Immunopathogenesis of AIDS, an historical perspective:

Or

30 years in 15 minutes

Michael M. Lederman, MD

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

Barre-Sinoussi et al,Science 1983

Popovic et al Science,1984Levy et al Science, 1984

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

Peripheraltissues

Homeostaticproliferation

Tenner Racz ‘93Cheynier ’94Pantaleo ‘94Altfeld ‘02Brenchley ‘04Biancotto ‘07

See Wednesday LB: JC Mudd

Increased fibrosis in the HIV+lymph node

Estes, Schacker and Haase

Predicts failure of CD4 T cell restoration on HAARTSchacker AIDS ‘05

Impairs intercellular communicationZeng et al, JCI ‘11

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

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

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

High turnover of both CD4 and CD8 T cells in HIV infection is attenuated by

antiviral therapy

Kovacs et al J Exp Med ‘01

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)

HIV infection rapidly depletes gut effector memory CD4 T cells

Brenchley et al JEM 2004

HIV- HIV+

Veazey ’98; Guadalupe ’03; Mehandru ‘04Matapallil ‘05

Plasma LPS levels are increased in chronic HIV infection

Brenchley et al, Nat Med 06

Levels of microbial products correlate inversely with magnitude of CD4 T cell

restoration on HAART

0 20 40 60 80 100 120 140 1600

100

200

300

400

500

600

700

800

R² = 0.251623364284143

Plasma 16s DNA levels copies/ul

CD

4 T

ce

ll in

cre

ase

at

48

wee

ks

Jiang et al J Inf Dis ‘09 Brenchley et al Nat Med ‘06

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)

Naive

CM

CM

Naive

Naive

Naive

CM

CMAPC

CM

CM

CM

APC

APC

A model of immune activation and pathogenesis in the HIV+ lymph node

E

E

E

E

E

ME

E

EE

100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 1500 1600 1700 1800

CD4

0%

5%

10%

15%

Per

cen

tEven after > 5 yrs of HAART and current VL BLD, ~20%

of adult pts have CD4 T cell counts below the defined normal range

>5 yearsValid N 340Median 609Percentile 25 412Percentile 75 802Percentile 2.5 122.525Percentile 97.5 1417.88Minimum 48Maximum 1822

2, 740Normal (95%) range

Rodriguez, Myerson

350

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

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___

Increased inflammation, coagulation and evidence of monocyte activation in immune failure despite virologic

control

____p < 0.09_____

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?

Immune Failure despite virologic controlWhat 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?

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

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 PaiardiniDrexel Jeffrey JacobsonU. Minnesota Tim Schacker

UCSF: Steven Deeks Peter Hunt Hiroyu HatanoU. Penn Mike BettsU. Paris Yves Levy