医学免疫学课件：HAART时代的HIV病人免疫重建

1、IMMUNE RECONSTITUTION OF HIV PATIENTS IN THE ERA OF HAARTHAARTHighly Active Antiretroviral TherapyCombination of 2 NRTIs+ NNRTIOR2 NRTIs+ Protease Inhibitor(PI)OR3 NRTIs2CONSOLIDATED GUIDELINES ON THE USE OF ANTIRETROVIRAL DRUGS FOR TREATING AND PREVENTING HIV INFECTION.WHO. JUNE 2013Outline Immunop

2、athogenesis of HIVImmune reconstitution under HAARTEffects MechanismRelated factorsComplicationAdditional therapeutic options34/hiv/data/art_2003_2015.png?ua=116 out of 37Immunopathogenesis of HIV5Peter Parham. The Immune System. 4th edition. 2015CD4+ T cellsDC cellsMacrophagesDC cellsMacrophagesImm

3、unopathogenesis of HIV6memory CD4+ CCR5+ T cellsWHY?Ca2+ inflowInterfered protein synthesisCytokine inducingTarget uninfected CD4 cellsCTL and antibody inducing78Immunopathogenesis of HIVAberrant immune activationPeter Parham. The Immune System. 4th edition. 2015Immune reconstitution9First proposed

4、in 1997CD4+ T cell numberLevel of immune activationClinical conditionImmune reconstitution10*Amelie Guihot et al. Trends in Immunology. Immune reconstitution after a decade of combined antiretroviral therapies for human immunodeficiency virus. 2011;32:131-13711*Amelie Guihot et al. Trends in Immunol

5、ogy. Immune reconstitution after a decade of combined antiretroviral therapies for human immunodeficiency virus. 2011;32:131-137IL-7-dependent T cell homeostasisAge 30immunologic non-response despite HIV virologic suppression12Age 75Up to 20%* Eleanor M.P. Wilson et al. Immunol Rev. Immune restorati

6、on after antiretroviral therapy: the pitfalls of hasty or incomplete repairs. 2013; 254:343-354Mechanisms of CD4+T cell restoration13Julie C.Gaardbo et al. Clinical and Developmental Immunology. Incomplete Immune Recovery in HIV Infection: Mechanisms, Relevance for Clinical Care, and Possible Soluti

7、ons. 2012. doi:10.1155/2012/670957Factors affecting immune reconstitution 14Marilia Rita Pinzone et al. Clinical and Developmental Immunology. HIV RNA Suppression and Immune Restoration:CanWe Do Better? 2012. doi:10.1155/2012/515962T cell proliferationAnti-apoptoticKEY ELEMENTDepletion of CD4 T cell

8、s in mucosal lymphoid tissueMicrobial translocationSystemic immune activation15Godelieve J.de Bree et al. Curr Opin Infect Dis. B cells in HIV pathogenesis. 2015;28:000-000IRIS: Immune Reconstitution Inflammatory Syndrome16*Daniel L.Barber et al. Nature Reviews, Microbiology. Immune reconstitution i

9、nflammatorysyndrome: the trouble with immunity when you had none. 2012; 10:150-156Immunological hyper-responsivenessPreventionInitiate treatment of opportunistic infection before administering ARTCurrent therapeutic option: corticosteroids17*Daniel L.Barber et al. Nature Reviews, Microbiology. Immun

10、e reconstitution inflammatorysyndrome: the trouble with immunity when you had none. 2012; 10:150-156Non-specific; severe side effectsTherapeutic options18Marilia Rita Pinzone et al. Clinical and Developmental Immunology. HIV RNA Suppression and Immune Restoration:CanWe Do Better? 2012. doi:10.1155/2

11、012/515962rIL-2Expansion of naive CD4+ compartmentQuantityQuality: CD4+ CD28+Proliferation of CD8+ T cellsInhibit HIV replication in macrophages19Marilia Rita Pinzone et al. Clinical and Developmental Immunology. HIV RNA Suppression and Immune Restoration:CanWe Do Better? 2012. doi:10.1155/2012/5159

12、62IL-7Essential regulator of T-cell homeostasisIncrease in CD4+ cell counts (central memory cells & naive cells)Lower expression of PD-120Marilia Rita Pinzone et al. Clinical and Developmental Immunology. HIV RNA Suppression and Immune Restoration:CanWe Do Better? 2012. doi:10.1155/2012/515962Gene e

13、diting CCR5- CD4 T cells21Alice K. Pau et al. Infect Dis Clin North Am. Antiretroviral therapy: Currents Drugs. 2014;28:371-402Gene editing CCR5- CD4 T cells12 patientsChronic aviremic HIV infection under HAART6 received infusion of 10 billion autologous CD4 T cells modified with ZFN22Pablo Tebas et

14、 al. NEJM. Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV. 2014;370:901-910Gene editing CCR5- CD4 T cells23Pablo Tebas et al. NEJM. Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV. 2014;370:901-910Factors inducing24ReferencesStephen A Migueles

15、 et al. Nature Immunology. Success and failure of the cellular immune response against HIV-1. 2015;16:563-570Peter Parham. The Immune System. 4th edition. 2015Godelieve J.de Bree et al. Curr Opin Infect Dis. B cells in HIV pathogenesis. 2015;28:000-000Jean-Pierre Routy et al. Expert Review of Clinic

16、al Immunology. HIV immunotherapy comes of age: implications for prevention, treatment and cure. DOI: 10.1586/1744666X.2016.1112269Pablo Tebas et al. NEJM. Gene Editing of CCR5 in Autologous CD4 T Cells of Persons Infected with HIV. 2014;370:901-910Alice K. Pau et al. Infect Dis Clin North Am. Antire

17、troviral therapy: Currents Drugs. 2014;28:371-402Eleanor M.P. Wilson et al. Immunol Rev. Immune restoration after antiretroviral therapy: the pitfalls of hasty or incomplete repairs. 2013; 254:343-354Julie C.Gaardbo et al. Clinical and Developmental Immunology. Incomplete Immune Recovery in HIV Infe

18、ction: Mechanisms, Relevance for Clinical Care, and Possible Solutions. 2012. doi:10.1155/2012/670957Marilia Rita Pinzone et al. Clinical and Developmental Immunology. HIV RNA Suppression and Immune Restoration: CanWe Do Better? 2012. doi:10.1155/2012/515962Daniel L.Barber et al. Nature Reviews, Microbiology. Immune reconstitution inflammatory syndrome: the trouble with immunity when you had none. 2012; 10:150-156Amelie Guihot et al. Trends in