

    3. Reduced life expectancy despite improved survival in the HAART era Adapted from Lohse N, et al. Ann Intern Med 2007;146:87–95

    4. D:A:D: Persistent Immunosuppression Increases Mortality Cohort study of > 23,000 cohort (Europe, Australia, US) 76,577 patient-years of follow-up 1,248 (5.3%) deaths from 2000-2004 Both HIV- and non-HIV–related mortality associated with CD4+ cell count depletion Weber R, et al.12th CROI; 2005. Abstract 595

    5. Immune Failure in the Special Immunology Unit

    6. HIV replication is necessary to drive the immune deficiency (CD4 depletion) of AIDS Is it sufficient? If not, what other factors are involved? Can understanding these factors help us manage patients who fail to restore immune competence despite suppressive antiviral therapy? Rodríguez et al, JAMA 2006

    7. T cell homeostasis

    8. Living with Lentiviruses: non-human primate natural hosts of SIV infection don’t seem to mind it - why? Asian rhesus macaque High level viremia Circulating CD4 depletion OI risk and death High level immune activation African sooty mangabey High level viremia CD4 depletion extremely rare No OIs Low level immune activation

    9. The fate of circulating S-phase T cells in HIV infection Sieg et al J Leuk Biol ‘08

    10. Interval Summary Progressive HIV (and SIV) infection is characterized by enhanced immune activation Biological consequences include abnormal sequestration of cells in the secondary lymphoid tissues, failed entry into cell cycle, accelerated cell death, and functional immune impairment Clinical consequences include ongoing morbidity and mortality and subclinical immune deficiency What are the potential drivers of immune activation in HIV infection?

    11. Plasma LPS levels are increased in chronic HIV infection Brenchley et al, Nat Med 06

    12. Levels of circulating microbial products correlate with indices of immune activation Brenchley et al Nat Med ‘06 Jiang et al J Infect Dis '09

    13. Levels of microbial products correlate inversely with magnitude of CD4 T cell restoration on HAART

    14. Microbial products increase in pathogenic but not in non-pathogenic SIV infection

    15. Microbial Products activate CD4+ T cells to enter cell cycle and CD8+ T cells to express CD69 Funderburg et al PLOS One ‘08

    16. Inflammatory and Coagulation Markers predict morbidity in SMART Interleukin-6 D-dimers C Reactive Protein Kuller et al PLOS Med ‘08

    17. Microbial Products induce expression of Interleukin-6 in vitro

    18. The procoagulant Tissue Factor is Increased in HIV infection Funderburg et al Blood ‘10

    19. Microbial Products drive coagulation via induction of Tissue Factor Funderburg et al Blood ‘10

    20. Interval Summary Microbial products are one of the potential drivers of immune activation in HIV infection Elevated with progression of HIV disease Induce multiple markers of immune activation and arrested CD4 T cell turnover Provide a pathway to explain the procoagulant state commonly seen in progressive HV infection 20

    21. Immune Activation/Failure: The CLIF Study A detailed cross sectional study of immune failure in “successfully” treated HIV infection. Immune Failure: On combination antiretrovirals for at least 2 yrs VL below limits of detection for at least 2 years Most recent CD4 T cells <350/uL Immune Success: As above but with CD4 T cells >500/uL Univariate predictors of immune failure: Older age Female sex; non-caucasian race Lower nadir CD4 count 21

    22. All CD4 cell maturation subsets are decreased in Immune Failure

    23. Both CD4 and CD8 T Cells Are Activated in Immune Failure

    24. Though both CD4 and CD8 cells are activated, cycling is increased only among CD4 T cells

    25. Increased Inflammation, Coagulation and Microbial Translocation in Immune Failure

    26. Interval Summary In immune failure patients, CD4 and CD8 cells are persistently activated All maturation subsets of CD4+ T cells are activated But only CD4 cells are cycling, particularly memory CD4+ T cells CD4+ T cells display a senescent phenotype in immune failure Immune failure is related to increased markers of inflammation, coagulation, and microbial translocation Most importantly, this phenotype is remarkably similar to the in vitro effect of microbial products 26

    27. Potential strategies to manage immunologic failure (1) Prevent advanced immune deficiency Broader HIV screening It’s easier to start lifelong medications when they are better tolerated Starting earlier… and earlier… Review therapeutic regimen Consider revising meds accused of bone marrow toxicity (clue: decreases in other blood elements) ARVs: Tenofovir/Didanosine linked to immune failure PIs and better CD4 increases - unproven role in this setting. CCR5 inhibitors and better CD4 increases?– effect in this setting controversial. No CD4 rise, but activation reported to decrease (Wilkin) or decrease (Hunt)

    28. Potential strategies to manage immunologic failure (2) Enhance CD4 T cell numbers No clinical benefit of IL-2 administration After IL-7 administration: The CD4 T cells look “good” Clinical benefit unproven ARV intensification? Nonsignificant CD4 T cell increases after raltegravir intensification and slight decrease in immune activation – Buzon Nat Med’10 No decrease in immune activation after raltegravir intensification in immune failure – Gandhi PLOS Med ‘10, Hatano J Inf Dis ’11 By blocking microbial translocation or its downstream effects? Oral Sevalemer – binds LPS Chloroquine blocks immune activation in untreated HIV infection – Murray J Virol ’10 ACTG 5258 results pending

    29. Summary Immune activation/inflammation/coagulation -characteristic of HIV infection and likely play key roles in pathogenesis of disease and immune failure Drivers are complex and likely include HIV, other viruses, eg CMV, microbial translocation and homeostatic responses Interventional studies needed to explore treatment strategies and models of pathogenesis

    30. Thanks to: CWRU: Michael M. Lederman Scott Sieg Nick Funderburg Enrique Espinosa Wei Jiang Kathy Medvik Joseph C. Mudd UCSF: Steven Deeks Peter Hunt Hiroyu Hatano

More Related