1. Immunopathogenesis of AIDS, an historical perspective: Or 30 years in 15 minutes Michael M. Lederman, MD

2. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency MS Gottlieb, R Schroff, HM Schanker, JD Weisman, PT Fan, RA Wolf, and A Saxon An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction H Masur, MA Michelis, JB Greene, I Onorato, RA Stouwe, RS Holzman, G Wormser, L Brettman, M Lange, HW Murray, and S Cunningham-Rundles Dec 10, 1981

3. Barre-Sinoussi et al, Science 1983 Popovic et al Science,1984 Levy et al Science, 1984

5. antigen Central memory cells Effector cells Naïve T cells antigen Lymph Node The lymph node in HIV infection is inflammatory and enriched with effector T cells Peripheral tissues Homeostatic proliferation Tenner Racz ‘93 Cheynier ’94 Pantaleo ‘94 Altfeld ‘02 Brenchley ‘04 Biancotto ‘07 See Wednesday LB: JC Mudd

6. Increased fibrosis in the HIV+lymph node Estes, Schacker and Haase Predicts failure of CD4 T cell restoration on HAART Schacker AIDS ‘05 Impairs intercellular communication Zeng et al, JCI ‘11

7. antigen Central memory cell Effector cell Naïve T cells Homeostatic proliferation (IL-7 dependent) Thymus antigen Lymph Node CD4 T cell homeostasis is broadly impaired in HIV infection Bone Marrow Periphery

8. Pneumocystis carinii pneumonia and mucosal candidiasis in previously healthy homosexual men: evidence of a new acquired cellular immunodeficiency MS Gottlieb, R Schroff, HM Schanker, JD Weisman, PT Fan, RA Wolf, and A Saxon An outbreak of community-acquired Pneumocystis carinii pneumonia: initial manifestation of cellular immune dysfunction H Masur, MA Michelis, JB Greene, I Onorato, RA Stouwe, RS Holzman, G Wormser, L Brettman, M Lange, HW Murray, and S Cunningham-Rundles Dec 10, 1981 T10 = CD38

9. Immune activation predicts HIV disease progression Immune activation predicts HIV disease progression – CD38 – a better predictor of disease progression than VL. (Liu JAIDS ’98, Giorgi JID ’99, Deeks ’04, Wilson ‘04) Janice Giorgi

10. High turnover of both CD4 and CD8 T cells in HIV infection is attenuated by antiviral therapy Kovacs et al J Exp Med ‘01

11. So if immune activation drives HIV pathogenesis (CD4 depletion),what drives immune activation? A homeostatic response to cytopenia? (Srinivasula et al ‘11) HIV itself? –Via antigen specific T cell activation and expansion? –Via products such as envelope that bind and activate cellular coreceptors? (Herbeuval et al ‘05) –Via viral elements that activate innate immune receptors? (Heil et al ‘04, Fontaneau et al ’04, Meier et al ‘07) An immune deficient environment that permits replication of other microbes (eg CMV, other herpesviruses, HCV) (Lisco et al ‘09, Hunt et al ’11)

12. HIV infection rapidly depletes gut effector memory CD4 T cells Brenchley et al JEM 2004 HIV-HIV+ Veazey ’98; Guadalupe ’03; Mehandru ‘04 Matapallil ‘05

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

14. Levels of microbial products correlate inversely with magnitude of CD4 T cell restoration on HAART Plasma 16s DNA levels copies/ul CD4 T cell increase at 48 weeks Jiang et al J Inf Dis ‘09 Brenchley et al Nat Med ‘06

15. HIV disease is characterized by heightened inflammation and coagulation The environment in both blood and lymph nodes is inflammatory (Pantaleo ‘94, Andersson ‘00, Biancotto ‘07, Kalayjian ‘10) Indices of inflammation (IL-6, CRP) and coagulation (d- dimers) predict all cause mortality (Kuller ‘08) Activated CD4 T cells show signatures of high level type 1 interferon exposure (Sedhagat ‘08) And Immune Cells show signs of exhaustion and senescence Increased expression of CD57, PD-1, shortened telomeres (Vanham ‘90; Effros ’96; Trautmann ‘06, Day ‘06; Petrovas ‘06)

16. Naive CM Naive CM APC CM APC A model of immune activation and pathogenesis in the HIV+ lymph node E E E E E M E E E E

17. Even after > 5 yrs of HAART and current VL BLD, ~20% of adult pts have CD4 T cell counts below the defined normal range >5 years Valid N340 Median609 Percentile 25412 Percentile 75802 Percentile 2.5122.525 Percentile 97.51417.88 Minimum48 Maximum1822 2, 740 Normal (95%) range Rodriguez, Myerson 350

18. Despite “complete” virologic control on ARVs, immune failure patients have increased T cell activation –Teixiera AIDS ’01: age and low thymic output –Anthony JAIDS ’03: immune activation and turnover –Benveniste JID ‘05: Low thymic output –Fernandez Clin Imm ‘06: immune activation and senescence –Gandhi JAIDS ‘06: women restore better –Hunt JID ‘08 Immune activation and microbial translocation –Marchetti AIDS ‘08: immune activation and microbial translocation –Rajasuriar JID ‘10: Linkage to IL-7Ra haplotype –Sandler et al JID (in press) immune activation and microbia –Gazzola CID ‘09: Excellent review of immune failure Fernandez ’06; Hunt ‘08; Marchetti ‘08; Sandler ’11; Lederman ‘11

19. Though both CD4 and CD8 T cells are activated in Immune Failure, cell cycling is increased only among CD4 T cells _____P<0.001_____________ __P<0.001___

20. Increased inflammation, coagulation and evidence of monocyte activation in immune failure despite virologic control ____p < 0.09_____

21. What we know HIV is the cause of AIDS HIV linked to immune activation; plausible drivers of activation identified Immune activation is linked to disease course Inflammatory cytokine levels are increased What we don’t know Exactly how HIV causes AIDS Which “drivers” are most important in which setting Causality likely; proof lacking Which cytokines mediate pathogenesis; which are just markers of infection? Will blocking these pathways block activation? Will blocking these pathways alter disease course? To what degree and at what point are these pathways reversible?

22. Immune Failure despite virologic control What we know Increased T cell activation; increased CD4 T cell cycling Increased coagulation and inflammation What we don’t know How much T cell activation is “push” and how much is “pull”? –And among plausible “pushers” which pathways are most important? What is the link between T cell activation and inflammation/coagulation The degree to which “drivers” and mediators of morbidity in immune failure are linked to the drivers of pathogenesis in untreated HIV infection?

23. A Way Forward Interventional Trials targeting key pathways of “activation” can concurrently test hypotheses of pathogenesis and also explore promising treatment strategies for persons at risk for morbidity

24. Thanks to: CWRU: Scott Sieg Benigno Rodriguez JC Mudd Nick Funderburg Brian Clagett Len Calabrese Carey Shive Wei Jiang VGTI: Rafick Sekaly Elias Haddad Nicolas Chomont Lydie Trautmann Rush: Alan Landay NIH Jason Brenchley Danny Douek Netanya Sandler Mary Carrington Leonid Margolis Irini Sereti Jake Estes Emory Guido Silvestri Mirko Paiardini Drexel Jeffrey Jacobson U. Minnesota Tim Schacker UCSF: Steven Deeks Peter Hunt Hiroyu Hatano U. Penn Mike Betts U. Paris Yves Levy